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1. Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases

Author

Hannah M. Martin, Yi Liu, Tom R. Gaunt, Michael V. Holmes, Matthew R. Nelson, Jie Zheng, Benjamin B. Sun, Stephen Burgess, George Davey Smith, Jamie Robinson, John Danesh, James R Staley, Shan Luo, Robert A. Scott, Pau Erola, Karol Estrada, Dawn M. Waterworth, Gibran Hemani, Benjamin Elsworth, Alex Gutteridge, Valeriia Haberland, Charles Laurin, Heiko Runz, Denis Baird, Venexia M Walker, Tom G. Richardson, Mark R. Hurle, Jimmy Z. Liu, Joseph C. Maranville, Adam S. Butterworth, Philip C Haycock, James Yarmolinsky, Rita Santos, Linda McCarthy, Zheng, Jie [0000-0002-6623-6839], Haberland, Valeriia [0000-0002-3874-0683], Robinson, Jamie [0000-0001-8721-6514], Richardson, Tom G [0000-0002-7918-2040], Elsworth, Benjamin [0000-0001-7328-4233], Sun, Benjamin B [0000-0001-6347-2281], Smith, George Davey [0000-0002-1407-8314], Butterworth, Adam S [0000-0002-6915-9015], Hemani, Gibran [0000-0003-0920-1055], Scott, Robert A [0000-0003-3634-3016], Gaunt, Tom R [0000-0003-0924-3247], and Apollo - University of Cambridge Repository

Subjects
Proteomics, Linkage disequilibrium, Proteome, Genome-wide association study, Computational biology, 030204 cardiovascular system & hematology, Phenome, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Mendelian randomization, Human proteome project, Genetics, Humans, Genetic Predisposition to Disease, health care economics and organizations, Genetic association, 030304 developmental biology, 0303 health sciences, Drug discovery, High-throughput screening, Colocalization, Mendelian Randomization Analysis, Blood Proteins, Phenotype, 3. Good health, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

The human proteome is a major source of therapeutic targets. Recent genetic association analyses of the plasma proteome enable systematic evaluation of the causal consequences of variation in plasma protein levels. Here, we estimated the effects of 1002 proteins on 225 phenotypes using two-sample Mendelian randomization (MR) and colocalization. Of 413 associations supported by evidence from MR, 130 (31.5%) were not supported by results of colocalization analyses, suggesting that genetic confounding due to linkage disequilibrium (LD) is widespread in naive phenome-wide association studies of proteins. Combining MR and colocalization evidence in cis-only analyses, we identified 111 putatively causal effects between 65 proteins and 52 disease-related phenotypes (www.epigraphdb.org/pqtl/). Evaluation of data from historic drug development programmes showed that target-indication pairs with MR and colocalization support were more likely to be approved, evidencing the value of our approach in identifying and prioritising potential therapeutic targets.

Published
2020

2. Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality

Author

A. Mark Richards, W.H. Wilson Tang, Julie A. Johnson, Stanley L. Hazen, Danilo Fliser, Heribert Schunkert, Yan Gong, Andreas Martinsson, Peter Lipp, Yi-An Ko, Stephen Zewinger, Andrej Teren, Marcus E. Kleber, Ian Ford, Sarah Triem, David J. Stott, Matthias C. Reichert, Hannah Campbell, Dawn M. Waterworth, Ulrich Laufs, Caitrin W. McDonough, Stefan Wagenpfeil, Marcin Krawczyk, Michael Böhm, J. Wouter Jukema, Naveed Sattar, Shichao Pang, Markus Scholz, Rafael Kramann, Stella Trompet, Philipp Ege, Niclas Eriksson, David Schmit, Christie M. Ballantyne, Claes Held, Marie-Pierre Dubé, Winfried März, Thimoteus Speer, Jörn Walter, Stefan James, Maxine Sun, Hooman Allayee, Lars Wallentin, Harvey D. White, Vicky A. Cameron, Stefan J Schunk, Sharon Cresci, Barbara A. Niemeyer, Susanne N. Weber, Anna P. Pilbrow, Emmanuel Ampofo, J. Gustav Smith, Sascha Tierling, Jean-Claude Tardif, Robert N. Doughty, Rhonda M. Cooper-DeHoff, Arshed A. Quyyumi, Ralph Burkhardt, John A. Spertus, Chang Liu, Eric Boerwinkle, Wolfgang Koenig, Tamim Sarakpi, Yassamin Feroz-Zada, Jaana Hartiala, Isabella Jaumann, Vinicius Tragante, and Megan L. Grove

Subjects
Inflammasomes, Inflammation, 030204 cardiovascular system & hematology, Systemic inflammation, Coronary artery disease, Inflammasome, 03 medical and health sciences, 0302 clinical medicine, NLRP3, NLR Family, Pyrin Domain-Containing 3 Protein, medicine, Humans, Cardiac and Cardiovascular Systems, Serum amyloid A, Allele, 030304 developmental biology, 0303 health sciences, Kardiologi, biology, integumentary system, business.industry, C-reactive protein, R1, 3. Good health, Minor allele frequency, Cardiovascular diseases, Immunology, biology.protein, Leukocytes, Mononuclear, Apolipoprotein C3, medicine.symptom, Cardiology and Cardiovascular Medicine, business, medicine.drug
Abstract

Aims Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1β can therapeutically be targeted. Associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown. Methods and results We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on the individual participant level in an explorative gene-centric approach without performing multiple testing. Functional relevance of single-nucleotide polymorphisms on NLRP3 inflammasome activation has been evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent (minor allele frequency 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Carriers of the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g. urate, triglycerides, apolipoprotein C3) modulated the association between rs10754555 and mortality. Conclusion The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provides evidence for a substantial role of genetically driven systemic inflammation in CVD and highlights the NLRP3 inflammasome as a therapeutic target.

Published
2021

3. Genome-wide association study identifies 48 common genetic variants associated with handedness

Author

Inês Barroso, Gail Davies, H.-Erich Wichmann, Bjarke Feenstra, Peter Vollenweider, Nicholas J. Timpson, Alan F. Wright, Frank Geller, Gérard Waeber, John M. Starr, Benjamin M. Neale, George Davey Smith, Tõnu Esko, Ruth J. F. Loos, Andrew A. Hicks, Pedro Marques-Vidal, Dorret I. Boomsma, Harry Campbell, Zoltán Kutalik, David M. Evans, Scott D. Gordon, Eva Albrecht, Peter P. Pramstaller, Leena Peltonen, Jing Hua Zhao, Lavinia Paternoster, Thomas Hansen, Massimo Mangino, Fazil Aliev, Beate St Pourcain, Panos Deloukas, Heather A. Boyd, Guillaume Paré, Marco P. Boks, Monique M.B. Breteler, Jouke-Jan Hottenga, Xin Li, Kari Stefansson, Ian J. Deary, Jari Lahti, Inga Prokopenko, Nicholas Eriksson, Lili Milani, Nicholas J. Wareham, Jordan W. Smoller, Norman Klopp, Lynn Cherkas, Reedik Mägi, Margaret J. Wright, Peter Kraft, Jacques S. Beckmann, Brenda W.J.H. Penninx, Gabriel Cuellar-Partida, André G. Uitterlinden, Fernando Rivadeneira, Wendy L. McArdle, Johan G. Eriksson, Jiali Han, Jennifer E. Huffman, Andres Metspalu, J.M. Vink, Frank J. A. van Rooij, Christian Gieger, M. Arfan Ikram, Cecilia M. Lindgren, Aarno Palotie, Daniel I. Chasman, Joyce Y. Tung, Liang-Dar Hwang, David A. Hinds, Elisabeth Widen, Caroline Hayward, Michelle Luciano, Johannes H. Smit, Gonneke Willemsen, Dale R. Nyholt, Carolina Medina-Gomez, Nicole M. Warrington, Teemu Palviainen, Stacy Steinberg, Kay-Tee Khaw, Kevin S. O’Connell, Bettina Konte, Gudmar Thorleifsson, Eco J. C. de Geus, John P. Kemp, Mads Melbye, Mark I. McCarthy, Sarah E. Medland, Jaakko Kaprio, Cameron D. Palmer, Joel N. Hirschhorn, Ina Giegling, Scott Melville, Thomas Werge, Nicole Soranzo, Sigurdur H. Magnusson, Maris Teder-Laving, Hreinn Stefansson, Kauko Heikkilä, Cornelia M. van Duijn, David L. Duffy, Samuli Ripatti, Igor Rudan, Annette M. Hartmann, Ole A. Andreassen, Mari Nelis, Ozren Polasek, Vincent Mooser, Mousheng Xu, Eero Vuoksimaa, Katri Räikkönen, Nicholas G. Martin, Dan Rujescu, Tim D. Spector, Dawn M. Waterworth, Danielle M. Dick, Roel A. Ophoff, Epidemiology, Internal Medicine, Psychiatry, Biological Psychology, APH - Mental Health, APH - Methodology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Epidemiology and Data Science, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Pediatric surgery, and APH - Digital Health

Subjects
Male, Netherlands Twin Register (NTR), Linkage disequilibrium, Genome-wide association study, LANGUAGE DOMINANCE, Functional Laterality, Linkage Disequilibrium, Behavioral Neuroscience, 0302 clinical medicine, ddc:150, Gene Frequency, SCHIZOPHRENIA, Genetics, 0303 health sciences, Middle Aged, genetics [Genetic Variation], genetics [Functional Laterality], Schizophrenia, ASYMMETRY, genetics [Polymorphism, Single Nucleotide], Female, Adult, Social Psychology, LATERALIZATION, Experimental and Cognitive Psychology, genetics [Genetic Loci], Biology, Quantitative trait locus, Genetic correlation, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, LINKAGE ANALYSIS, METAANALYSIS, MICROTUBULE, AUTISM, ORIGINS, SCREEN, Quantitative Trait, Heritable, Sex Factors, Genetic linkage, medicine, Humans, Bipolar disorder, 030304 developmental biology, Genetic association study, Aged, Genetic Variation, medicine.disease, Genetic Loci, Autism, genetics [Gene Frequency], Developmental Psychopathology, 030217 neurology & neurosurgery, Neuroscience, Genome-Wide Association Study
Abstract

Handedness, a consistent asymmetry in skill or use of the hands, has been studied extensively because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and 32 studies from the International Handedness Consortium, we conducted the world’s largest genome-wide association study of handedness (1,534,836 right-handed, 194,198 (11.0%) left-handed and 37,637 (2.1%) ambidextrous individuals). We found 41 genetic loci associated with left-handedness and seven associated with ambidexterity at genome-wide levels of significance (P < 5×10−8). Tissue enrichment analysis implicated the central nervous system and brain tissues including the hippocampus and cerebrum in the etiology of left-handedness. Pathways including regulation of microtubules, neurogenesis, axonogenesis and hippocampus morphology were also highlighted. We found suggestive positive genetic correlations between being left-handed and some neuropsychiatric traits including schizophrenia and bipolar disorder. SNP heritability analyses indicated that additive genetic effects of genotyped variants explained 5.9% (95% CI = 5.8% – 6.0%) of the underlying liability of being left-handed, while the narrow sense heritability was estimated at 12% (95% CI = 7.2% – 17.7%). Further, we show that genetic correlation between left-handedness and ambidexterity is low (rg = 0.26; 95% CI = 0.08 – 0.43) implying that these traits are largely influenced by different genetic mechanisms. In conclusion, our findings suggest that handedness, like many other complex traits is highly polygenic, and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders that has been observed in multiple observational studies.

Published
2021

4. Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline

Author

Lukas Habegger, Charumathi Sabanayagam, Michael Preuss, Laura M. Raffield, Mary F. Feitosa, Bamidele O. Tayo, Kevin Ho, Leo-Pekka Lyytikäinen, Florian Kronenberg, Valencia Hui Xian Foo, Adrienne Tin, Michael Cantor, Nisha Bansal, Tarunveer S. Ahluwalia, Melanie Waldenberger, Sarah A. Pendergrass, Behrooz Z. Alizadeh, Wolfgang Koenig, Qiong Yang, Xiaodong Bai, Christoph Wanner, Ben Schöttker, Giovanni Coppola, A. R. Shuldiner, Leslie A. Lange, Piyush Gampawar, Markus Scholz, Tien Yin Wong, Mary L. Biggs, Morris Swertz, Alicia Hawes, Girish N. Nadkarni, Christina-Alexandra Schulz, Chiea Chuen Khor, Ricardo H. Ulloa, Jeffrey C. Staples, Miao-Li Chee, Laura M. Yerges-Armstrong, Andrew Blumenfeld, Karlhans Endlich, Bernhard Banas, Bruce H.R. Wolffenbuttel, Kai-Uwe Eckardt, Pavel Hamet, Carsten A. Böger, Harold Snieder, Marcus B. Jones, Judy Wang, Shih-Jen Hwang, Mathias Gorski, Anselm Hoppmann, Josyf C. Mychaleckyj, Bernd Holleczek, Pamela R. Matias-Garcia, Rainer Rettig, Karsten B. Sieber, Manasi Pradhan, Pashupati P. Mishra, Peter Rossing, Matthias Wuttke, Miao-Ling Chee, H. Marike Boezen, Yong Li, M. Arfan Ikram, Jeffrey G. Reid, Teresa Nutile, Maria Sotiropoulos Padilla, Lude Franke, Robert J. Carroll, Luca A. Lotta, Bernhard K. Krämer, Kjell Nikus, Jerome I. Rotter, Thomas Meitinger, Lars Wallentin, Cisca Wijmenga, Kent D. Taylor, Holly Kramer, Louis Widom, Olli T. Raitakari, Marcus E. Kleber, Man Li, Nina Hutri-Kähönen, Massimiliano Cocca, Reinhold Schmidt, John D. Overton, Cristian Pattaro, Michael Lattari, Sarah E. Wolf, Jin-Fang Chai, Karina Toledo, Brigitte Kühnel, Zhenhua Gu, Peter Almgren, Caitlin Forsythe, Yuri Milaneschi, Stephan J. L. Bakker, Layal Chaker, Dawn M. Waterworth, Silke Szymczak, James G. Wilson, Peter J. van der Most, Michelle L. O'Donoghue, William Salerno, Masayuki Yasuda, Sahar Ghasemi, Eric Boerwinkle, Josef Coresh, Ilja M. Nolte, Kia Manoochehri, Konstantin Strauch, Thomas D. Schleicher, Myriam Rheinberger, Audrey Y. Chu, Sanaz Sedaghat, Sandra Freitag-Wolf, Boting Ning, Matthias Nauck, Christina Beechert, Helena Schmidt, Harvey D. White, Nina Mononen, Johanne Tremblay, Navya Shilpa Josyula, Mika Kähönen, Katrin Horn, Andre Franke, Marianne Rots, Bettina Jung, Alexander R. Rosenkranz, Christian M. Shaffer, Mary Ann Lukas, Gerjan Navis, Christian Gieger, John Chalmers, Shareef Khalid, Uwe Völker, Marju Orho-Melander, Iris M. Heid, Brenda W.J.H. Penninx, A. Baras, Alexander Lopez, Evan Maxwell, Ruth J. F. Loos, Erin D. Fuller, Christa Meisinger, Gonçalo R. Abecasis, Suganthi Balasubramanian, Chris H. L. Thio, Martin H. de Borst, Stefan Coassin, Ching-Yu Cheng, Wolfgang Lieb, Kenneth Rice, Alexander Teumer, Mark Woodward, Gisu Eom, Hermann Brenner, Thomas W. Winkler, Anna Köttgen, Edith Hofer, Aris Economides, Ron T. Gansevoort, Pim van der Harst, Lyndon J. Mitnaul, Bruce M. Psaty, Erwin P. Bottinger, Olle Melander, Niek Verweij, Frauke Degenhardt, Yan Zhang, Mohsen Ghanbari, Veronika Wanner, Terho Lehtimäki, Leland Barnard, Tampere University, Primary Health Care, Department of Paediatrics, Clinical Medicine, Department of Clinical Physiology and Nuclear Medicine, Department of Clinical Chemistry, TAYS Heart Centre, Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Department of Marketing Management, Epidemiology, Internal Medicine, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, and APH - Digital Health

Subjects
0301 basic medicine, medicine.medical_specialty, Genome-wide association study, 030232 urology & nephrology, Protein Disulfide-Isomerases, Hasso-Plattner-Institut für Digital Engineering GmbH, Renal function, Locus (genetics), Biology, AMP-Activated Protein Kinases, Kidney, 3121 Internal medicine, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, end-stage kidney disease, rapid eGFRcrea decline, Urologi och njurmedicin, medicine, Humans, Urology and Nephrology, ddc:610, Allele, Genetic association, Genetics, Creatinine, genome-wide association study, Acute kidney injury, acute kidney injury, medicine.disease, United Kingdom, ddc, 030104 developmental biology, chemistry, Nephrology, Medical genetics, 3111 Biomedicine, 610 Medizin und Gesundheit, Glomerular Filtration Rate
Abstract

Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m(2)/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m(2) at follow-up among those with eGFRcrea 60 mL/min/1.73m(2) or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or (LARP4B). Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function., Zweitveröffentlichungen der Universität Potsdam : Reihe der Digital Engineering Fakultät; 19

Published
2021

5. Genome-wide association study identifies 48 common genetic variants associated with handedness

Author

Christian Gieger, Teemu Palviainen, Bettina Konte, Peter P. Pramstaller, Aarno Palotie, Elisabeth Widen, Monique M.B. Breteler, Caroline Hayward, Xin Li, Tim D. Spector, Jing Hua Zhao, John M. Starr, David M. Evans, Nicholas G. Martin, Wendy L. McArdle, Nicole Soranzo, Mads Melbye, Peter Kraft, André G. Uitterlinden, Beate St Pourcain, Massimo Mangino, Daniel I. Chasman, Jacques S. Beckmann, Gabriel Cuellar Partida, George Davey Smith, Cecilia M. Lindgren, Johan G. Eriksson, Alan F. Wright, Kauko Heikkilä, Eva Albrecht, Gudmar Thorleifsson, Mari Nelis, Nicholas Eriksson, Dawn M. Waterworth, Leena Peltonen, Frank J. A. van Rooij, Jari Lahti, Maris Teder-Laving, Igor Rudan, Annette M. Hartmann, Guillaume Paré, Ole A. Andreassen, Mohammad Arfan Ikram, Stacy Steinberg, Bjarke Feenstra, Peter Vollenweider, Sarah E. Medland, Brenda W.J.H. Penninx, Mark I. McCarthy, Jordan W. Smoller, Fazil Aliev, Joel N. Hirschhorn, Dan Rujescu, J.M. Vink, Dorret I. Boomsma, Harry Campbell, Pedro Marques-Vidal, David A. Hinds, Tõnu Esko, Ruth J. F. Loos, Zoltán Kutalik, Jouke-Jan Hottenga, Reedik Mägi, Dale R. Nyholt, Kari Stefansson, Kevin S. O’Connell, Hreinn Stefansson, Scott Melville, Andres Metspalu, Inês Barroso, Marco P. Boks, Gail Davies, Lavinia Paternoster, Thomas Hansen, Norman Klopp, H.-Erich Wichmann, David L. Duffy, Lili Milani, Heather A. Boyd, Michelle Luciano, Benjamin M. Neale, Margaret J. Wright, Fernando Rivadeneira, Liang-Dar Hwang, Scott D. Gordon, Jiali Han, Jennifer E. Huffman, Danielle M. Dick, Roel A. Ophoff, Ozren Polasek, Nicholas J. Wareham, Vincent Mooser, Mousheng Xu, Johannes H. Smit, Gonneke Willemsen, Ian J. Deary, Panos Deloukas, John P. Kemp, Cornelia M. van Duijn, Samuli Ripatti, Joyce Y. Tung, Eco J. C. de Geus, Cameron D. Palmer, Ina Giegling, Katri Räikkönen, Thomas Werge, Eero Vuoksimaa, Andrew A. Hicks, Inga Prokopenko, Lynn Cherkas, Sigurdur H. Magnusson, Gérard Waeber, Nicholas J. Timpson, Frank Geller, Carolina Medina-Gomez, Nicole M. Warrington, Kay-Tee Khaw, and Jaakko Kaprio

Subjects
Genetics, 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, Genetic variants, Biology, Association (psychology), Biobank, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Handedness, a consistent asymmetry in skill or use of the hands, has been studied extensively because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and 32 studies from the International Handedness Consortium, we conducted the world’s largest genome-wide association study of handedness (1,534,836 right-handed, 194,198 (11.0%) left-handed and 37,637 (2.1%) ambidextrous individuals). We found 41 genetic loci associated with left-handedness and seven associated with ambidexterity at genome-wide levels of significance (P < 5×10−8). Tissue enrichment analysis implicated the central nervous system and brain tissues including the hippocampus and cerebrum in the etiology of left-handedness. Pathways including regulation of microtubules, neurogenesis, axonogenesis and hippocampus morphology were also highlighted. We found suggestive positive genetic correlations between being left-handed and some neuropsychiatric traits including schizophrenia and bipolar disorder. SNP heritability analyses indicated that additive genetic effects of genotyped variants explained 5.9% (95% CI = 5.8% – 6.0%) of the underlying liability of being left-handed, while the narrow sense heritability was estimated at 12% (95% CI = 7.2% – 17.7%). Further, we show that genetic correlation between left-handedness and ambidexterity is low (rg = 0.26; 95% CI = 0.08 – 0.43) implying that these traits are largely influenced by different genetic mechanisms. In conclusion, our findings suggest that handedness, like many other complex traits is highly polygenic, and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders that has been observed in multiple observational studies.

Published
2019

6. Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals

Author

Anne-Claire Vergnaud, Nauder Faraday, Tim Kacprowski, Lisa R. Yanek, Oscar H. Franco, Yongmei Liu, Andreas Greinacher, Gina M. Peloso, Cristen J. Willer, Leslie A. Lange, Eric S. Torstenson, Reedik Mägi, Jeanette Erdmann, Ethan M. Lange, Deborah A. Nickerson, Henry Völzke, David R. Crosslin, Gunnar Engström, Albert V. Smith, André G. Uitterlinden, Salman M. Tajuddin, W. David Hill, Diane M. Becker, Paul Elliot, Caterina Vacchi-Suzzi, Linda M. Polfus, Traci M. Bartz, Nathalie Chami, Abbas Dehghan, Mike A. Nalls, John D. Eicher, Leo-Pekka Lyytikäinen, Evelin Mihailov, Uwe Völker, Caroline Hayward, Ioanna Tzoulaki, Myriam Fornage, Marju Orho-Melander, Mary Cushman, Lars Wallentin, Terho Lehtimäki, Ayush Giri, Laura M. Raffield, Lewis C. Becker, Yingchang Lu, Emma Raitoharju, Sekar Kathiresan, Simon de Denus, Ruth J. F. Loos, James S. Floyd, Dawn M. Waterworth, James G. Wilson, Nathan Pankratz, Lenore J. Launer, Andrew D. Johnson, Andrew J. Slater, Jean-Claude Tardif, Raha Pazoki, Evangelos Evangelou, Kenneth Rice, Harvey D. White, Marie-Pierre Dubé, Frank J. A. van Rooij, Akihiro Nomura, Tamara B. Harris, Vilmundur Gudnason, Gonçalo R. Abecasis, Alan B. Zonderman, Guillaume Lettre, Todd L. Edwards, Amber A. Burt, Ani Manichaikul, Heribert Schunkert, Ming-Huei Chen, Ian J. Deary, Michelle L. O'Donoghue, Jennifer A. Brody, Russell P. Tracy, Tõnu Esko, Mika Kähönen, Panos Deloukas, Eric Boerwinkle, Rasika A. Mathias, Dajiang J. Liu, Jin Li, Santhi K. Ganesh, David C. Liewald, Paul L. Auer, Digna R. Velez Edwards, Erwin P. Bottinger, Nina Mononen, Claudia Schurmann, Michele K. Evans, John M. Starr, Thomas Thiele, Jussi Hernesniemi, Jerome I. Rotter, Rakale C. Quarells, He Gao, Kjell Nikus, Stephen S. Rich, Heather M. Highland, Bruce M. Psaty, Ursula M. Schick, Andres Metspalu, Melissa A. Richard, Neil A. Zakai, Olle Melander, John D. Rioux, Olli T. Raitakari, Alexander P. Reiner, Joel N. Hirschhorn, Nilesh J. Samani, Epidemiology, Internal Medicine, Home Office, National Institute for Health Research, and Medical Research Council (MRC)

Subjects
0301 basic medicine, Blood Platelets, Male, CARDIoGRAM Exome Consortium, Genome-wide association study, 030204 cardiovascular system & hematology, Biology, Myocardial Infarction Genetics Consortium, Article, 03 medical and health sciences, 0302 clinical medicine, Genetics, Humans, Platelet, Exome, Genetics(clinical), Mean platelet volume, Allele frequency, Genotyping, Genetics (clinical), Genetics & Heredity, Platelet Count, ta1184, Genetic Variation, Global Lipids Genetics Consortium, 11 Medical And Health Sciences, 06 Biological Sciences, FCER1A, Genetic architecture, 030104 developmental biology, Hemostasis, Immunology, Female, Mean Platelet Volume, Genome-Wide Association Study
Abstract

Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.

Published
2016

7. Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases

Author

Yingchang Lu, Lisa R. Yanek, Evangelos Evangelou, Andreas Greinacher, Leslie A. Lange, Albert Hofman, Rakale C. Quarells, Christopher J. O'Donnell, Simon de Denus, Marcus Dörr, Tamara B. Harris, Mary Cushman, Lars Wallentin, Digna R. Velez Edwards, Michelle L. O'Donoghue, Deborah A. Nickerson, Lisa Bastarache, Caterina Vacchi-Suzzi, Harvey D. White, Rasika A. Mathias, Jin Li, Santhi K. Ganesh, Leo-Pekka Lyytikäinen, Kjell Nikus, Ayush Giri, Paul Elliott, John M. Starr, Ruth J. F. Loos, Vilmundur Gudnason, Ioanna Tzoulaki, Myriam Fornage, Joshua C. Denny, Alan B. Zonderman, Caroline Hayward, Lewis C. Becker, Raha Pazoki, Guillaume Lettre, Lenore J. Launer, Ursula M. Schick, Michele K. Evans, Andrew J. Slater, Diane M. Becker, Jean-Claude Tardif, Ethan M. Lange, John D. Eicher, He Gao, James S. Floyd, Eric Boerwinkle, Paul L. Auer, Nathalie Chami, Frank J. A. van Rooij, Claudia Schurmann, Nele Friedrich, Kent D. Taylor, Andres Metspalu, Todd L. Edwards, Anne-Claire Vergnaud, Yongmei Liu, W. David Hill, Nauder Faraday, Terho Lehtimäki, Amber A. Burt, Jerome I. Rotter, Albert V. Smith, Tõnu Esko, Traci M. Bartz, Tim Kacprowski, Mike A. Nalls, Alexander P. Reiner, Ani Manichaikul, Ian J. Deary, Eric S. Torstenson, Laura M. Raffield, David C. Liewald, Ming-Huei Chen, Erwin P. Bottinger, Reedik Mägi, Andrew D. Johnson, Melissa A. Richard, Neil A. Zakai, John D. Rioux, Mika Kähönen, Stephen S. Rich, Heather M. Highland, Bruce M. Psaty, Joel N. Hirschhorn, Salman M. Tajuddin, Linda M. Polfus, Dawn M. Waterworth, James G. Wilson, Nathan Pankratz, Abbas Dehghan, Evelin Mihailov, David R. Crosslin, André G. Uitterlinden, Georg Homuth, Jennifer A. Brody, Gastroenterology & Hepatology, Epidemiology, and Internal Medicine

Subjects
0301 basic medicine, Quality Control, Myeloid, 1.1 Normal biological development and functioning, Genome-wide association study, Biology, Autoimmune Disease, Medical and Health Sciences, Article, 03 medical and health sciences, Underpinning research, White blood cell, medicine, Leukocytes, Genetics, Humans, 2.1 Biological and endogenous factors, Genetics(clinical), Exome, Aetiology, Genetics (clinical), Genetic association, Genetics & Heredity, Medical And Health Sciences, Neutrophil clearance, Hematopoietic stem cell differentiation, Inflammatory and immune system, Human Genome, Genetic Pleiotropy, Hematology, Biological Sciences, Acquired immune system, Stem Cell Research, 3. Good health, Blood Cell Count, 030104 developmental biology, medicine.anatomical_structure, Immune System Diseases, Genetic Loci, Immunology, Stem Cell Research - Nonembryonic - Non-Human, Genome-Wide Association Study
Abstract

White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of ∼157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases.

Published
2016

8. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

Author

Alison Pattie, Ailith Pirie, Francis S. Collins, Charles Kooperberg, Nienke van Leeuwen, Carmel Moore, Sharon L.R. Kardia, Neil R. Robertson, Lisa Bastarache, Allan Linneberg, Peter T. Campbell, Helena Kuivaniemi, Struan F.A. Grant, Sascha Fauser, Sekar Kathiresan, Lars Lind, Erin B. Ware, Olli T. Raitakari, Dawn M. Waterworth, James G. Wilson, Markus Perola, Chris J. Packard, Michelle L. O'Donoghue, Fredrik Karpe, Roel A. Ophoff, Sailaja Vedantam, Artitaya Lophatananon, Uwe Völker, Emmanouil Tsafantakis, Hakon Hakonarson, Dajiang J. Liu, Craig E. Pennell, Xueling Sim, Jennifer E. Huffman, Sandosh Padmanabhan, Digna R. Velez Edwards, Michiel L. Bots, Ayush Giri, Renée de Mutsert, Emanuele Di Angelantonio, Nicholas J. Wareham, Jin Li, Gail P. Jarvik, Evangelos Evangelou, Anne Tybjærg-Hansen, Patricia B. Munroe, Penny Gordon-Larsen, Lia E. Bang, Ivan Brandslund, Hester M. den Ruijter, Jussi Hernesniemi, Nancy L. Heard-Costa, Angela L. Mazul, Jonathan Tyrer, Danish Saleheen, Mark J. Caulfield, John Andrew Pospisilik, Annette Peters, Caroline Hayward, Iris M. Heid, J. Wouter Jukema, Valérie Turcot, Matt Neville, Rudolf Uher, Patricia A. Peyser, Jessica D. Faul, Asif Rasheed, Shuai Wang, John C. Chambers, Jordi Corominas Galbany, Murray H. Brilliant, Yucheng Jia, Torben Hansen, Veikko Salomaa, Mary F. Feitosa, Mathias Gorski, Li-An Lin, George Dedoussis, Honghuang Lin, Ethan M. Lange, Veronique Vitart, Bratati Kahali, Alexander Teumer, Jerome I. Rotter, Wayne H-H Sheu, Vilmantas Giedraitis, Aliki-Eleni Farmaki, Lorraine Southam, Ele Ferrannini, Anette P. Gjesing, Krina T. Zondervan, Stavroula Kanoni, David J. Roberts, Rebecca S. Fine, Svati H. Shah, Tugce Karaderi, Claudia Langenberg, Stefan Johansson, Elizabeth K. Speliotes, Alexander P. Reiner, Ching-Ti Liu, Yiqin Wang, Pål R. Njølstad, Gabriel Cuellar-Partida, Amanda J. Cox, Tim D. Spector, Paul W. Franks, Anke Tönjes, John D. Rioux, Jeffrey Haessler, Paul L. Auer, Ingrid B. Borecki, Deborah J. Thompson, Weihua Zhang, John R. B. Perry, Paul Elliott, Folkert W. Asselbergs, Myriam Fornage, Ken Sin Lo, Marie Moitry, Paul Mitchell, Martin den Heijer, Zoltán Kutalik, Tune H. Pers, Kari Stefansson, Kari Kuulasmaa, Robert E. Schoen, Mark C.H. De Groot, Laura M. Yerges-Armstrong, Jing Hua Zhao, Beverley Balkau, Peggy L. Peissig, Michael Boehnke, Janie Corley, Katharine R. Owen, Unnur Thorsteinsdottir, Naveed Sattar, Sita H. Vermeulen, Thomas N. Person, Mark I. McCarthy, Paul I.W. de Bakker, David Lamparter, Poorva Mudgal, Nicholette D. Palmer, Maria Karaleftheri, Jan-Håkan Jansson, Ozren Polasek, Ruth J. F. Loos, Daniel R. Witte, Dermot F. Reilly, Anubha Mahajan, Stella Trompet, James A. Perry, Yingchang Lu, Claudia Schurmann, Yii-Der Ida Chen, Hidetoshi Kitajima, Dale R. Nyholt, John Danesh, Pamela J. Schreiner, Narisu Narisu, Jose C. Florez, Adelheid Lempradl, Gerome Breen, Torben Jørgensen, Anu Loukola, Joe Dennis, Hans-Jörgen Grabe, Vilmundur Gudnason, Timo A. Lakka, Heather M. Highland, Sven Bergmann, Marie-Pierre Dubé, Giovanni Veronesi, Martina Müller-Nurasyid, Jaakko Tuomilehto, Nele Friedrich, Joel N. Hirschhorn, Pia R. Kamstrup, Nilesh J. Samani, Josh C. Denny, Mika Kähönen, Massimiliano Cocca, Liang Sun, Karina Meidtner, Carsten A. Böger, Sara M. Willems, Marcelo P. Segura-Lepe, Johanna Kuusisto, Hanieh Yaghootkar, Konstantin Strauch, Ruth Frikke-Schmidt, Jane Gibson, Matti Uusitupa, Oscar H. Franco, Yongmei Liu, Heather M. Stringham, Rohit Varma, Grant W. Montgomery, Dennis O. Mook-Kanamori, Stefania Cappellani, Paul L. Huang, Albert V. Smith, Eric Kim, Anke R. Hammerschlag, Katherine S. Ruth, Carolina Medina-Gomez, Gerard Pasterkamp, Cristen J. Willer, Alisa K. Manning, Frida Renström, René S. Kahn, Lili Milani, Feijie Wang, Tessel E. Galesloot, Fernando Rivadeneira, Leo-Pekka Lyytikäinen, Adam S. Butterworth, Tamara B. Harris, Matthew A. Allison, Paul M. Ridker, David J. Carey, Todd L. Edwards, Panos Deloukas, Xiuqing Guo, Lawrence F. Bielak, Leena Moilanen, Heiner Boeing, Peter Kovacs, Karen L. Mohlke, Myriam Rheinberger, Cramer Christensen, Betina H. Thuesen, Mike A. Nalls, Erik Ingelsson, Nicholas G. D. Masca, Colin N. A. Palmer, Audrey E. Hendricks, Linda Broer, Vanisha Mistry, Praveen Surendran, Audrey Y. Chu, Rainer Rauramaa, Angela D'Eustacchio, Helen Griffiths, Satu Männistö, Patrick T. Ellinor, Terho Lehtimäki, Katherine E. Tansey, I. Sadaf Farooqi, Gaëlle Marenne, Anneke I. den Hollander, Jessica van Setten, Hannu Puolijoki, Tinca J. C. Polderman, Timothy M. Frayling, Niels Grarup, Eric Boerwinkle, Gonçalo R. Abecasis, Adam E. Locke, Mengmeng Du, Manuel A. Rivas, Philippe Amouyel, Jaakko Kaprio, Leslie A. Lange, Loes M. Olde Loohuis, Trevor A. Mori, Lambertus A. Kiemeney, Wei Zhao, Eva Rb Petersen, Huaixing Li, Thomas W. Winkler, Tellervo Korhonen, Kathleen Stirrups, Jean Ferrières, Wei Zhou, Ian J. Deary, Guillaume Lettre, M. Arfan Ikram, Alex W. Hewitt, Marit E. Jørgensen, Ian Ford, Liang He, Mark Walker, Stefan Gustafsson, Andre Franke, Yao Hu, Jaana Lindström, Jonathan P. Bradfield, Anne E. Justice, Kristin L. Young, Sander W. van der Laan, Shuang Feng, Yadav Sapkota, Douglas F. Easton, Cornelia M. van Duijn, Amy J. Swift, Kjell Nikus, Helen R. Warren, Christian Theil Have, Wei Gan, Steven A. Lubitz, Harvey D. White, Pirjo Komulainen, John M. Starr, Jeffrey R. O'Connel, Anette Varbo, Daniel I. Chasman, Ruifang Li-Gao, Lynne E. Wagenknecht, Matthias Blüher, Xiaowei Zhan, Thomas F. Vogt, Eleftheria Zeggini, Tamuno Alfred, Katja K.H. Aben, Lars Wallentin, Joanna M. M. Howson, Jie Yao, Eulalia Catamo, Henrik Vestergaard, Gina M. Peloso, Markku Laakso, Matthias B. Schulze, Hayato Tada, Jennifer Wessel, Andrew R. Wood, Erwin P. Bottinger, Cora E. Lewis, Robin Young, Carol A. Wang, Oddgeir L. Holmen, Andrew J. Slater, Jean-Claude Tardif, Xu Lin, Inês Barroso, Gail Davies, Tibor V. Varga, Andrew J. Lotery, Igor Rudan, Andrew T. Hattersley, Michael Stumvoll, David Ellinghaus, Andrew C. Heath, Frank Kee, Christopher P. Nelson, Donald W. Bowden, Alison M. Dunning, Marianne Benn, Oluf Pedersen, Amber A. Burt, Aniruddh P. Patel, G. Kees Hovingh, David S. Crosslin, Gorm B. Jensen, Keng-Hung Lin, Dewan S. Alam, Jian'an Luan, Ying Wu, Tõnu Esko, Kathleen Mullan Harris, Antonietta Robino, Anne U. Jackson, Eirini Marouli, Robert A. Scott, Jette Bork-Jensen, Olov Rolandsson, Nanette R. Lee, Gerard Tromp, Megan L. Grove, Suthesh Sivapalaratnam, Sameer E. Al-Harthi, Roberta McKean-Cowdin, Paolo Gasparini, Ellen W. Demerath, Marco Brumat, Maggie C.Y. Ng, Børge G. Nordestgaard, Kari E. North, Rajiv Chowdhury, Mauno Vanhala, Andrew P. Morris, Sarah E. Medland, Sune F. Nielsen, Ilaria Gandin, Øyvind Helgeland, James P. Cook, Kent D. Taylor, Andrew D. Morris, Gudmar Thorleifsson, André G. Uitterlinden, Pang Yao, Valgerdur Steinthorsdottir, Eric B. Larson, Kerrin S. Small, Cecilia M. Lindgren, Dragana Vuckovic, Mariaelisa Graff, Fotios Drenos, Jaspal S. Kooner, Schurmann, Claudia [0000-0003-4158-9192], Justice, Anne E [0000-0002-8903-8712], Giri, Ayush [0000-0002-7786-4670], Locke, Adam E [0000-0001-6227-198X], Young, Kristin L [0000-0003-0070-6145], Medina-Gomez, Carolina [0000-0001-7999-5538], Winkler, Thomas W [0000-0003-0292-5421], Zeggini, Eleftheria [0000-0003-4238-659X], Zhao, Wei [0000-0002-8301-9297], Zondervan, Krina T [0000-0002-0275-9905], Pospisilik, John A [0000-0002-9745-0977], Rivadeneira, Fernando [0000-0001-9435-9441], Deloukas, Panos [0000-0001-9251-070X], Apollo - University of Cambridge Repository, Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, ACS - Atherosclerosis & ischemic syndromes, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Radiology & Nuclear Medicine, CHD Exome+ Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, EPIC InterAct Consortium, INTERVAL Study, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Understanding Society Scientific Group, Biological Psychology, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, British Heart Foundation, Wellcome Trust, Medical Research Council (MRC), National Institute for Health Research, Home Office, National Institutes of Health, Imperial College Healthcare NHS Trust- BRC Funding, Turcot, Valérie, Lu, Yingchang, Highland, Heather M., Schurmann, Claudia, Justice, Anne E., Fine, Rebecca S., Bradfield, Jonathan P., Esko, Tõnu, Giri, Ayush, Graff, Mariaelisa, Guo, Xiuqing, Hendricks, Audrey E., Karaderi, Tugce, Lempradl, Adelheid, Locke, Adam E., Mahajan, Anubha, Marouli, Eirini, Sivapalaratnam, Suthesh, Young, Kristin L., Alfred, Tamuno, Feitosa, Mary F., Masca, Nicholas G. D., Manning, Alisa K., Medina-Gomez, Carolina, Mudgal, Poorva, Ng, Maggie C. Y., Reiner, Alex P., Vedantam, Sailaja, Willems, Sara M., Winkler, Thomas W., Abecasis, Gonçalo, Aben, Katja K., Alam, Dewan S., Alharthi, Sameer E., Allison, Matthew, Amouyel, Philippe, Asselbergs, Folkert W., Auer, Paul L., Balkau, Beverley, Bang, Lia E., Barroso, Inê, Bastarache, Lisa, Benn, Marianne, Bergmann, Sven, Bielak, Lawrence F., Blüher, Matthia, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A., Bork-Jensen, Jette, Bots, Michiel L., Bottinger, Erwin P., Bowden, Donald W., Brandslund, Ivan, Breen, Gerome, Brilliant, Murray H., Broer, Linda, Brumat, Marco, Burt, Amber A., Butterworth, Adam S., Campbell, Peter T., Cappellani, Stefania, Carey, David J., Catamo, Eulalia, Caulfield, Mark J., Chambers, John C., Chasman, Daniel I., Chen, Yii-Der I., Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y., Cocca, Massimiliano, Collins, Francis S., Cook, James P., Corley, Janie, Corominas Galbany, Jordi, Cox, Amanda J., Crosslin, David S., Cuellar-Partida, Gabriel, D'Eustacchio, Angela, Danesh, John, Davies, Gail, Bakker, Paul I. W., Groot, Mark C. H., Mutsert, Renée, Deary, Ian J., Dedoussis, George, Demerath, Ellen W., Heijer, Martin, Hollander, Anneke I., Ruijter, Hester M., Dennis, Joe G., Denny, Josh C., Angelantonio, Emanuele, Drenos, Fotio, Du, Mengmeng, Dubé, Marie-Pierre, Dunning, Alison M., Easton, Douglas F., Edwards, Todd L., Ellinghaus, David, Ellinor, Patrick T., Elliott, Paul, Evangelou, Evangelo, Farmaki, Aliki-Eleni, Farooqi, I. Sadaf, Faul, Jessica D., Fauser, Sascha, Feng, Shuang, Ferrannini, Ele, Ferrieres, Jean, Florez, Jose C., Ford, Ian, Fornage, Myriam, Franco, Oscar H., Franke, Andre, Franks, Paul W., Friedrich, Nele, Frikke-Schmidt, Ruth, Galesloot, Tessel E., Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Gibson, Jane, Giedraitis, Vilmanta, Gjesing, Anette P., Gordon-Larsen, Penny, Gorski, Mathia, Grabe, Hans-Jörgen, Grant, Struan F. A., Grarup, Niel, Griffiths, Helen L., Grove, Megan L., Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeff, Hakonarson, Hakon, Hammerschlag, Anke R., Hansen, Torben, Harris, Kathleen Mullan, Harris, Tamara B., Hattersley, Andrew T., Have, Christian T., Hayward, Caroline, He, Liang, Heard-Costa, Nancy L., Heath, Andrew C., Heid, Iris M., Helgeland, Øyvind, Hernesniemi, Jussi, Hewitt, Alex W., Holmen, Oddgeir L., Hovingh, G. Kee, Howson, Joanna M. M., Hu, Yao, Huang, Paul L., Huffman, Jennifer E., Ikram, M. Arfan, Ingelsson, Erik, Jackson, Anne U., Jansson, Jan-Håkan, Jarvik, Gail P., Jensen, Gorm B., Jia, Yucheng, Johansson, Stefan, Jørgensen, Marit E., Jørgensen, Torben, Jukema, J. Wouter, Kahali, Bratati, Kahn, René S., Kähönen, Mika, Kamstrup, Pia R., Kanoni, Stavroula, Kaprio, Jaakko, Karaleftheri, Maria, Kardia, Sharon L. R., Karpe, Fredrik, Kathiresan, Sekar, Kee, Frank, Kiemeney, Lambertus A., Kim, Eric, Kitajima, Hidetoshi, Komulainen, Pirjo, Kooner, Jaspal S., Kooperberg, Charle, Korhonen, Tellervo, Kovacs, Peter, Kuivaniemi, Helena, Kutalik, Zoltán, Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A., Lamparter, David, Lange, Ethan M., Lange, Leslie A., Langenberg, Claudia, Larson, Eric B., Lee, Nanette R., Lehtimäki, Terho, Lewis, Cora E., Li, Huaixing, Li, Jin, Li-Gao, Ruifang, Lin, Honghuang, Lin, Keng-Hung, Lin, Li-An, Lin, Xu, Lind, Lar, Lindström, Jaana, Linneberg, Allan, Liu, Ching-Ti, Liu, Dajiang J., Liu, Yongmei, Lo, Ken S., Lophatananon, Artitaya, Lotery, Andrew J., Loukola, Anu, Luan, Jian'An, Lubitz, Steven A., Lyytikäinen, Leo-Pekka, Männistö, Satu, Marenne, Gaëlle, Mazul, Angela L., Mccarthy, Mark I., McKean-Cowdin, Roberta, Medland, Sarah E., Meidtner, Karina, Milani, Lili, Mistry, Vanisha, Mitchell, Paul, Mohlke, Karen L., Moilanen, Leena, Moitry, Marie, Montgomery, Grant W., Mook-Kanamori, Dennis O., Moore, Carmel, Mori, Trevor A., Morris, Andrew D., Morris, Andrew P., Müller-Nurasyid, Martina, Munroe, Patricia B., Nalls, Mike A., Narisu, Narisu, Nelson, Christopher P., Neville, Matt, Nielsen, Sune F., Nikus, Kjell, Njølstad, Pål R., Nordestgaard, Børge G., Nyholt, Dale R., O'Connel, Jeffrey R., O'Donoghue, Michelle L., Olde Loohuis, Loes M., Ophoff, Roel A., Owen, Katharine R., Packard, Chris J., Padmanabhan, Sandosh, Palmer, Colin N. A., Palmer, Nicholette D., Pasterkamp, Gerard, Patel, Aniruddh P., Pattie, Alison, Pedersen, Oluf, Peissig, Peggy L., Peloso, Gina M., Pennell, Craig E., Perola, Marku, Perry, James A., Perry, John R. B., Pers, Tune H., Person, Thomas N., Peters, Annette, Petersen, Eva R. B., Peyser, Patricia A., Pirie, Ailith, Polasek, Ozren, Polderman, Tinca J., Puolijoki, Hannu, Raitakari, Olli T., Rasheed, Asif, Rauramaa, Rainer, Reilly, Dermot F., Renström, Frida, Rheinberger, Myriam, Ridker, Paul M., Rioux, John D., Rivas, Manuel A., Roberts, David J., Robertson, Neil R., Robino, Antonietta, Rolandsson, Olov, Rudan, Igor, Ruth, Katherine S., Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Sapkota, Yadav, Sattar, Naveed, Schoen, Robert E., Schreiner, Pamela J., Schulze, Matthias B., Scott, Robert A., Segura-Lepe, Marcelo P., Shah, Svati H., Sheu, Wayne H. -H., Sim, Xueling, Slater, Andrew J., Small, Kerrin S., Smith, Albert V., Southam, Lorraine, Spector, Timothy D., Speliotes, Elizabeth K., Starr, John M., Stefansson, Kari, Steinthorsdottir, Valgerdur, Stirrups, Kathleen E., Strauch, Konstantin, Stringham, Heather M., Stumvoll, Michael, Sun, Liang, Surendran, Praveen, Swift, Amy J., Tada, Hayato, Tansey, Katherine E., Tardif, Jean-Claude, Taylor, Kent D., Teumer, Alexander, Thompson, Deborah J., Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thuesen, Betina H., Tönjes, Anke, Tromp, Gerard, Trompet, Stella, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Tybjaerg-Hansen, Anne, Tyrer, Jonathan P., Uher, Rudolf, Uitterlinden, André G., Uusitupa, Matti, Laan, Sander W., Duijn, Cornelia M., Leeuwen, Nienke, Van Setten, Jessica, Vanhala, Mauno, Varbo, Anette, Varga, Tibor V., Varma, Rohit, Velez Edwards, Digna R., Vermeulen, Sita H., Veronesi, Giovanni, Vestergaard, Henrik, Vitart, Veronique, Vogt, Thomas F., Völker, Uwe, Vuckovic, Dragana, Wagenknecht, Lynne E., Walker, Mark, Wallentin, Lar, Wang, Feijie, Wang, Carol A., Wang, Shuai, Wang, Yiqin, Ware, Erin B., Wareham, Nicholas J., Warren, Helen R., Waterworth, Dawn M., Wessel, Jennifer, White, Harvey D., Willer, Cristen J., Wilson, James G., Witte, Daniel R., Wood, Andrew R., Wu, Ying, Yaghootkar, Hanieh, Yao, Jie, Yao, Pang, Yerges-Armstrong, Laura M., Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zhou, Wei, Zondervan, Krina T, Rotter, Jerome I., Pospisilik, John A., Rivadeneira, Fernando, Borecki, Ingrid B., Deloukas, Pano, Frayling, Timothy M., Lettre, Guillaume, North, Kari E., Lindgren, Cecilia M., Hirschhorn, Joel N., Loos, Ruth J. F., Internal medicine, AGEM - Endocrinology, metabolism and nutrition, Amsterdam Movement Sciences - Rehabilitation & Development, Amsterdam Movement Sciences - Restoration and Development, APH - Aging & Later Life, Physiology, and VU University medical center

Subjects
0301 basic medicine, Male, ReproGen Consortium, MathematicsofComputing_GENERAL, Genome-wide association study, medicine.disease_cause, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Body Mass Index, genetics [Obesity], 0302 clinical medicine, Gene Frequency, Glucose homeostasis, Adult, Animals, Drosophila/genetics, Energy Intake/genetics, Energy Metabolism/genetics, Female, Genetic Variation, Humans, Obesity/genetics, Proteins/genetics, Syndrome, 11 Medical and Health Sciences, 2. Zero hunger, Genetics, Genetics & Heredity, Mutation, CHD Exome+ Consortium, body mass index, TheoryofComputation_GENERAL, T2D-Genes Consortium, GENOME-WIDE ASSOCIATION, MELANOCORTIN-4 RECEPTOR GENE, DONEPEZIL 23 MG, FRAMESHIFT MUTATION, GLUCOSE-HOMEOSTASIS, HYPOTHALAMIC AMPK, CODING VARIANTS, BLOOD-PRESSURE, RARE, LOCI, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Drosophila, ExomeBP Consortium, Life Sciences & Biomedicine, INTERVAL Study, Understanding Society Scientific Group, EPIC InterAct Consortium, genetics [Energy Metabolism], Biology, EPIC-CVD Consortium, Frameshift mutation, 03 medical and health sciences, MAGIC Investigators, All institutes and research themes of the Radboud University Medical Center, Genetic, SDG 3 - Good Health and Well-being, ddc:570, genetics [Drosophila], medicine, Journal Article, Global Lipids Genetic Consortium, Obesity, Gene, Allele frequency, Genetic association, Science & Technology, Proteins, 06 Biological Sciences, genetics [Proteins], Minor allele frequency, 030104 developmental biology, GoT2D Genes Consortium, Energy Intake, Energy Metabolism, genetics [Energy Intake], 030217 neurology & neurosurgery, Developmental Biology
Abstract

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.

Published
2018

9. Large meta-analysis of genome-wide association studies identifies five loci for lean body mass

Author

Jing Hua Zhao, Hyung Jin Choi, Leslie J. Baier, Vilmundur Gudnason, Melina Claussnitzer, Jian Shen, Mary F. Feitosa, Melissa E. Garcia, Douglas P. Kiel, Murielle Bochud, Christian Gieger, L. B. Husted, Kristina Åkesson, Alan Hubbard, John-Olov Jansson, Jacqueline S. L. Kloth, Yanhua Zhou, Richard L. Prince, Angela Döring, H.-Erich Wichmann, Thomas Girke, Monica J. Hubal, Mark A. Tarnopolsky, Laura M. Yerges-Armstrong, Yi-Hsiang Hsu, Patricia A. Thompson, Mattias Lorentzon, Gudmar Thorleifsson, Wen-Chi Chou, Karin M. A. Swart, Tim D. Spector, Braxton D. Mitchell, Kim M. Huffman, Inês Barroso, Igor Rudan, William E. Kraus, Nicholas J. Wareham, Chan Soo Shin, Jaakko Tuomilehto, Gunnar Sigurdsson, Bok Ghee Han, Munro Peacock, Mao Fu, Unnur Thorsteinsdottir, Gregory Livshits, Laura J. Scott, Jane A. Cauley, Heikki A. Koistinen, Arjun Verma, Peggy M. Cawthon, Carrie M. Nielson, Aron S. Buchman, Aarno Palotie, Daniel S. Evans, Elisabeth Widen, Caroline Hayward, Frances M K Williams, Nam H. Cho, Peter Vollenweider, Liisa Byberg, Robert Luben, Veikko Salomaa, Alena Stančáková, Markus M. Lerch, Jian'an Luan, Eric P. Hoffman, Thomas Lang, Jari Lahti, Mike Erdos, Stephen C. J. Parker, Ida Malkin, Jaspal S. Kooner, Francis S. Collins, Claes Ohlsson, James F. Wilson, Ben A. Oostra, Carolina Medina-Gomez, Toby Johnson, Cornelia M. van Duijn, Joel Eriksson, Natalia Campos Obanda, Samuli Ripatti, Kay-Tee Khaw, Ryan P. Welch, Jeffrey R. O'Connell, Karl Michaëlsson, Erik Ingelsson, Elizabeth A. Streeten, Eric E. Schadt, Markus Perola, Albert V. Smith, Henna Cederberg, Ruth J. F. Loos, Michael J. Econs, Thomas Illig, Ingrid B. Borecki, Unnur Styrkarsdottir, Kari Stefansson, Anne B. Newman, Ozren Polasek, Weihua Zhang, Shad B. Smith, Wen Chi Hsueh, Serkalem Demissie, Najaf Amin, Simon Melov, Lenore J. Launer, Harald Grallert, E. Steinhagen-Thiessen, Jean Wactawski-Wende, Stuart H. Ralston, Leif Mosekilde, Liesbeth Vandenput, Zoltán Kutalik, Nicole L. Glazer, Teemu Kuulasmaa, Lisette Stolk, Johanna Kuusisto, Lei Yu, Steven R. Cummings, Cynthia A. Thomson, Harry Campbell, Mark Walker, Lars Lind, André G. Uitterlinden, Albert Hofman, Linda Broer, Vicky Ossowski, John C. Chambers, Jerome I. Rotter, Gregory J. Tranah, Östen Ljunggren, Tamara B. Harris, Ali A. Aghdassi, Nicole Soranzo, Jong-Young Lee, Bruce M. Psaty, Magnus Karlsson, Luda Diatchenko, Nicole C. Wright, A.W. Enneman, Cecilia M. Lindgren, Yongmei Liu, Sabine Schipf, Tian Liu, Annette Peters, Daniel L. Koller, Georg Homuth, Ilja Demuth, Andrew P. Morris, Jagvir Grewal, Katri Räikkönen, Markku Laakso, Tuomas O. Kilpeläinen, Michael Boehnke, Fernando Rivadeneira, David A. Bennett, Joban Sehmi, Gudny Eiriksdottir, Rainer Biffar, Till Ittermann, Natasja M. van Schoor, Michael N. Weedon, Zhao Chen, Norman Klopp, Antti Jula, Bente L. Langdahl, William Maixner, Håkan Melhus, Rosalie A. M. Dhonukshe-Rutten, Dan Mellström, Robert L. Hanson, M. Carola Zillikens, Janina S. Ried, David Karasik, Suzanne Satterfield, Stephen B. Kritchevsky, Henry Völzke, Karol Estrada, Thomas Meitinger, Sian Tsung Tan, John A Robbins, Dawn M. Waterworth, Lars Bertram, Fiona E. McGuigan, Philip L. De Jager, Youfang Liu, Emmi Tikkanen, Eric S. Orwoll, Weijia Xie, Joanne M. Jordan, Johan G. Eriksson, Joshua R. Lewis, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, School of Medicine / Clinical Medicine, Internal Medicine, Epidemiology, Clinical Genetics, Luan, Jian'an [0000-0003-3137-6337], Barroso, Ines [0000-0001-5800-4520], Khaw, Kay-Tee [0000-0002-8802-2903], Luben, Robert [0000-0002-5088-6343], Soranzo, Nicole [0000-0003-1095-3852], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, APH - Societal Participation & Health, APH - Aging & Later Life, APH - Health Behaviors & Chronic Diseases, Epidemiology and Data Science, APH - Personalized Medicine, Clinicum, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Diabetes and Obesity Research Program, Research Programs Unit, University of Helsinki, Department of Medicine, Endokrinologian yksikkö, Medicum, Department of Psychology and Logopedics, Institute for Molecular Medicine Finland, Aarno Palotie / Principal Investigator, Department of Medical and Clinical Genetics, Quantitative Genetics, Samuli Olli Ripatti / Principal Investigator, Biostatistics Helsinki, Elisabeth Ingrid Maria Widen / Principal Investigator, HUS Internal Medicine and Rehabilitation, Developmental Psychology Research Group, Complex Disease Genetics, Genomics of Neurological and Neuropsychiatric Disorders, and Genomic Discoveries and Clinical Translation

Subjects
0301 basic medicine, Medicin och hälsovetenskap, 17-Hydroxysteroid Dehydrogenases, General Physics and Astronomy, Physiology, Genome-wide association study, VARIANTS, Bioinformatics, Medical and Health Sciences, Genome-wide association studies, 0302 clinical medicine, ADAMTS Proteins, Versicans, Regulatory Elements, Transcriptional, GENE-EXPRESSION, INSULIN-RESISTANCE, Extracellular Matrix Proteins, Multidisciplinary, Aldehyde Oxidoreductases, Multidisciplinary Sciences, Phenotype, OBESITY, Body Composition, Science & Technology - Other Topics, Medical genetics, BONE-MINERAL DENSITY, PHYSICAL-DISABILITY, Bioelectrical impedance analysis, 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit, medicine.medical_specialty, Science, Quantitative Trait Loci, UNITED-STATES, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Biology, Predictive markers, Polymorphism, Single Nucleotide, SARCOPENIA, General Biochemistry, Genetics and Molecular Biology, SKELETAL-MUSCLE MASS, 03 medical and health sciences, Insulin resistance, Thinness, MD Multidisciplinary, Journal Article, medicine, Humans, Life Science, Erfðafræði, Human height, Science & Technology, predictive markers, General Chemistry, Rannsóknir, Líkamsvöxtur, Arfgengi, medicine.disease, Obesity, Onderwijsinstituut, 030104 developmental biology, 3121 General medicine, internal medicine and other clinical medicine, Sarcopenia, genome-wide association studies, Lean body mass, Insulin Receptor Substrate Proteins, gene expression, Gene expression, HUMAN HEIGHT, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p, We acknowledge the essential role of the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium in development and support of this manuscript. CHARGE members include the Netherland’s Rotterdam Study (RS), Framingham Heart Study (FHS), Cardiovascular Health Study (CHS), the NHLBI’s Atherosclerosis Risk in Communities (ARIC) Study, and Iceland’s Age, Gene/Environment Susceptibility (AGES) Reykjavik Study. Age, Gene/Environment Susceptibility Reykjavik Study (AGES-Reykjavik): has been funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee, (VSN: 00-063) and the Data Protection Authority. The researchers are indebted to the participants for their willingness to participate in the study. Old Order Amish (OOA): this work was supported by NIH research grants U01 HL72515, U01 GM074518, R01 HL088119, R01 AR046838, and U01 HL084756. Partial funding was also provided by the Mid-Atlantic Nutrition and Obesity Research Center of Maryland (P30 DK072488).). L.M.Y.-A. was supported by F32AR059469 from NIH/NIAMS. M.F. was supported by American Heart Association grant 10SDG2690004. Cardiovascular Health Study (CHS): This CHS research was supported by NHLBI contracts N01-HC- 85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086; N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, N01-HC-85239, and by HHSN268201200036C and NHLBI grants HL080295, HL087652, HL105756, HL103612, HL120393, and HL130114 with additional contribution from NINDS. Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-027058 from the NIA. See also http://www.chs-nhlbi.org/pi.htm. DNA handling and genotyping at Cedars-Sinai Medical Center was supported in part by the National Center for Research Resources, grant UL1RR033176, and is now at the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124; in addition to the National Institute of Diabetes and Digestive and Kidney Disease grant DK063491 to the Southern California Diabetes Endocrinology Research Center. CoLaus: The CoLaus study received financial contributions from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, and the Swiss National Science Foundation (grants 33CSCO-122661, 33CS30-139468, and 33CS30-148401). We thank Vincent Mooser and Gérard Waeber, Co-PIs of the CoLaus study. Special thanks to Yolande Barreau, Mathieu Firmann, Vladimir Mayor, Anne-Lise Bastian, Binasa Ramic, Martine Moranville, Martine Baumer, Marcy Sagette, Jeanne Ecoffey, and Sylvie Mermoud for data collection. Data analysis was supervised by Sven Bergmann and Jacques S. Beckmann. The computations for this paper were performed in part at the Vital-IT Center for high-performance computing of the Swiss Institute of Bioinformatics. deCODE Study: The study was funded by deCODE Genetics, ehf. We thank all the participants of this study, the staff of deCODE Genetics core facilities and recruitment center and the densitometry clinic at the University Hospital for their important contributions to this work. The EPIC Study: The EPIC Obesity study is funded by Cancer Research United Kingdom and the Medical Research Council. I.B. acknowledges support from EU FP6 funding (contract no. LSHM-CT-2003-503041) and by the Wellcome Trust (WT098051). Erasmus Rucphen Family (ERF) Study: The study was supported by grants from The Netherlands Organisation for Scientific Research (NWO), Erasmus MC, the Centre for Medical Systems Biology (CMSB), and the European Community’s Seventh Framework Programme (FP7/2007-2013), ENGAGE Consortium, grant agreement HEALTH-F4-2007-201413. We are grateful to all general practitioners for their contributions, to Petra Veraart for her help in genealogy, Jeannette Vergeer for the supervision of the laboratory work and Peter Snijders for his help in data collection. Fenland: The Fenland Study is funded by the Wellcome Trust and the Medical Research Council, as well as by the Support for Science Funding programme and CamStrad. We are grateful to all the volunteers for their time and help, and to the General Practitioners and practice staff for help with recruitment. We thank the Fenland Study co-ordination team and the Field Epidemiology team of the MRC Epidemiology Unit for recruitment and clinical testing. Tuomas O. Kilpeläinen was supported by the Danish Council for Independent Research (DFF—1333-00124 and Sapere Aude program grant DFF—1331-00730B). Framingham Osteoporosis Study (FOS)/Framingham Heart Study (FHS): The study was funded by grants from the US National Institute for Arthritis, Musculoskeletal and Skin Diseases and National Institute on Aging (R01 AR 41398 and U24AG051129; D.P.K. and R01AR057118; D.K. D.K. was also supported by FP7-PEOPLE-2012-Marie Curie Career Integration Grants (CIG)). The Framingham Heart Study of the National Heart, Lung, and Blood Institute of the National Institutes of Health and Boston University School of Medicine were supported by the National Heart, Lung, and Blood Institute’s Framingham Heart Study (N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (N02-HL-6-4278). Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. eQTL HOb Study: The study was supported by Genome Quebec, Genome Canada and the Canadian Institutes of Health Research (CIHR). Gothenburg Osteoporosis and Obesity Determinants Study (GOOD): The study was funded by the Swedish Research Council, the Swedish Foundation for Strategic Research, The ALF/LUA research grant in Gothenburg, the Lundberg Foundation, the Emil and Vera Cornell Foundation, the Torsten and Ragnar Söderberg’s Foundation, Petrus and Augusta Hedlunds Foundation, the Västra Götaland Foundation, and the Göteborg Medical Society. We would like to thank Dr Tobias A. Knoch, Luc V. de Zeeuw, Anis Abuseiris, and Rob de Graaf as well as their institutions the Erasmus Computing Grid, Rotterdam, The Netherlands, and especially the national German MediGRID and Services@MediGRID part of the German D-Grid, both funded by the German Bundesministerium fuer Forschung und Technology under grants #01 AK 803 A-H and # 01 IG 07015G for access to their grid resources. We also thank Karol Estrada, Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands for advice regarding the grid resources. Health Aging and Body Composition Study (Health ABC): This study was funded by the National Institutes of Aging. This research was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. Indiana: We thank the individuals who participated in this study, as well as the study coordinators, without whom this work would not have been possible. This work was supported by National Institutes of Health grants R01 AG 041517 and M01 RR-00750. Genotyping services were provided by CIDR. CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, National Library of Medicine. Kora (KORA F3 and KORA F4): The KORA research platform was initiated and financed by the Helmholtz Center Munich, German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Part of this work was financed by the German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823). Our research was supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. The London Life Sciences Population (LOLIPOP): The study was funded by the British Heart Foundation, Wellcome Trust, the Medical Research Council, and Kidney Research UK. The study also receives support from a National Institute for Health Research (NIHR) programme grant. Rotterdam Study (RSI, RSII & RSIII): The generation and management of GWAS genotype data for the Rotterdam Study (RS I, RS II, RS III) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. The GWAS datasets are supported by the Netherlands Organisation of Scientific Research NWO Investments (no. 175.010.2005.011, 911-03-012), the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA), project no. 050-060-810. We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera, Marjolein Peters, MSc, and Carolina Medina-Gomez, MSc, for their help in creating the GWAS database, and Karol Estrada, PhD, Yurii Aulchenko, PhD, and Carolina Medina-Gomez, PhD, for the creation and analysis of imputed data. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. We are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. We thank Dr Karol Estrada, Dr Fernando Rivadeneira, Dr Tobias A. Knoch, Anis Abuseiris, and Rob de Graaf (Erasmus MC Rotterdam, The Netherlands) for their help in creating GRIMP, and we thank BigGRID, MediGRID, and Services@MediGRID/D-Grid (funded by the German Bundesministerium fuer Forschung und Technology; grants 01 AK 803 A-H, 01 IG 07015G) for access to their grid computing resources. Rush Memory and Aging Project (MAP): The Memory and Aging Project was supported by National Institute on Aging grants R01AG17917, R01AG15819, and R01AG24480, the Illinois Department of Public Health, the Rush Clinical Translational Science Consortium, and a gift from Ms Marsha Dowd. TwinsUK (TUK): The study was funded by the Wellcome Trust, Arthritis Research UK, and the Chronic Disease Research Foundation. The study also received support from a National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London. We thank the staff and volunteers of the TwinsUK study. The study was also supported by Israel Science Foundation, grant number 994/10. Age, Gene/Environment Susceptibility Reykjavik Study (AGES-Reykjavik) has been funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee (VSN: 00-063) and the Data Protection Authority. The researchers are indebted to the participants for their willingness to participate in the study. Berlin Aging Study II (BASE-II) was supported by the German Federal Ministry of Education and Research (BMBF (grants #16SV5536K, #16SV5537, #16SV5538, and #16SV5837; previously #01UW0808)). Additional contributions (e.g., financial, equipment, logistics, personnel) are made from each of the other participating sites, i.e., the Max Planck Institute for Human Development (MPIB), Max Planck Institute for Molecular Genetics (MPIMG), Charite University Medicine, German Institute for Economic Research (DIW), all located in Berlin, Germany, and University of Lübeck in Lübeck, Germany. B-vitamins in the prevention of osteoporotic fractures (B-PROOF): B-PROOF is supported and funded by The Netherlands Organization for Health Research and Development (ZonMw, grant 6130.0031), the Hague; unrestricted grant from NZO (Dutch Dairy Association), Zoetermeer; Orthica, Almere; NCHA (Netherlands Consortium Healthy Ageing) Leiden/Rotterdam; Ministry of Economic Affairs, Agriculture and Innovation (project KB-15-004-003), the Hague; Wageningen University, Wageningen; VU University Medical Center, Amsterdam; Erasmus Medical Center, Rotterdam. All organizations are based in the Netherlands. We thank Dr Tobias A. Knoch, Anis Abuseiris, Karol Estrada, and Rob de Graaf as well as their institutions the Erasmus Grid Office, Erasmus MC Rotterdam, The Netherlands, and especially the national German MediGRID and Services@MediGRID part of the German D-Grid, both funded by the German Bundesministerium fuer Forschung und Technology (grants #01 AK 803 A-H and #01 IG 07015G) for access to their gird resources. Further, we gratefully thank all participants. Calcium Intake Fracture Outcome Study (CAIFOS): This study was funded by Healthway Health Promotion Foundation of Western Australia, Australasian Menopause Society and the Australian National Health and Medical Research Council Project Grants (254627, 303169, and 572604). We are grateful to the participants of the CAIFOS Study. The salary of Dr Lewis is supported by a National Health and Medical Research Council of Australia Career Development Fellowship. Danish Osteoporosis Study (DOPS): The study was supported by Karen Elise Jensen foundation. Family Heart Study (FamHS): The study was supported by NIH grants R01-HL-117078, R01-HL-087700, and R01-HL-088215 from NHLBI; and R01-DK-089256 and R01-DK-075681 from NIDDK. GenMets (Health 2000): S.R. was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (213506 and 129680), Academy of Finland (251217), the Finnish foundation for Cardiovascular Research and the Sigrid Juselius Foundation. S.M. was supported by grants #136895 and #141005, V.S. by grants #139635 and 129494, and M.P. by grant #269517 from the Academy of Finland and a grant from the Finnish Foundation for Cardiovascular Research. M.P. was supported by the Yrjö Jahnsson Foundation. Helsinki Birth Cohort Study (HBCS): We thank all study participants as well as everybody involved in the HBCS. HBCS has been supported by grants from the Academy of Finland, the Finnish Diabetes Research Society, Samfundet Folkhälsann, Novo Nordisk Foundation, Liv och Hälsa, Finska Läkaresällskapet, Signe and Ane Gyllenberg Foundation, University of Helsinki, European Science Foundation (EUROSTRESS), Ministry of Education, Ahokas Foundation, Emil Aaltonen Foundation, Juho Vainio Foundation, and Wellcome Trust (grant number WT089062). Johnston County Study: The Johnston County Osteoarthritis Project is supported in part by cooperative agreements S043, S1734, and S3486 from the Centers for Disease Control and Prevention/Association of Schools of Public Health; the NIAMS Multipurpose Arthritis and Musculoskeletal Disease Center grant 5-P60-AR30701; and the NIAMS Multidisciplinary Clinical Research Center grant 5 P60 AR49465-03. Genotyping services were provided by Algynomics company. Korean Genome Epidemiology Study (KoGES): Korean Genome Epidemiology Study (KoGES): This work was supported by the Research Program funded by the Korea Centers for Disease Control and Prevention (found 2001-347-6111-221, 2002-347-6111-221, 2009-E71007-00, 2010-E71004-00). Kora F3 and Kora F4: The KORA research platform was initiated and financed by the Helmholtz Center Munich, German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Part of this work was financed by the German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823). Our research was supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. LOLIP-REP-IA610: The study was supported by the Wellcome Trust. We thank the participants and research teams involved in LOLIPOP. LOLIP-REP-IA_I: The study was supported by the British Heart Foundation Grant SP/04/002. LOLIP-REP-IA_P: The study was supported by the British Heart Foundation Grant SP/04/002. METSIM: The study was supported by the Academy of Finland, the Finnish Diabetes Research Foundation, the Finnish Cardiovascular Research Foundation, the Strategic Research Funding from the University of Eastern Finland, Kuopio, and the EVO grant 5263 from the Kuopio University Hospital. MrOS Sweden: Financial support was received from the Swedish Research Council (2006-3832), the Swedish Foundation for Strategic Research, the ALF/LUA research grant in Gothenburg, the Lundberg Foundation, the Torsten and Ragnar Söderberg’s Foundation, Petrus and Augusta Hedlunds Foundation, the Västra Götaland Foundation, the Göteborg Medical Society, and the Novo Nordisk foundation. Greta and Johan Kock Foundation, A. Påhlsson Foundation, A. Osterlund Foundation, Malmö University Hospital Research Foundation, Research and Development Council of Region Skåne, Sweden, the Swedish Medical Society. MrOS US: The Osteoporotic Fractures in Men (MrOS) Study is supported by National Institutes of Health funding. The following institutes provide support: the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Center for Advancing Translational Sciences (NCATS), and NIH Roadmap for Medical Research under the following grant numbers: U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, and UL1 TR000128. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) provided funding for the MrOS ancillary study “GWAS in MrOS and SOF” under the grant number RC2ARO58973. Osteoporosis Prospective Risk Assessment study (OPRA): This work was supported by grants from the Swedish Research Council (K2009-53X-14691-07-3, K2010-77PK-21362-01-2), FAS (grant 2007-2125), Greta and Johan Kock Foundation, A. Påhlsson Foundation, A. Osterlund Foundation, Malmö University Hospital Research Foundation, Research and Development Council of Region Skåne, Sweden, the Swedish Medical Society. We are thankful to all the women who kindly participated in the study and to the staff at the Clinical and Molecular Osteoporosis Research Unit for helping in recruitment of study individuals. Orkney Complex Disease Study (ORCADES): ORCADES was supported by the Chief Scientist Office of the Scottish Government (CZB/4/276, CZB/4/710), the Royal Society, the MRC Human Genetics Unit, Arthritis Research UK (17539) and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh. We acknowledge the invaluable contributions of Lorraine Anderson and the research nurses in Orkney, the administrative team in Edinburgh and the people of Orkney. PEAK 25: This work was supported by grants from the Swedish Research Council (K2009-53X-14691-07-3, K2010-77PK-21362-01-2), FAS (grant 2007-2125), Greta and Johan Kock Foundation, A. Påhlsson Foundation, A. Osterlund Foundation, Malmö University Hospital Research Foundation, Research and Development Council of Region Skåne, Sweden, the Swedish Medical Society. We are thankful to all the women who kindly participated in the study and to the staff at the Clinical and Molecular Osteoporosis Research Unit for helping in recruitment of study individuals. Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS): The study was supported by grants from the Swedish research council (projects 2008-2202 and 2005-8214) and ALF/LUA research grants from Uppsala university hospital, Uppsala, Sweden. Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC): The RISC study is supported by European Union Grant QLG1-CT-2001-01252 and AstraZeneca. We thank Merck Research Labs for conducting DNA genotyping on RISC samples.Rotterdam III: Rotterdam Study (RS): See discovery. SHIP and SHIP TREND: This work was supported by SHIP, which is part of the Community Medicine Research Network of the University of Greifswald, Germany, by the Federal Ministry of Education and Research (01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania and the network “Greifswald Approach to Individualized Medicine (GANI_MED)” funded by the Federal Ministry of Education and Research (03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the “Center of Knowledge Interchange” program of the Siemens. A.G. and the Cache´ Campus program of the InterSystems GmbH. The SHIP authors are grateful to the contribution of Florian Ernst, Anja Wiechert, and Astrid Petersmann in generating the SNP data and to Mario Stanke for the opportunity to use his Server Cluster for SNP Imputation. Data analyses were further supported by the German Research Foundation (DFG Vo 955/10-1) and the Federal Ministry of Nutrition, Agriculture and Consumer’s Safety. SOF: The Study of Osteoporotic Fractures (SOF) is supported by National Institutes of Health funding. The National Institute on Aging (NIA) provides support under the following grant numbers: R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, and R01 AG027576. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) provided funding for the SOF ancillary study “GWAS in MrOS and SOF” under the grant number RC2ARO58973. Uppsala Longitudinal Study of Adult Men (ULSAM): The study was funded by grants from the Swedish research council (projects 2008-2202 and 2005-8214), the Wallenberg foundation, and ALF/LUA research grants from Uppsala university hospital, Uppsala, Sweden. Andrew P. Morris is a Wellcome Trust Senior Fellow in Basic Biomedical Science, grant number WT098017. CROATIA-VIS (VIS): The CROATIA-Vis study was funded by grants from the Medical Research Council (UK) and Republic of Croatia Ministry of Science, Education and Sports research grants to I.R. (108-1080315-0302). We acknowledge the staff of several institutions in Croatia that supported the field work, including but not limited to The University of Split and Zagreb Medical Schools, the Institute for Anthropological Research in Zagreb and Croatian Institute for Public Health. The SNP genotyping for the CROATIA-Vis cohort was performed in the core genotyping laboratory of the Wellcome Trust Clinical Research Facility at the Western General Hospital, Edinburgh, Scotland. Women’s Health Initiative (WHI): The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts N01WH22110, 24152, 32100–2, 32105–6, 32108–9, 32111–13, 32115, 32118–32119, 32122, 42107–26, 42129–32, and 44221. We thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A listing of WHI investigators can be found at https://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Short%20List.pdf. FUSION: This research was supported in part by US National Institutes of Health grants 1-ZIA-HG000024 (to F.S.C.), U01DK062370 (to M.B.), R00DK099240 (to S.C.J.P.), the American Diabetes Association Pathway to Stop Diabetes Grant 1-14-INI-07 (to S.C.J.P.), and Academy of Finland Grants 271961 and 272741 (to M.L.) and 258753 (to H.A.K.). We thank all the subjects for participation and the study personnel for excellent technical assistance. The Pima Indian Study: This study was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH, USA. Studies of a Targeted Risk Reduction Intervention with Defined Exercise (STRRIDE): This study was supported by the National Heart Lung and Blood Institute of the National Institutes of Health, HL57453 (WEK). Gene expression in old and young muscle biopsies: S.M. and T.G. were supported in part by NIH U24AG051129.

Published
2017

10. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation

Author

Angelo Scuteri, Chris Wallace, Rachel Hackett, Sonja I. Berndt, Richard B. Hayes, Peter Vollenweider, Susan M. Ring, Lauren Gianniny, Alistair S. Hall, Christopher J. Gillson, Karani Santhanakrishnan Vimaleswaran, Karol Estrada, Thomas Meitinger, Kay-Tee Khaw, Nicholas J. Timpson, Willem H. Ouwehand, Cristen J. Willer, Andy R Ness, Peter S. Chines, Wendy L. McArdle, I. Sadaf Farooqi, Eleftheria Zeggini, Jouko Saramies, Amanda J. Bennett, Matthew A. Sims, Richard M. Watanabe, David M. Evans, Patricia B. Munroe, Toshiko Tanaka, Francis S. Collins, Peter Kraft, Morris Brown, Inês Barroso, Sheila Bingham, John M. C. Connell, Jian'an Luan, Pekka Jousilahti, Amanda F. Elliott, Lachlan J. M. Coin, Parimal Deodhar, Kijoung Song, Ruth J. F. Loos, Eleanor Wheeler, George Davey Smith, Kate Northstone, Joshua C. Randall, Claudia Lamina, André G. Uitterlinden, Dawn M. Waterworth, Tim D. Spector, Robert Luben, Veikko Salomaa, Vincent Mooser, Candace Guiducci, Andrew T. Hattersley, Guillaume Lettre, Guangju Zhai, Gonçalo R. Abecasis, Jaana Laitinen, Cyrus Cooper, David J. Hunter, Noël P. Burtt, Timo T. Valle, Carolin Purmann, Narisu Narisu, Lori L. Bonnycastle, Steven A. McCarroll, Christian Gieger, Albert Hofman, Laura J. Scott, Iris M. Heid, Lu Qi, Kevin B. Jacobs, Toby Johnson, Cornelia M. van Duijn, David Altshuler, David Hadley, Marjo-Riitta Järvelin, Johannes Hebebrand, Stephen J. Chanock, Stephen O'Rahilly, Jaakko Tuomilehto, Cecilia M. Lindgren, Y. C. Loraine Tung, Panagiotis Deloukas, Manjinder S. Sandhu, H-Erich Wichmann, Antonella Mulas, Matthew G. Rees, Jack M. Guralnik, Elaine M. Dennison, Timothy M. Frayling, David P. Strachan, Jonathan Stephens, Inga Prokopenko, Mikko Kuokkanen, Shengxu Li, Leif Groop, Jing Hua Zhao, Paul Elliott, David Schlessinger, Ken K. Ong, Peter Almgren, Massimo Mangino, Manuela Uda, Zorica Jovanovic, Karen L. Mohlke, Leena Peltonen, Michael N. Weedon, Elizabeth K. Speliotes, Markku Laakso, Bo Isomaa, Serena Sanna, Mark J. Caulfield, Gérard Waeber, Martin Ridderstråle, Luigi Ferrucci, Anne U. Jackson, Suzanne Stevens, Aimo Ruokonen, Jacqueline C. M. Witteman, Nicole Soranzo, Kaisa Silander, Mark I. McCarthy, Joel N. Hirschhorn, Nilesh J. Samani, Frank B. Hu, Michael R. Erdos, Paul Scheet, Leonie C. Jacobs, Rosa Maria Roccasecca, Heather M. Stringham, Helen N. Lyon, Konstantinos A. Papadakis, Aki S. Havulinna, Michael Boehnke, Richard N. Bergman, Nicholas J. Wareham, M. Carola Zillikens, Nicholas A. Watkins, Tiinamaija Tuomi, Fernando Rivadeneira, Noha Lim, Edward G. Lakatta, and Johanna Kuusisto

Subjects
Central Nervous System, medicine.medical_specialty, Quantitative Trait Loci, Medizin, Gene Dosage, 030209 endocrinology & metabolism, Genome-wide association study, Locus (genetics), Biology, FTO gene, Polymorphism, Single Nucleotide, Article, Body Mass Index, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Quantitative Trait, Heritable, SH2B1, Meta-Analysis as Topic, Internal medicine, Genetics, medicine, Humans, Genetic Predisposition to Disease, Obesity, Alleles, 030304 developmental biology, 2. Zero hunger, 0303 health sciences, Neuronal growth regulator 1, Anthropometry, Genetics of obesity, Body Weight, 3. Good health, Endocrinology, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Genome-Wide Association Study, Colaus Study, Body mass index
Abstract

Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 × 10⁻⁸): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity. © 2009 Nature America, Inc. All rights reserved.

Published
2016

11. Mendelian randomization studies do not support a causal role for reduced circulating adiponectin levels in insulin resistance and type 2 diabetes

Author

Claudia Lamina, Dawn M. Waterworth, Ramachandran S. Vasan, Alan R. Sinaiko, Jorma Viikari, Alena Stančáková, Nita G. Forouhi, Leo-Pekka Lyytikäinen, Chloe Y Y Cheung, Torben Hansen, Bernhard Paulweber, Ying Wu, Christie M. Ballantyne, Jaakko Tuomilehto, Karen S.L. Lam, Jussi Paananen, James B. Meigs, Jing Hua Zhao, Francis S. Collins, Hans U. Häring, Marie-France Hivert, Joshua W. Knowles, Zari Dastani, Andrew T. Hattersley, Ele Ferrannini, Ching-Ti Liu, Sarah Buxbaum, Mika Kähönen, Peter Henneman, Aurelian Bidulescu, Michael Boehnke, Ruth J. F. Loos, Fatiha el Bouazzaoui, Ulf Smith, Tim D. Spector, Josée Dupuis, Weijia Xie, Thomas Quertermous, Robert K. Semple, Lyudmyla Kedenko, John J. Nolan, Andrew D. Morris, Anne U. Jackson, Cornelia M. van Duijn, Ko Willems van Dijk, Markku Laakso, Robert A. Scott, Na Zhu, Oluf Pedersen, Terho Lehtimäki, Claudia Langenberg, Ke Hao, Christopher J. Gillson, Olli T. Raitakari, Mark I. McCarthy, Florian Kronenberg, Jaeyoung Hong, James S. Pankow, Debbie A Lawlor, Nicholas J. Wareham, Karen L. Mohlke, Timothy M. Frayling, Tanya M. Teslovich, Sandra H. Dunn, Alessandro Doria, Cecilia M. Lindgren, Richard N. Bergman, Johanna Kuusisto, Hanieh Yaghootkar, Liling Warren, Stefan Gustafsson, Erik Ingelsson, Colin N. A. Palmer, Mark Walker, Themistocles L. Assimes, J. Brent Richards, Epidemiology, and Medical Microbiology & Infectious Diseases

Subjects
Blood Glucose, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Type 2 diabetes, ADIPOQ Gene, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, MOLECULAR-WEIGHT ADIPONECTIN GREATER-THAN-G PLASMA ADIPONECTIN ADIPOSE-TISSUE ASSOCIATION ANALYSES METABOLIC PROFILE GENETIC-VARIANTS SUPPRESSION TEST GLYCEMIC TRAITS OBESE WOMEN, 0302 clinical medicine, Insulin resistance, SDG 3 - Good Health and Well-being, Diabetes mellitus, Internal medicine, Mendelian randomization, Odds Ratio, Internal Medicine, medicine, Humans, Genetic Predisposition to Disease, Original Research, 030304 developmental biology, 0303 health sciences, Adiponectin, Genetic Variation, Genetics/Genomes/Proteomics/Metabolomics, Mendelian Randomization Analysis, Odds ratio, medicine.disease, 3. Good health, Endocrinology, Diabetes Mellitus, Type 2, Regression Analysis, Female, Insulin Resistance
Abstract

Adiponectin is strongly inversely associated with insulin resistance and type 2 diabetes, but its causal role remains controversial. We used a Mendelian randomization approach to test the hypothesis that adiponectin causally influences insulin resistance and type 2 diabetes. We used genetic variants at the ADIPOQ gene as instruments to calculate a regression slope between adiponectin levels and metabolic traits (up to 31,000 individuals) and a combination of instrumental variables and summary statistics–based genetic risk scores to test the associations with gold-standard measures of insulin sensitivity (2,969 individuals) and type 2 diabetes (15,960 case subjects and 64,731 control subjects). In conventional regression analyses, a 1-SD decrease in adiponectin levels was correlated with a 0.31-SD (95% CI 0.26–0.35) increase in fasting insulin, a 0.34-SD (0.30–0.38) decrease in insulin sensitivity, and a type 2 diabetes odds ratio (OR) of 1.75 (1.47–2.13). The instrumental variable analysis revealed no evidence of a causal association between genetically lower circulating adiponectin and higher fasting insulin (0.02 SD; 95% CI −0.07 to 0.11; N = 29,771), nominal evidence of a causal relationship with lower insulin sensitivity (−0.20 SD; 95% CI −0.38 to −0.02; N = 1,860), and no evidence of a relationship with type 2 diabetes (OR 0.94; 95% CI 0.75–1.19; N = 2,777 case subjects and 13,011 control subjects). Using the ADIPOQ summary statistics genetic risk scores, we found no evidence of an association between adiponectin-lowering alleles and insulin sensitivity (effect per weighted adiponectin-lowering allele: −0.03 SD; 95% CI −0.07 to 0.01; N = 2,969) or type 2 diabetes (OR per weighted adiponectin-lowering allele: 0.99; 95% CI 0.95–1.04; 15,960 case subjects vs. 64,731 control subjects). These results do not provide any consistent evidence that interventions aimed at increasing adiponectin levels will improve insulin sensitivity or risk of type 2 diabetes.

Published
2016

12. Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits

Author

Torben Hansen, Marie-Pierre Dubé, Frank J. A. van Rooij, Todd L. Edwards, Michele K. Evans, Tõnu Esko, Paul Elliott, Leslie A. Lange, Kjell Nikus, Jette Bork-Jensen, Caterina Vacchi-Suzzi, Mika Kähönen, John M. Starr, Jennifer A. Brody, Ethan M. Lange, Christopher J. O'Donnell, John D. Eicher, Marju Orho-Melander, Kent D. Taylor, Vilmundur Gudnason, Yingchang Lu, Betina H. Thuesen, Amber A. Burt, Lisa R. Yanek, Andreas Greinacher, Leo-Pekka Lyytikäinen, Albert V. Smith, Eric Boerwinkle, Ming-Huei Chen, Paul L. Auer, Laura M. Raffield, Ani Manichaikul, Kenneth Rice, Frank Schmidt, Evangelos Evangelou, Russell P. Tracy, Nathalie Chami, Ayush Giri, Jussi Hernesniemi, Andrew D. Johnson, Ruth J. F. Loos, Sekar Kathiresan, Salman M. Tajuddin, Nina Mononen, Emma Raitoharju, Dawn M. Waterworth, James G. Wilson, Linda M. Polfus, Akihiro Nomura, Tamara B. Harris, Guillaume Lettre, Astrid Petersmann, Marguerite R. Irvin, Jerome I. Rotter, Alexander P. Reiner, Niels Grarup, Latisha Love-Gregory, Claudia Schurmann, Michelle L. O'Donoghue, Ursula M. Schick, Raha Pazoki, Lars Wallentin, Anne-Claire Vergnaud, Nauder Faraday, W. David Hill, Cornelia M. van Duijn, Nathan Pankratz, Rasika A. Mathias, Joel N. Hirschhorn, Jin Li, Santhi K. Ganesh, Tim Kacprowski, Traci M. Bartz, Mike A. Nalls, Samuel Lessard, Albert Hofman, Reedik Mägi, Ioanna Tzoulaki, Myriam Fornage, Evelin Mihailov, He Gao, Lewis C. Becker, Lenore J. Launer, Fernando Rivadeneira, Deborah A. Nickerson, Simon de Denus, Andrew J. Slater, Allan Linneberg, Andres Metspalu, Oluf Pedersen, Olli T. Raitakari, Harvey D. White, Yongmei Liu, Heather M. Highland, Bruce M. Psaty, Melissa A. Richard, Neil A. Zakai, Olle Melander, David R. Crosslin, Gunnar Engström, Ian J. Deary, Digna R. Velez Edwards, David C. Liewald, Mary Cushman, Erwin P. Bottinger, Eric S. Torstenson, Alan B. Zonderman, Nada A. Abumrad, Diane M. Becker, Terho Lehtimäki, Caroline Hayward, James S. Floyd, Alexander Teumer, Epidemiology, and Internal Medicine

Subjects
0301 basic medicine, Hemolytic anemia, Erythrocyte Indices, Erythrocytes, Genotype, Quantitative Trait Loci, Mean corpuscular hemoglobin, 030204 cardiovascular system & hematology, Biology, Allelic Imbalance, Article, 03 medical and health sciences, Hemoglobins, 0302 clinical medicine, Sideroblastic anemia, Gene Frequency, Pleiotropy, hemic and lymphatic diseases, Genetics, medicine, Humans, Genetics(clinical), Erythropoiesis, Exome, Allele frequency, Mean corpuscular volume, Genetics (clinical), Genetics & Heredity, Medical And Health Sciences, medicine.diagnostic_test, ta1184, Genetic Variation, Genetic Pleiotropy, Biological Sciences, ta3121, medicine.disease, 3. Good health, Minor allele frequency, Black or African American, 030104 developmental biology, Hematocrit
Abstract

Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 × 10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 × 10(-8) for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 × 10(-11)) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 × 10(-9)). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 × 10(-7)). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.

Published
2016

13. Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels

Author

Clive Osmond, Felix R. Day, Nicholas J. Timpson, Lars Lind, Sven Bergmann, Seppo Koskinen, Gordon D.O. Lowe, Christian Gieger, Andrew A. Hicks, Wolfgang Koenig, Alexander W. Drong, P. Eline Slagboom, Massimo Mangino, Leo-Pekka Lyytikäinen, Åsa K. Hedman, Frank B. Hu, Ian Ford, Antoinette Amuzu, Aarno Palotie, Xiuqing Guo, Juan P. Casas, Elisabeth Widen, Pekka Jousilahti, David R. Crosslin, Dawn M. Waterworth, Richard H. Myers, Yingchang Lu, Tanja Zeller, Peter P. Pramstaller, Antti Jula, Yii-Der Ida Chen, Christina Meisinger, Paul M. Ridker, Annette Peters, Alicja A. Skowronski, Kati Kristiansson, Claire Bellis, Sara M. Willems, John-Olov Jansson, Hae-Won Uh, Fabiola Del Greco M, Daniel I. Chasman, Frida Renström, Claes Ohlsson, Robert J. Klein, Tamara B. Harris, Matthew A. Allison, Mike A. Nalls, Luigi Ferrucci, Ingrid Meulenbelt, Erik Ingelsson, Qi Sun, Gérard Waeber, Brendan M. Buckley, Anton J. N. de Craen, Niels Grarup, Joris Deelen, Susan E. Hankinson, Inês Barroso, Albert Hofman, Dan Mellström, Stefan Gustafsson, J. Brent Richards, Tune H. Pers, Stefan Söderberg, Paul Knekt, Marie-Claude Vohl, Caroline Dale, Naveed Sattar, Mark Walker, Jing Hua Zhao, Mika Kähönen, Toshiko Tanaka, Henrik Vestergaard, Diana van Heemst, Oluf Pedersen, Rudolph L. Leibel, Peter Henneman, Nancy S. Jenny, Stella Trompet, Peter Kraft, Mary F. Feitosa, Melissa E. Garcia, Pedro Marques-Vidal, Laura J. Rasmussen-Torvik, Thorkild I. A. Sørensen, André G. Uitterlinden, Claude Bouchard, Jorma Viikari, Terho Lehtimäki, Jayne F. Martin Carli, Yiying Zhang, Ruth J. F. Loos, Cristina Menni, Andrea Ioan-Facsinay, Anubha Mahajan, Satu Männistö, Karl-Heinz Ladwig, Tim D. Spector, Paul W. Franks, Marit E. Jørgensen, Christian Herder, Ursula M. Schick, Heinz-Erich Wichmann, Zari Dastani, Nicholas J. Wareham, Joop Jukema, Lynda M. Rose, Risto Huupponen, Cecilia M. Lindgren, James E. Hayes, Lavinia Paternoster, Eero Kajantie, Eric E. Schadt, Tuomas O. Kilpeläinen, Yongmei Liu, Louis Pérusse, Magnus Karlsson, Timothy M. Frayling, Charles A. LeDuc, Jari Lahti, Tiina Laatikainen, Fernando Rivadeneira, Mark A. Sarzynski, David J. Hunter, Harald Grallert, Cornelia M. van Duijn, Markku Heliövaara, Thomas Illig, Arne Astrup, Ko Willems van Dijk, Winfried März, Tom R. Gaunt, Torben Hansen, Peter Vollenweider, Erkki Vartiainen, J.C. Kwekkeboom, Francis M. Finucane, Andrew R. Wood, Marian Beekman, Ingrid B. Borecki, Jennifer Kriebel, Joel Eriksson, Zoltán Kutalik, Dena G. Hernandez, Jie Yao, Margreet Kloppenburg, Mattias Lorentzon, Johan G. Eriksson, Stefan Böhringer, Ayse Demirkan, John Blangero, Graciela E. Delgado, Treva Rice, David B. Savage, Dorota Pasko, Olli T. Raitakari, Najaf Amin, Göran Hallmans, Wolfgang Rathmann, Stefania Bandinelli, Andrew P. Morris, Aki S. Havulinna, Yolande F. M. Ramos, Jian'an Luan, Robert A. Scott, Tarunveer S. Ahluwalia, Liesbeth Vandenput, Marcus E. Kleber, Markus Perola, Aaron Isaacs, Dabeeru C. Rao, Claudia Langenberg, Aruna D. Pradhan, Torben Jørgensen, Tuomo Rankinen, Yun Ju Sung, Helsinki Collegium for Advanced Studies, Behavioural Sciences, Institute for Molecular Medicine Finland, Elisabeth Ingrid Maria Widen / Principal Investigator, University of Helsinki, Children's Hospital, Lastentautien yksikkö, Aarno Palotie / Principal Investigator, Clinicum, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Quantitative Genetics, Developmental Psychology Research Group, Genomics of Neurological and Neuropsychiatric Disorders, Genomic Discoveries and Clinical Translation, School of Medicine / Public Health, Epidemiology, Dermatology, Clinical Genetics, Internal Medicine, RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, RS: FHML MaCSBio, Biochemie, Human Genetics, Zhao, Jing Hua [0000-0003-4930-3582], Luan, Jian'an [0000-0003-3137-6337], Barroso, Ines [0000-0001-5800-4520], Day, Felix [0000-0003-3789-7651], Savage, David [0000-0002-7857-7032], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Leptin, Adipose Tissue/metabolism, Male, RNA, Messenger/genetics, Medicin och hälsovetenskap, General Physics and Astronomy, Adipose tissue, Medical and Health Sciences, Tissue Culture Techniques, chemistry.chemical_compound, Mice, Adipocyte, GENE-EXPRESSION, Genetics, INSULIN-RESISTANCE, Multidisciplinary, Leptin Deficiency, digestive, oral, and skin physiology, Public Health, Global Health, Social Medicine and Epidemiology, 3. Good health, ADIPOSE-TISSUE, FAT MASS, Adipose Tissue, Gene Knockdown Techniques, Medical Genetics, RECOMBINANT LEPTIN, hormones, hormone substitutes, and hormone antagonists, medicine.medical_specialty, SERUM LEPTIN, 515 Psychology, Science, PROVIDES INSIGHTS, WEIGHT-LOSS, Locus (genetics), Biology, General Biochemistry, Genetics and Molecular Biology, Article, Peptide hormones, 03 medical and health sciences, EARLY-ONSET OBESITY, Insulin resistance, Internal medicine, medicine, Animals, ddc:610, RNA, Messenger, Clinical genetics, Obesity, Medicinsk genetik, Leptin receptor, Gene Expression Regulation/physiology, General Chemistry, ta3121, medicine.disease, PLASMA LEPTIN, Genome-Wide Association Study, Leptin/blood, Leptin/genetics, RNA, Messenger/metabolism, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, 030104 developmental biology, Endocrinology, chemistry, Gene Expression Regulation, 3111 Biomedicine
Abstract

Article, Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P, published version, peerReviewed

Published
2016

14. Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Author

Peter Kovacs, Alan F. Wright, Stephen Turner, Michèle M. Sale, Siim Sõber, Janoš Terzić, Elin Org, Richard S. Cooper, Alena Stančáková, Jerome I. Rotter, W. H. Linda Kao, Albert Hofman, Andrew B. Singleton, Florian Kronenberg, Jianjun Liu, Nicole L. Glazer, Christopher W. Knouff, Jennifer L. Bragg-Gresham, Juha Karjalainen, Li Ching Chang, Benjamin J. Wright, Jacqueline C.M. Witteman, Martin G. Larson, Klaus Stark, Richard J. Rodeheffer, Sharon L.R. Kardia, Douglas M. Ruderfer, Sheila Ulivi, Madhumathi Rao, Andrew A. Hicks, Eva Brand, Viviane Nicaud, Stephen G. Ball, Anna Köttgen, Germaine C. Verwoert, Anders Hamsten, Nick Shrine, Uwe Völker, Stefan Kloiber, Stephen Hancock, Emelia J. Benjamin, Bok Ghee Han, Kenneth Rice, Mark Woodward, Veronique Vitart, Karl Andersen, Nicholas J. Wareham, Robert Roberts, Maja Barbalić, David Couper, Yukinori Okada, André G. Uitterlinden, Sekar Kathiresan, Leo-Pekka Lyytikäinen, Pankaj Arora, Tatijana Zemunik, David S. Siscovick, Simonetta Guarrera, Dawn M. Waterworth, Tatjana Stojakovic, Braxton D. Mitchell, Devin Absher, Carmen A. Peralta, Mika Kivimäki, Xueling Sim, Norihiro Kato, Philippe Froguel, Keith L. Keene, Donna K. Arnett, Naoyuki Kamatani, Tazeen H. Jafar, Idris Guessous, Gunnar Jacobs, Michael M. Hoffmann, Kari Stefansson, Christian Hengstenberg, Tomonori Okamura, Inga Prokopenko, Christina Willenborg, Peter S. Braund, Rainer Rettig, Francesco U.S. Mattace-Raso, Vikal Tripathy, F. Gerald R. Fowkes, Laura R. Loehr, Harry Campbell, Margherita Cavalieri, Olle Melander, Hao Mei, I. Mateo Leach, Nicholette D. Palmer, Eva Albrecht, Naoharu Iwai, Stefan Martin Brand, Toshiko Tanaka, Jackie A. Cooper, Omri Gottesman, Manuela Uda, Angelo Scuteri, Aroon D. Hingorani, Cristiano Fava, Yusuke Nakamura, Jiang He, Min Jin Go, Serge Hercberg, Wendy L. McArdle, Philipp S. Wild, Florian Ernst, Paul Mitchell, Wolfgang Koenig, Caroline S. Fox, S. J.Cathy Fann, Janine F. Felix, Anna F. Dominiczak, Mike A. Nalls, Erik Ingelsson, Mario A. Morken, Susana Eyheramendy, Christopher Newton-Cheh, Igor Rudan, D. G. Vinay, Christopher P. Nelson, Ervin R. Fox, Xiuqing Guo, Jing Hua Zhao, Rick Twee-Hee Ong, Margaret M. Redfield, Oscar H. Franco, Yongmei Liu, Fulvio Ricceri, Mark A. Hlatky, Bernhard Paulweber, Mingyao Li, Themistocles L. Assimes, Karl Winkler, Inês Barroso, Sylvia E. Rosas, M Walker, Richard W Morris, Bo Hedblad, Hakon Hakonarson, Sonny Dandona, Peter H. Whincup, Martin Adam, Vilmundur Gudnason, Daniel Ackermann, Qiong Yang, Cuno S. P. M. Uiterwaal, Paul M. Ridker, George Davey Smith, Li Chen, C. Sinning, Terri L. Young, Jer-Yuarn Wu, Walter Palmas, Will Longstreth, Joe Devaney, Pavel Hamet, Xiaofeng Zhu, Fredrik Nyberg, Wilfried Renner, Anuj Goel, L. Adrienne Cupples, Nish Chaturvedi, Iftikhar J. Kullo, Nicholas D. Hastie, Aude Saint-Pierre, Panos Deloukas, Smita R. Kulkarni, Eric Boerwinkle, Wolfram Goessling, Gian Andri Thun, Eric J.G. Sijbrands, Shih-Jen Hwang, Carole Proust, Hirotsugu Ueshima, Kristian Hveem, Pierre Meneton, Joshua C. Denny, Olivier Devuyst, Kerri L. Wiggins, Ming-Huei Chen, Robert W. Lawrence, Robert L. Wilensky, Andre Franke, Nicole Soranzo, Simon Heath, Margot Haun, Karlhans Endlich, David Altshuler, Harald Grallert, Laurence Tiret, Luigi Ferrucci, Caroline Hayward, Sudha Seshadri, Bénédicte Stengel, Lynne E. Wagenknecht, John Attia, Andreas Ziegler, Renate B. Schnabel, Stefan Schreiber, Santosh Dahgam, Kurt Lohman, Christian M. Shaffer, Barbara Ludwig, Katalin Susztak, Chien-Hsiun Chen, Michele K. Evans, Paolo Vineis, Guo Li, Thomas J. Wang, Meena Kumari, Heather M. Stringham, Bruce M. Psaty, Norman Klopp, Halit Ongen, Ben A. Oostra, Stefan Coassin, Petra Bruse, Wei-Min Chen, Unnur Thorsteinsdottir, Charles N. Rotimi, Robert J. Carroll, Muredach P. Reilly, Niek Verweij, Dena G. Hernandez, Amy J. Swift, Barbara Kollerits, Hyung Lae Kim, Cristian Pattaro, Ivana Kolcic, Ronit Katz, John M. C. 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R., Fortmann, Stephen, Go, Alan, Hlatky, Mark, Iribarren, Carlo, Knowles, Joshua, Myers, Richard, Quertermous, Thoma, Sidney, Steven, Risch, Neil, Tang, Hua, Blankenberg, Stefan, Schnabel, Renate, Sinning, Christoph, Lackner, Karl J., Tiret, Laurence, Nicaud, Viviane, Cambien, Francoi, Bickel, Christoph, Rupprecht, Hans J., Perret, Claire, Proust, Carole, Münzel, Thomas F., Barbalic, Maja, Chen, Ida Yii Der, Demissie Banjaw, Serkalem, Folsom, Aaron, Lumley, Thoma, Marciante, Kristin, Taylor, Kent D., Volcik, Kelly, Gretarsdottir, Solveig, Gulcher, Jeffrey R., Kong, Augustine, Stefansson, Kari, Thorgeirsson, Gudmundur, Andersen, Karl, Fischer, Marcu, Grosshennig, Anika, Linsel Nitschke, Patrick, Stark, Klau, Schreiber, Stefan, Aherrahrou, Zouhair, Bruse, Petra, Doering, Angela, Klopp, Norman, Diemert, Patrick, Loley, Christina, Medack, Anja, Nahrstedt, Janja, Peters, Annette, Wagner, Arnika K., Willenborg, Christina, Böhm, Bernhard O., Dobnig, Harald, Grammer, Tanja B., Hoffmann, Michael M., Meinitzer, Andrea, Winkelmann, Bernhard R., Pilz, Stefan, Renner, Wilfried, Scharnagl, Hubert, Stojakovic, Tatjana, Tomaschitz, Andrea, Winkler, Karl, Guiducci, Candace, Burtt, Noel, Gabriel, Stacey B., Dandona, Sonny, Jarinova, Olga, Qu, Liming, Wilensky, Robert, Matthai, William, Hakonarson, Hakon H., Devaney, Joe, Burnett, Mary Susan, Pichard, Augusto D., Kent, Kenneth M., Satler, Lowell, Lindsay, Joseph M., Waksman, Ron, Knouff, Christopher W., Waterworth, Dawn M., Walker, Max C., Epstein, Stephen E., Rader, Daniel J., Nelson, Christopher P., Wright, Benjamin J., Balmforth, Anthony J., Ball, Stephen G., Loehr, Laura R., Rosamond, Wayne D., Benjamin, Emelia, Haritunians, Talin, Couper, David, Murabito, Joanne, Wang, Ying A., Stricker, Bruno H., Chang, Patricia P., Willerson, James T., Felix, Stephan B., Watzinger, Norbert, Aragam, Jayashri, Zweiker, Robert, Lind, Lar, Rodeheffer, Richard J., Greiser, Karin Halina, Deckers, Jaap W., Stritzke, Jan, Ingelsson, Erik, Kullo, Iftikhar, Haerting, Johanne, Reffelmann, Thorsten, Redfield, Margaret M., Werdan, Karl, Mitchell, Gary F., Arnett, Donna K., Gottdiener, John S., Blettner, Maria, Friedrich, Nele, Kovacs, Peter, Wild, Philipp S., Froguel, Philippe, Rettig, Rainer, Mägi, Reedik, Biffar, Reiner, Schmidt, Reinhold, Middelberg, Rita P. S., Carroll, Robert J., Penninx, Brenda W., Scott, Rodney J., Katz, Ronit, Sedaghat, Sanaz, Wild, Sarah H., Kardia, Sharon L. R., Ulivi, Sheila, Hwang, Shih Jen, Enroth, Stefan, Kloiber, Stefan, Trompet, Stella, Stengel, Benedicte, Hancock, Stephen J., Turner, Stephen T., Rosas, Sylvia E., Stracke, Sylvia, Harris, Tamara B., Zeller, Tanja, Zemunik, Tatijana, Lehtimäki, Terho, Illig, Thoma, Aspelund, Thor, Nikopensius, Tiit, Esko, Tonu, Tanaka, Toshiko, Gyllensten, Ulf, Völker, Uwe, Emilsson, Valur, Vitart, Veronique, Aalto, Ville, Gudnason, Vilmundur, Chouraki, Vincent, Chen, Wei Min, Igl, Wilmar, März, Winfried, Koenig, Wolfgang, Lieb, Wolfgang, Loos, Ruth J. F., Liu, Yongmei, Snieder, Harold, Pramstaller, Peter P., Parsa, Afshin, O'Connell, Jeffrey R., Susztak, Katalin, Hamet, Pavel, Tremblay, Johanne, De Boer, Ian H., Böger, Carsten A., Goessling, Wolfram, Chasman, Daniel I., Köttgen, Anna, Kao, W. H. Linda, Fox, Caroline S., RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, Biochemie, RS: FHML MaCSBio, Ehret, Georg Benedikt, Guessous, Idris, Gaspoz, Jean-Michel, Life Course Epidemiology (LCE), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Polymer Chemistry and Bioengineering, Value, Affordability and Sustainability (VALUE), Stem Cell Aging Leukemia and Lymphoma (SALL), Epidemiology, Public Health, Internal Medicine, Clinical Genetics, Erasmus MC other, Genetic Identification, ICBP Consortium, AGEN Consortium, CHARGe-Heart Failure Group, ECHOGen Consortium, CARDIOGRAM, Abecasis, GR., Adair, LS., Alexander, M., Altshuler, D., Amin, N., Arking, DE., Arora, P., Aulchenko, Y., Bakker, SJ., Bandinelli, S., Barroso, I., Beckmann, JS., Beilby, JP., Bergman, RN., Bergmann, S., Bis, JC., Boehnke, M., Bonnycastle, LL., Bornstein, SR., Bots, ML., Bragg-Gresham, JL., Brand, SM., Brand, E., Braund, PS., Brown, MJ., Burton, PR., Casas, JP., Caulfield, MJ., Chakravarti, A., Chambers, JC., Chandak, GR., Chang, YP., Charchar, FJ., Chaturvedi, N., Shin Cho, Y., Clarke, R., Collins, FS., Collins, R., Connell, JM., Cooper, JA., Cooper, MN., Cooper, RS., Corsi, AM., Dörr, M., Dahgam, S., Danesh, J., Davey Smith, G., Day, IN., Deloukas, P., Denniff, M., Dominiczak, AF., Dong, Y., Doumatey, A., Elliott, P., Elosua, R., Erdmann, J., Eyheramendy, S., Farrall, M., Fava, C., Forrester, T., Fowkes, FG., Fox, ER., Frayling, TM., Galan, P., Ganesh, SK., Garcia, M., Gaunt, TR., Glazer, NL., Go, MJ., Goel, A., Grässler, J., Grobbee, DE., Groop, L., Guarrera, S., Guo, X., Hadley, D., Hamsten, A., Han, BG., Hardy, R., Hartikainen, AL., Heath, S., Heckbert, SR., Hedblad, B., Hercberg, S., Hernandez, D., Hicks, AA., Hilton, G., Hingorani, AD., Bolton, JA., Hopewell, JC., Howard, P., Humphries, SE., Hunt, SC., Hveem, K., Ikram, MA., Islam, M., Iwai, N., Jarvelin, MR., Jackson, AU., Jafar, TH., Janipalli, CS., Johnson, T., Kathiresan, S., Khaw, KT., Kim, HL., Kinra, S., Kita, Y., Kivimaki, M., Kooner, JS., Kumar, MJ., Kuh, D., Kulkarni, SR., Kumari, M., Kuusisto, J., Kuznetsova, T., Laakso, M., Laan, M., Laitinen, J., Lakatta, EG., Langefeld, CD., Larson, MG., Lathrop, M., Lawlor, DA., Lawrence, RW., Lee, JY., Lee, NR., Levy, D., Li, Y., Longstreth, WT., Luan£££Jian'an£££ J., Lucas, G., Ludwig, B., Mangino, M., Mani, KR., Marmot, MG., Mattace-Raso, FU., Matullo, G., McArdle, WL., McKenzie, CA., Meitinger, T., Melander, O., Meneton, P., Meschia, JF., Miki, T., Milaneschi, Y., Mohlke, KL., Mooser, V., Morken, MA., Morris, RW., Mosley, TH., Najjar, S., Narisu, N., Newton-Cheh, C., Nguyen, KD., Nilsson, P., Nyberg, F., O'Donnell, CJ., Ogihara, T., Ohkubo, T., Okamura, T., Ong, RT., Ongen, H., Onland-Moret, NC., O'Reilly, PF., Org, E., Orru, M., Palmas, W., Palmen, J., Palmer, LJ., Palmer, ND., Parker, AN., Peden, JF., Peltonen, L., Perola, M., Pihur, V., Platou, CG., Plump, A., Prabhakaran, D., Psaty, BM., Raffel, LJ., Rao, DC., Rasheed, A., Ricceri, F., Rice, KM., Rosengren, A., Rotter, JI., Rudock, ME., Sõber, S., Salako, T., Saleheen, D., Salomaa, V., Samani, NJ., Schwartz, SM., Schwarz, PE., Scott, LJ., Scott, J., Scuteri, A., Sehmi, JS., Seielstad, M., Seshadri, S., Sharma, P., Shaw-Hawkins, S., Shi, G., Shrine, NR., Sijbrands, EJ., Sim, X., Singleton, A., Sjögren, M., Smith, NL., Soler Artigas, M., Spector, TD., Staessen, JA., Stancakova, A., Steinle, NI., Strachan, DP., Stringham, HM., Sun, YV., Swift, AJ., Tabara, Y., Tai, ES., Talmud, PJ., Taylor, A., Terzic, J., Thelle, DS., Tobin, MD., Tomaszewski, M., Tripathy, V., Tuomilehto, J., Tzoulaki, I., Uda, M., Ueshima, H., Uiterwaal, CS., Umemura, S., van der Harst, P., van der Schouw YT., van Gilst WH., Vartiainen, E., Vasan, RS., Veldre, G., Verwoert, GC., Viigimaa, M., Vinay, DG., Vineis, P., Voight, BF., Vollenweider, P., Wagenknecht, LE., Wain, LV., Wang, X., Wang, TJ., Wareham, NJ., Watkins, H., Weder, AB., Whincup, PH., Wiggins, KL., Witteman, JC., Wong, A., Wu, Y., Yajnik, CS., Yao, J., Young, JH., Zelenika, D., Zhai, G., Zhang, W., Zhang, F., Zhao, JH., Zhu, H., Zhu, X., Zitting, P., Zukowska-Szczechowska, E., Okada, Y., Wu, JY., Gu, D., Takeuchi, F., Takahashi, A., Maeda, S., Tsunoda, T., Chen, P., Lim, SC., Wong, TY., Liu, J., Young, TL., Aung, T., Teo, YY., Kim, YJ., Kang, D., Chen, CH., Tsai, FJ., Chang, LC., Fann, SJ., Mei, H., Hixson, JE., Chen, S., Katsuya, T., Isono, M., Albrecht, E., Yamamoto, K., Kubo, M., Nakamura, Y., Kamatani, N., Kato, N., He, J., Chen, YT., Tanaka, T., Reilly, MP., Schunkert, H., Assimes, TL., Hall, A., Hengstenberg, C., König, IR., Laaksonen, R., McPherson, R., Thompson, JR., Thorsteinsdottir, U., Ziegler, A., Absher, D., Chen, L., Cupples, LA., Halperin, E., Li, M., Musunuru, K., Preuss, M., Schillert, A., Thorleifsson, G., Wells, GA., Holm, H., Roberts, R., Stewart, AF., Fortmann, S., Go, A., Hlatky, M., Iribarren, C., Knowles, J., Myers, R., Quertermous, T., Sidney, S., Risch, N., Tang, H., Blankenberg, S., Schnabel, R., Sinning, C., Lackner, KJ., Tiret, L., Nicaud, V., Cambien, F., Bickel, C., Rupprecht, HJ., Perret, C., Proust, C., Münzel, TF., Barbalic, M., Chen, IY., Demissie-Banjaw, S., Folsom, A., Lumley, T., Marciante, K., Taylor, KD., Volcik, K., Gretarsdottir, S., Gulcher, JR., Kong, A., Stefansson, K., Thorgeirsson, G., Andersen, K., Fischer, M., Grosshennig, A., Linsel-Nitschke, P., Stark, K., Schreiber, S., Aherrahrou, Z., Bruse, P., Doering, A., Klopp, N., Diemert, P., Loley, C., Medack, A., Nahrstedt, J., Peters, A., Wagner, AK., Willenborg, C., Böhm, BO., Dobnig, H., Grammer, TB., Hoffmann, MM., Meinitzer, A., Winkelmann, BR., Pilz, S., Renner, W., Scharnagl, H., Stojakovic, T., Tomaschitz, A., Winkler, K., Guiducci, C., Burtt, N., Gabriel, SB., Dandona, S., Jarinova, O., Qu, L., Wilensky, R., Matthai, W., Hakonarson, HH., Devaney, J., Burnett, MS., Pichard, AD., Kent, KM., Satler, L., Lindsay, JM., Waksman, R., Knouff, CW., Waterworth, DM., Walker, MC., Epstein, SE., Rader, DJ., Nelson, CP., Wright, BJ., Balmforth, AJ., Ball, SG., Loehr, LR., Rosamond, WD., Benjamin, E., Haritunians, T., Couper, D., Murabito, J., Wang, YA., Stricker, BH., Chang, PP., Willerson, JT., Felix, SB., Watzinger, N., Aragam, J., Zweiker, R., Lind, L., Rodeheffer, RJ., Greiser, KH., Deckers, JW., Stritzke, J., Ingelsson, E., Kullo, I., Haerting, J., Reffelmann, T., Redfield, MM., Werdan, K., Mitchell, GF., Arnett, DK., Gottdiener, JS., Blettner, M., and Friedrich, N.

Subjects
0301 basic medicine, Nephrology, Genetics and Molecular Biology (all), estimated glomerular filtration rate, estimated glomerular filtration rate, chronic kidney disease, genetic determinants, General Physics and Astronomy, Kidney development, Genome-wide association study, Biochemistry, Settore MED/14 - NEFROLOGIA, Renal Insufficiency, Chronic, Genetics, AGEN Consortium, ddc:616, education.field_of_study, Kidney, Stage renal-disease, Multidisciplinary, Genome-wide association, CHARGe-Heart Failure Group, Gene Expression Regulation, Genome-Wide Association Study, Genotype, Humans, Renal Insufficiency, Chronic, Genetic Predisposition to Disease, Biochemistry, Genetics and Molecular Biology (all), Chemistry (all), Physics and Astronomy (all), Metaanalysis, Renal Insufficiency, Chronic/genetics, Biological sciences, Serum creatinine, medicine.anatomical_structure, Efficient, Ronyons -- Fisiologia, Hypertension, ICBP Consortium, Transmembrane transporter activity, genetic association, loci, kidney function, CARDIOGRAM, Human, medicine.medical_specialty, Science, Population, Renal function, ECHOGen Consortium, Replication, Biology, Environment, Research Support, General Biochemistry, Genetics and Molecular Biology, N.I.H, genetic determinants, 03 medical and health sciences, GENOME-WIDE ASSOCIATION, FALSE DISCOVERY RATES, STAGE RENAL-DISEASE, SERUM CREATININE, METAANALYSIS, VARIANTS, INDIVIDUALS, POPULATION, RISK, HYPERTENSION, Kidney function, Research Support, N.I.H., Extramural, Internal medicine, MD Multidisciplinary, medicine, Journal Article, eGFRcrea, eGFRcys, ddc:610, Genetik, Mortality, education, ddc:613, urogenital system, Individuals, Extramural, General Chemistry, ta3121, medicine.disease, R1, 030104 developmental biology, 570 Life sciences, biology, Genètica, chronic kidney disease, Kidney disease, Meta-Analysis
Abstract

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. J.T. and P.H. are consultants for Servier. J.C. received research grants and honoraria from Servier. K.S. obtained research support from Boehringer Ingelheim. The remaining authors declared no competing financial interests.

Published
2016

15. A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance

Author

John R. B. Perry, James B. Meigs, José Dupuis, Luigi Ferrucci, Johan G. Eriksson, Vilmundur Gudnason, Eric J.G. Sijbrands, Jeanette S. Andrews, Jonna L. Grimsby, Lawrence F. Bielak, Peter Kovacs, Panos Deloukas, Marijana Peričić, Johannes H. Smit, Ruth J. F. Loos, Gonneke Willemsen, Eric Boerwinkle, Ben A. Oostra, Manuel Serrano-Ríos, Alena Stančáková, Meena Kumari, Antti Jula, Michael Marmot, Caroline S. Fox, Simon Heath, Guo Li, Ola Hansson, Gerard Waeber, Anne U. Jackson, Nicholas L. Smith, Markku Laakso, George Dedoussis, Aarno Palotie, Sara M. Willems, John F. Peden, Elisabeth Widen, Caroline Hayward, Alan F. Wright, Claes Ladenvall, May E. Montasser, María Teresa Martínez-Larrad, Peter Vollenweider, Louis Pérusse, Tamara B. Harris, Wen Hong L. Kao, Danijela Budimir, Denis Rybin, David B. Savage, Michael A. Province, Alisa K. Manning, Bruna Gigante, Najaf Amin, Lenore J. Launer, Naveed Sattar, Lori L. Bonnycastle, Göran Hallmans, Jeffrey R. O'Connell, Stéphane Lobbens, Jacques S. Beckmann, Gemma Cadby, J. Wouter Jukema, Maria Dimitriou, Michael Stumvoll, Max Vikström, Rona J. Strawbridge, Hugh Watkins, Lyle J. Palmer, Johanna Kuusisto, Aimo Ruokonen, Hanieh Yaghootkar, Yan V. Sun, Inês Barroso, Amy J. Swift, Nancy L. Pedersen, Lars Lind, Mladen Boban, Nita G. Forouhi, Ken K. Ong, Ivana Kolcic, Anke Tönjes, Timothy M. Frayling, Paul W. Franks, Narisu Narisu, Karin Leander, Serge Hercberg, Diana Zelenika, Sharon L.R. Kardia, Min A. Jhun, Marjo-Riitta Järvelin, Stella Trompet, Jaakko Kaprio, Toshiko Tanaka, David S. Siscovick, Toby Johnson, Cornelia M. van Duijn, Veikko Salomaa, Jose C. Florez, James F. Wilson, Leena Peltonen, Pilar Galan, Robert Clarke, Andrew A. Hicks, Claudia Langenberg, Anders Hamsten, David Couper, Albert Hofman, Dawn M. Waterworth, John Blangero, James S. Pankow, Nabila Bouatia-Naji, Sirkka Keinänen-Kiukaanniemi, Mark I. McCarthy, Valeriya Lyssenko, Leif Groop, Brenda W.J.H. Penninx, Ching-Ti Liu, Anuj Goel, Marina Pehlić, Michael Boehnke, Mika Kivimäki, Maria Sabater-Lleal, Emil Rehnberg, Ingrid B. Borecki, Ozren Polasek, Eco J. C. de Geus, Peter P. Pramstaller, Igor Rudan, Richard M. Watanabe, Pierre Meneton, Iva Miljkovic, Vincent Mooser, G. Mark Lathrop, John Beilby, Laura J. Rasmussen-Torvik, Arturo Corbató-Anchuelo, Yvonne Böttcher, Richard N. Bergman, Daniel R. Barnes, Paul C. D. Johnson, Mustafa Atalay, Aroon D. Hingorani, Olga D. Carlson, Perttu Salo, Jacqueline C.M. Witteman, Udo Seedorf, Timo Saaristo, Jian'an Luan, Nicholas J. Wareham, Gudny Eiriksdottir, Matti Uusitupa, Yongmei Liu, Jaakko Tuomilehto, Yurii S. Aulchenko, Peter Schwarz, Robert A. Scott, Lina Zgaga, Joseph Hung, Reedik Mägi, Maria Grazia Franzosi, Eric J. Brunner, Claude Bouchard, Ian Ford, Francis S. Collins, Ulf de Faire, Benjamin F. Voight, Erik Ingelsson, Mario A. Morken, Stefania Bandinelli, Nicole L. Glazer, Dmitry Shungin, Lars Lannfelt, André G. Uitterlinden, Tatijana Zemunik, Markus Perola, Kenneth Rice, Veronique Vitart, Kerrin S. Small, Jouke-Jan Hottenga, Han Chen, Jerome I. Rotter, Philippe Froguel, Karen L. Mohlke, Marie-Claude Vohl, Dorret I. Boomsma, Harry Campbell, Peter S. Chines, Pau Navarro, Vasiliki Lagou, Albert V. Smith, Kathleen Stirrups, Josephine M. Egan, Alan R. Shuldiner, Katri Räikkönen, Inga Prokopenko, Ping An, Rainer Rauramaa, Beverley Balkau, Thor Aspelund, Eleanor Wheeler, Mariza de Andrade, Richa Saxena, Jari Lahti, Cécile Lecoeur, Timo A. Lakka, Jennie Hui, Michael R. Erdos, Stavroula Kanoni, Kirsten Ohm Kyvik, Bengt Sennblad, Sarah H. Wild, Patricia A. Peyser, Patrik K. E. Magnusson, Claire Bellis, Elodie Eury, Jaana Lindström, Boston University [Boston] (BU), Broad Institute of Harvard and MIT, Partenaires INRAE, Massachusetts General Hospital, Massachusetts General Hospital [Boston], Department of Genetics [Boston], Harvard Medical School [Boston] (HMS), Department of Medicine, Université de Sherbrooke (UdeS), Addenbrooke's Hospital, Harvard Medical School [Boston] (HMS)-Beth Israel Deaconess Medical Center [Boston] (BIDMC), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Université Lille Nord de France (COMUE), Department of Epidemiology, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System-Center for Social Epidemiology and Population Health, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford [Oxford], The Wellcome Trust Centre for Human Genetics [Oxford], The Netherlands Cancer Institute, Ontario Institute for Cancer Research, Mount Sinai Hospital [Toronto, Canada] (MSH), VU University Amsterdam, Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], University of Michigan System, Queen Mary University of London (QMUL), The Wellcome Trust Sanger Institute [Cambridge], Lund University [Lund], Diabetes Centre, Lund University, University of Helsinki, Wake Forest School of Medicine, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, University of Maryland School of Medicine, University of Maryland System, University of Edinburgh, University of Exeter, Department of Twin Research and Genetic Epidemiology, King's College London, London, Northwestern University [Evanston], National Institute of Health and Welfare, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Lund University Diabetes Centre, Umeå University, National Institutes of Health, Centre for Medical Systems Biology, Netherlands Genomics Initiative, Washington University in Saint Louis (WUSTL), Department of Health Sciences Research, Mayo Clinic, Wake Forest University, Icelandic Heart Association, Heart Preventive Clinic and Research Institute, University of Iceland, Institute of Biomedicine, Physiology, University of Eastern Finland, Institut National de la Santé et de la Recherche Médicale (INSERM), UMR S 1018, Université Paris-Sud - Paris 11 (UP11), Azienda Sanitaria Firenze, Department of Medical Genetics, Université de Lausanne (UNIL), Centre Hospitalier Universitaire Vaudois (CHUV), Queen Elizabeth II Medical Centre, Research Institute, University of Southern California (USC), University of Split, The University of Texas Health Science Center at Houston (UTHealth), Leipzig University, Pennington Biomedical Research Center, Department of Epidemiology & Public Health, University College of London [London] (UCL), San Carlos Clinical Hospital, University of North Carolina, Harokopio University, National Institute on Aging, Folkhälsan Research Centre, Vaasa Central Hospital, Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Psychiatry, EMGO - Lifestyle, overweight and diabetes, Epidemiology, Immunology, Erasmus School of Social and Behavioural Sciences, Clinical Genetics, Ophthalmology, Internal Medicine, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Multiple Tissue Human Expression Resource (MUTHER) Consortium, Ahmadi, K.R., Ainali, C., Barrett, A., Bataille, V., Bell, J.T., Buil, A., Deloukas, P., Dermitzakis, E.T., Dimas, A.S., Durbin, R., Glass, D., Grundberg, E., Hassanali, N., Hedman, Å.K., Ingle, C., Knowles, D., Krestyaninova, M., Lindgren, C.M., Lowe, C.E., McCarthy, M.I., Meduri, E., di Meglio, P., Min, J.L., Montgomery, S.B., Nestle, F.O., Nica, A.C., Nisbet, J., O'Rahilly, S., Parts, L., Potter, S., Sekowska, M., Shin, S.Y., Small, K.S., Soranzo, N., Spector, T.D., Surdulescu, G., Travers, M.E., Tsaprouni, L., Tsoka, S., Wilk, A., Yang, T.P., Zondervan, K.T., Voight, B.F., Scott, L.J., Steinthorsdottir, V., Morris, A.P., Dina, C., Welch, R.P., Zeggini, E., Huth, C., Aulchenko, Y.S., Thorleifsson, G., McCulloch, L.J., Ferreira, T., Grallert, H., Amin, N., Wu, G., Willer, C.J., Raychaudhuri, S., McCarroll, S.A., Langenberg, C., Hofmann, O.M., Dupuis, J., Qi, L., Segrè, A.V., van Hoek, M., Navarro, P., Ardlie, K., Balkau, B., Benediktsson, R., Bennett, A.J., Blagieva, R., Boerwinkle, E., Bonnycastle, L.L., Boström, K.B., Bravenboer, B., Bumpstead, S., Burtt, N.P., Charpentier, G., Chines, P.S., Cornelis, M., Couper, D.J., Crawford, G., Doney, A.S., Elliott, K.S., Elliott, A.L., Erdos, M.R., Fox, C.S., Franklin, C.S., Ganser, M., Gieger, C., Grarup, N., Green, T., Griffin, S., Groves, C.J., Guiducci, C., Hadjadj, S., Herder, C., Isomaa, B., Jackson, A.U., Johnson, P.R., Jørgensen, T., Kao, W.H., Klopp, N., Kong, A., Kraft, P., Kuusisto, J., Lauritzen, T., Li, M., Lieverse, A., Lyssenko, V., Marre, M., Meitinger, T., Midthjell, K., Morken, M.A., Narisu, N., Nilsson, P., Owen, K.R., Payne, F., Perry, J.R., Petersen, A.K., Platou, C., Proença, C., Prokopenko, I., Rathmann, W., Rayner, N.W., Robertson, N.R., Rocheleau, G., Roden, M., Sampson, M.J., Saxena, R., Shields, B.M., Shrader, P., Sigurdsson, G., Sparsø, T., Strassburger, K., Stringham, H.M., Sun, Q., Swift, A.J., Thorand, B., Tichet, J., Tuomi, T., van Dam, R.M., van Haeften, T.W., van Herpt, T., van Vliet-Ostaptchouk, J.V., Walters, G.B., Weedon, M.N., Wijmenga, C., Witteman, J., Bergman, R.N., Cauchi, S., Collins, F.S., Gloyn, A.L., Gyllensten, U., Hansen, T., Hide, W.A., Hitman, G.A., Hofman, A., Hunter, D.J., Hveem, K., Laakso, M., Mohlke, K.L., Morris, A.D., Palmer, C.N., Pramstaller, P.P., Rudan, I., Sijbrands, E., Stein, L.D., Tuomilehto, J., Uitterlinden, A., Walker, M., Wareham, N.J., Watanabe, R.M., Abecasis, G.R., Boehm, B.O., Campbell, H., Daly, M.J., Hattersley, A.T., Hu, F.B., Meigs, J.B., Pankow, J.S., Pedersen, O., Wichmann, H.E., Barroso, I., Florez, J.C., Frayling, T.M., Groop, L., Sladek, R., Thorsteinsdottir, U., Wilson, J.F., Illig, T., Froguel, P., van Duijn, C.M., Stefansson, K., Altshuler, D., Boehnke, M., Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA)

Subjects
Blood Glucose, Netherlands Twin Register (NTR), medicine.medical_treatment, [SDV]Life Sciences [q-bio], LOCI, Genome-wide association study, Type 2 diabetes, SUSCEPTIBILITY, Body Mass Index, GLUCOSE, Blood Glucose/metabolism, Cholesterol, HDL/metabolism, Diabetes Mellitus, Type 2/genetics, Genome-Wide Association Study, Humans, Insulin/metabolism, Insulin Resistance/genetics, Polymorphism, Single Nucleotide, 0302 clinical medicine, Insulin, 2. Zero hunger, Genetics, 0303 health sciences, COMMON VARIANTS, 3. Good health, ENVIRONMENT INTERACTION, OBESITY, CORONARY-ARTERY-DISEASE, medicine.medical_specialty, 030209 endocrinology & metabolism, Accounting, Biology, Article, 03 medical and health sciences, Insulin resistance, SDG 3 - Good Health and Well-being, Internal medicine, Diabetes mellitus, medicine, 030304 developmental biology, Genetic association, Glycemic, loci, SNP, insulin, business.industry, Cholesterol, HDL, medicine.disease, Obesity, POLYMORPHISM, ASSOCIATION ANALYSIS, Endocrinology, Diabetes Mellitus, Type 2, TYPE-2 DIABETES RISK, Insulin Resistance, business
Abstract

Group Authors : DIAGRAM Consortium MUTHER Consortium variants influencing fasting glycemic traits and insulin resistance Seuls les 100 premiers auteurs ont été conservés dans la publication. La liste complète des auteurs et des des affiliations est disponible sur la publication https://www.nature.com/articles/ng.2274.pdf p. 667-669.; International audience; Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and beta-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 x 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.

Published
2012

16. Novel method to estimate the phenotypic variation explained by genome-wide association studies reveals large fraction of the missing heritability

Author

Jacques S. Beckmann, Zoltán Kutalik, Sven Bergmann, Dawn M. Waterworth, and John C. Whittaker

Subjects
False discovery rate, Epidemiology, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Body Mass Index, 03 medical and health sciences, Meta-Analysis as Topic, Missing heritability problem, Genetic variation, Statistics, Humans, Genetics (clinical), 030304 developmental biology, Genetic association, Likelihood Functions, 0303 health sciences, Models, Statistical, Models, Genetic, Waist-Hip Ratio, 030305 genetics & heredity, Genetic Variation, Explained variation, Body Height, Phenotype, Sample size determination, Allelic heterogeneity, Genome-Wide Association Study
Abstract

Genome-wide association studies (GWAS) are conducted with the promise to discover novel genetic variants associated with diverse traits. For most traits, associated markers individually explain just a modest fraction of the phenotypic variation, but their number can well be in the hundreds. We developed a maximum likelihood method that allows us to infer the distribution of associated variants even when many of them were missed by chance. Compared to previous approaches, the novelty of our method is that it (a) does not require having an independent (unbiased) estimate of the effect sizes; (b) makes use of the complete distribution of P-values while allowing for the false discovery rate; (c) takes into account allelic heterogeneity and the SNP pruning strategy. We applied our method to the latest GWAS meta-analysis results of the GIANT consortium. It revealed that while the explained variance of genome-wide (GW) significant SNPs is around 1% for waist-hip ratio (WHR), the observed P-values provide evidence for the existence of variants explaining 10% (CI=[8.5-11.5%]) of the phenotypic variance in total. Similarly, the total explained variance likely to exist for height is estimated to be 29% (CI=[28-30%]), three times higher than what the observed GW significant SNPs give rise to. This methodology also enables us to predict the benefit of future GWA studies that aim to reveal more associated genetic markers via increased sample size.

Published
2011

17. Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption

Author

Michiel L. Bots, Georgy Bakalkin, Claire Troakes, Gérard Waeber, Anna-Liisa Hartikainen, Danielle M. Dick, Kay-Tee Khaw, Stéphane Cauchi, Toni-Kim Clarke, Jian'an Luan, Jaakko Kaprio, Charlotte Onland-Moret, Yurii S. Aulchenko, Wolfgang H. Sommer, Ben A. Oostra, Alberto Fernández-Medarde, Jouke-Jan Hottenga, Kari Stefansson, Angela Doering, Lachlan J. M. Coin, Kijoung Song, Ida Surakk, Sylvane Desrivières, Pimphen Charoen, Nicholas G. Martin, Jacqueline C.M. Witteman, John C. Chambers, Tim D. Spector, Stéphane Lobbens, Guangju Zhai, Peter Vollenweider, David Stacey, Anbarasu Lourdusamy, Ulrike Heberlein, Victor Hesselbrock, Leena Peltonen, James Scott, Miklós Palkovits, Albert Hofman, Xin Yuan, Cornelia M. van Duijn, Gunter Schumann, Yvonne T. van der Schouw, Nicole Vogelzangs, Nicole Soranzo, Paul Elliott, Brenda W.J.H. Penninx, Nicholas J. Wareham, Eugenio Santos, Silvia Polidoro, Diederick E. Grobbee, Norbert Dahmen, Daniel F. Gudbjartsson, Dorret I. Boomsma, Rainer Spanagel, Oliver Staehlin, Anke Tönjes, Matthieu Maroteaux, Ainhoa Bilbao, Eco J. C. de Geus, Francesca Ducci, Vincent Mooser, Mark I. McCarthy, Paolo Vineis, Christine Cavalcanti-Proença, Weihua Zhang, Nelson B. Freimer, Ruth J. F. Loos, Andres Metspalu, Tatiana Foroud, Rudolf A. de Boer, Thorarinn Tyrfingsson, Anneli Pouta, Beverley Balkau, Matti Isohanni, Paul F. O'Reilly, Massimo Mangino, Stephan J. L. Bakker, Elemi J. Breetvelt, Marjo-Riitta Järvelin, Tõnu Esko, Inga Prokopenko, Delphine Beury, Erich Wichmann, Gerjan Navis, Jaana Laitinen, John Whitfield, Karen H. Berger, Thorgeir E. Thorgeirsson, Alanna C. Easton, Brigitte Kuehnel, Ulla Sovio, Cuno S.P.M. Uiterwaal, Unnur Thorsteinsdottir, Fazil Aliev, Najaf Amin, Dale R. Nyholt, Alejandro Núñez, Dawn M. Waterworth, Mattijs E. Numans, Pim van der Harst, Michael Stumvoll, Howard J. Edenberg, Johannes H. Smit, Gonneke Willemsen, Andrew C. Heath, Simonetta Guarrera, Fulvio Ricceri, Joline W.J. Beulens, Giuseppe Matullo, Anokhi Ali Khan, Jean-Antoine Girault, Christian Mueller, Jaspal S. Kooner, André G. Uitterlinden, Jing Hua Zhao, Cardiovascular Centre (CVC), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Epidemiology, Clinical Genetics, Internal Medicine, Psychiatry, EMGO - Mental health, NCA - Attention & Cognition, NCA - Anxiety & Depression, Biological Psychology, Neuroscience Campus Amsterdam - Anxiety & Depression, Neuroscience Campus Amsterdam - Attention & Cognition, and EMGO+ - Mental Health

Subjects
Netherlands Twin Register (NTR), alcohol consumption, Population, autism, Single-nucleotide polymorphism, Genome-wide association study, genome-wide analysis, epidemiologic, transcriptional expression analysis, Biology, Quantitative trait locus, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, ADDICTIVE BEHAVIOR, DEPENDENCE, Genotype, medicine, SNP, education, Genotyping, 030304 developmental biology, Genetics, 0303 health sciences, education.field_of_study, Multidisciplinary, MEN, Alcohol Drinking/genetics, Alcohol Drinking/metabolism, Animals, Drosophila melanogaster/genetics, Drosophila melanogaster/metabolism, European Continental Ancestry Group/genetics, Female, Gene Expression Regulation/genetics, Genome-Wide Association Study, Humans, Male, Mice, Nuclear Proteins/biosynthesis, Nuclear Proteins/genetics, Polymorphism, Single Nucleotide, Proteins/genetics, Proteins/metabolism, Quantitative Trait, Heritable, Biological Sciences, medicine.disease, GENOTYPES, 3. Good health, DROSOPHILA, Autism, 030217 neurology & neurosurgery
Abstract

Alcohol consumption is a moderately heritable trait, but the genetic basis in humans is largely unknown, despite its clinical and societal importance. We report a genome-wide association study meta-analysis of ∼2.5 million directly genotyped or imputed SNPs with alcohol consumption (gram per day per kilogram body weight) among 12 population-based samples of European ancestry, comprising 26,316 individuals, with replication genotyping in an additional 21,185 individuals. SNP rs6943555 in autism susceptibility candidate 2 gene ( AUTS2 ) was associated with alcohol consumption at genome-wide significance ( P = 4 × 10 −8 to P = 4 × 10 −9 ). We found a genotype-specific expression of AUTS2 in 96 human prefrontal cortex samples ( P = 0.026) and significant ( P < 0.017) differences in expression of AUTS2 in whole-brain extracts of mice selected for differences in voluntary alcohol consumption. Down-regulation of an AUTS2 homolog caused reduced alcohol sensitivity in Drosophila ( P < 0.001). Our finding of a regulator of alcohol consumption adds knowledge to our understanding of genetic mechanisms influencing alcohol drinking behavior.

Published
2011

18. Hundreds of variants clustered in genomic loci and biological pathways affect human height

Author

Vilmundur Gudnason, Robert J. Weyant, Robert C. Kaplan, Jeffrey R. O'Connell, Panos Deloukas, Barbara McKnight, Alessandro De Grandi, Gert-Jan B. van Ommen, Eric Boerwinkle, Liming Liang, Douglas F. Levinson, Richard B. Hayes, Mark I. McCarthy, Andrew P. Morris, Joel N. Hirschhorn, Jaakko Kaprio, Nilesh J. Samani, Inke R. König, Frank B. Hu, Nicholas J. Wareham, Ozren Polasek, Michael C. Turchin, Daniel F. Gudbjartsson, Wilmar Igl, Vincent Mooser, Aki S. Havulinna, Themistocles L. Assimes, Cameron D. Palmer, Lachlan J. M. Coin, Eva Albrecht, Hana Lango Allen, Inês Barroso, Eco J. C. de Geus, H.-Erich Wichmann, Michael A. Province, Sarah H. Wild, Patricia B. Munroe, Jeanette Erdmann, Mattias Lorentzon, Michael Preuss, Nelson B. Freimer, Mika Kähönen, Tushar Bhangale, Nicole L. Glazer, Markku S. Nieminen, Andrew A. Hicks, Jonathan Tyrer, Grant W. Montgomery, Ruth J. F. Loos, Shaun Purcell, Manfred Kayser, Marjo-Riitta Järvelin, Guillaume Paré, Terho Lehtimäki, Irene Pichler, Ida Surakka, Tõnu Esko, Peter Kraft, Talin Haritunians, Juha Sinisalo, Mari Nelis, Veronique Vitart, Alan R. Sanders, Alistair S. Hall, Carlos Iribarren, Mark E. Cooper, André G. Uitterlinden, Peter Kovacs, David Schlessinger, Florian Ernst, Marja-Liisa Lokki, M. Juhani Junttila, Martin Ridderstråle, Jorma Viikari, Inga Prokopenko, Christopher J. O'Donnell, Jennie Hui, Aila Rissanen, Gonçalo R. Abecasis, Jouke-Jan Hottenga, Tomi Pastinen, Kevin B. Jacobs, Jan Smit, Kristin G. Ardlie, Niina Pellikka, Neil R. Robertson, Martina Müller, John F. Peden, Mary F. Feitosa, Thomas W. Winkler, Kari Stefansson, Jianjun Liu, Jaana Laitinen, Shen Haiqing, Martin Farrall, Nilanjan Chatterjee, Eleanor Wheeler, Tamara B. Harris, Åsa Johansson, Anders Hamsten, Elizabeth K. Speliotes, Larry D. Atwood, Valgerdur Steinthorsdottir, Elin Grundberg, Nicole Soranzo, Anna-Liisa Hartikainen, Devin Absher, Cecilia M. Lindgren, Rany M. Salem, Lorena Citterio, Karol Estrada, Sven Bergmann, Tony Kwan, Thomas Meitinger, Alan F. Wright, Richard N. Bergman, Sailaja Vedantam, Kirsi H. Pietiläinen, Lina Zgaga, Anne U. Jackson, Stefan Schreiber, Ju-Hyun Park, Nicola Glorioso, Jianxin Shi, Najaf Amin, Dale R. Nyholt, Lenore J. Launer, Heribert Schunkert, Thomas Quertermous, Mari Liis Tammesoo, Dorret I. Boomsma, Harry Campbell, Albert V. Smith, Andrew R. Wood, Caroline S. Fox, Paavo Zitting, Gabrielle Boucher, Alex N. Parker, Jennifer G. Sambrook, Joyce B. J. van Meurs, Heather M. Stringham, Marjolein J. Peters, Sekar Kathiresan, Elisabeth Widen, Caroline Hayward, Tim D. Spector, Dawn M. Waterworth, Carlo Rivolta, Antti Jula, Albert Hofman, Hugh Watkins, Wendy L. McArdle, Roberto Elosua, Markku Koiranen, Paul M. Ridker, Iris M. Heid, Lee M. Kaplan, Brenda W.J.H. Penninx, Peter M. Visscher, Claes Ohlsson, Per Hall, Benjamin F. Voight, Ben A. Oostra, Anna F. Dominiczak, Martin den Heijer, Andrea Maschio, Quince Gibson, Peter P. Pramstaller, Nigel W. Rayner, Carsten Oliver Schmidt, Toby Johnson, Henrik Grönberg, M. Carola Zillikens, Alan R. Shuldiner, Cornelia M. van Duijn, Samuli Ripatti, Erik Ingelsson, John R. Thompson, Stephen J. Chanock, Johannes Kettunen, David J. Hunter, Lyle J. Palmer, Ulf Gyllensten, Jianfeng Xu, Astrid Petersmann, Johan G. Eriksson, Guillaume Lettre, Teresa Ferreira, Fredrik Wiklund, Andreas Ziegler, Andres Metspalu, Jerome I. Rotter, Suzanne Rafelt, Julius S. Ngwa, Francis S. Collins, Michael N. Weedon, Thomas Illig, Wolfgang Hoffman, Nancy L. Heard-Costa, Anke Tönjes, Daniel I. Chasman, Alice M. Arnold, Olli T. Raitakari, Anna L. Dixon, Lu Qi, Michael E. Goddard, Anneli Pouta, Mark J. Caulfield, Liesbeth Vandenput, Christian Gieger, L. Adrienne Cupples, Veikko Salomaa, Elizabeth L. Altmaier, Nicholas G. Martin, Thomas D. Kocher, Jubao Duan, David S. Siscovick, Heikki V. Huikuri, Willem H. Ouwehand, Kari E. North, Christian Hengstenberg, Jacques S. Beckmann, Constance Chen, John Perry, Ana Marušić, Olle Melander, John D. Rioux, Erika Salvi, Andrew T. Hattersley, Paul Elliott, Leif Groop, Cristen J. Willer, Manuela Uda, Gudmar Thorleifsson, Eric E. Schadt, Charles C. White, Pablo V. Gejman, Serena Sanna, Ulla Sovio, Robert W. Lawrence, Unnur Thorsteinsdottir, Ayellet V. Segrè, Daniele Cusi, G. Bragi Walters, Ken Sin Lo, Ivana Kolcic, Igor Rudan, Sonja I. Berndt, Keri L. Monda, Soumya Raychaudhuri, Jian'an Luan, Joshua C. Randall, Anthony J. Balmforth, Yurii S. Aulchenko, Peter Almgren, Karen L. Mohlke, Timothy M. Frayling, Shamika Ketkar, Thomas H. Mosley, Markus Perola, Henry Völzke, Laura Zagato, Leena Peltonen, Seppo Koskinen, Massimo Mangino, Ke Hao, Tsegaselassie Workalemahu, Lambertus A. Kiemeney, Helene Alavere, Jaakko Tuomilehto, Reedik Mägi, James F. Wilson, Ingrid B. Borecki, Zoltán Kutalik, Michael Stumvoll, Dominique J. Verlaan, Arthur W. Musk, Eero Kajantie, Jian Yang, Joshua W. Knowles, Tuomas O. Kilpeläinen, Michael Boehnke, G. Mark Lathrop, John Beilby, Fernando Rivadeneira, Gudny Eiriksdottir, Gonneke Willemsen, Andrew C. Heath, Antonella Mulas, Katja K.H. Aben, David P. Strachan, Thor Aspelund, Jing Hua Zhao, Psychiatry, NCA - Anxiety & Depression, EMGO - Mental health, Internal Medicine, Epidemiology, Intensive Care, Clinical Genetics, Genetic Identification, Medical Research Council (MRC), Biological Psychology, Neuroscience Campus Amsterdam - Anxiety & Depression, EMGO+ - Mental Health, Genetics of Complex Traits, University of Exeter, Department of Epidemiology, Erasmus Medical Centre, Netherlands Genomics Initiative (NGI), Netherlands Genomics Initiative, Department of Medicine, Montreal, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Department of Biostatistics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, deCODE Genetics, deCODE genetics [Reykjavik], Divisions of Genetics and Endocrinology and Program in Genomics, Boston Children's Hospital, Metabolism Initiative and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Institut de Génomique d'Evry (IG), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, the Genetic Investigation of ANthropocentric Traits (GIANT) Consortium, Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)

Subjects
Netherlands Twin Register (NTR), Multifactorial Inheritance, [SDV]Life Sciences [q-bio], Genome-wide association study, Aetiology, screening and detection [ONCOL 5], 0302 clinical medicine, POPULATION, SNPS, Genetics, 0303 health sciences, Multidisciplinary, HERITABILITY, COMMON VARIANTS, Phenotype, DISEASES, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Science & Technology - Other Topics, GROWTH, Allelic heterogeneity, Chromosomes, Human, Pair 3, Metabolic Networks and Pathways, TRAITS, Common disease-common variant, General Science & Technology, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Article, Molecular epidemiology [NCEBP 1], 03 medical and health sciences, SDG 3 - Good Health and Well-being, ADULT, STRATIFICATION, MD Multidisciplinary, Humans, Genetic Predisposition to Disease, Genetic variability, 030304 developmental biology, Science & Technology, MULTIDISCIPLINARY SCIENCES, Genome, Human, Hormonal regulation [IGMD 6], Body Height, Genetic architecture, wide association analysis common variants heritability population adult stratification diseases traits growth snps, WIDE ASSOCIATION ANALYSIS, Genetic Loci, Evaluation of complex medical interventions [NCEBP 2], Polygene, Expression quantitative trait loci, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits1, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait2,3. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways ( P=0.016) and that underlie skeletal growth defects ( P

Published
2010

19. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

Author

Kenneth Rice, Amy J. Swift, Veronique Vitart, Lu Qi, Kaisa Silander, Olivier Le Bacquer, Laura Crisponi, David S. Siscovick, Bo Isomaa, Anne U. Jackson, Anke Tönjes, Richard N. Bergman, Rosa Maria Roccasecca, Luigi Ferrucci, Narisu Narisu, Kari Stefansson, Holly E. Syddall, Giuseppe Paolisso, Kim L. Ward, Paul Elliott, Scott M. Grundy, Paul Johnson, Jerome I. Rotter, Philippe Froguel, James B. Meigs, George Davey Smith, Andrew T. Hattersley, Leena Peltonen, Eric J.G. Sijbrands, Serena Sanna, María TeresaMartínez-Larrad, David Altshuler, Harald Grallert, Caroline S. Fox, Nita G. Forouhi, Dorret I. Boomsma, Harry Campbell, Jean Tichet, Angelo Scuteri, Aroon D. Hingorani, Daniel S. Pearson, Meena Kumari, Silvia Naitza, Shah Ebrahim, Manjinder S. Sandhu, Jose C. Florez, Cyrus Cooper, David M. Nathan, Joseph Hung, Fredrik Karpe, Ozren Polasek, Philip J. Barter, Ruth McPherson, Benjamin F. Voight, Wolfgang Rathmann, Abbas Dehghan, Udo Seedorf, Beverley M. Shields, Antti Jula, Pau Navarro, Josephine M. Egan, Rune R. Frants, Leif Groop, Gunnar Sigursson, Seppo Koskinen, Vincent Mooser, François Pattou, Jing Hua Zhao, Irene Pichler, John F. Peden, Göran Hallmans, Toshiko Tanaka, Ruth J. F. Loos, Peter Kovacs, Andrew D. Morris, Cécile Lecoeur, Jeffrey R. O'Connell, Massimo Mangino, Nicole Vogelzangs, Rhian Gwilliam, Gordon H. Williams, Carina Zabena, Naomi Hammond, Amélie Bonnefond, Björn Zethelius, Joachim Spranger, Nancy L. Pedersen, Christopher J. Groves, Nicholas J. Timpson, George Dedoussis, Veikko Salomaa, Peter Henneman, Andrew Walley, Serge Hercberg, Ian N. M. Day, Simon Heath, Matt Neville, Alex S. F. Doney, Robert Clarke, Olov Rolandsson, Panos Deloukas, Eric Boerwinkle, Y. AnteroKesaniemi, Mike Sampson, Gerard Waeber, Sven Bergmann, Ben A. Oostra, Manuel Serrano-Ríos, Mandy van Hoek, Christine Cavalcanti-Proença, Anna L. Gloyn, Ulla Sovio, Andrew P. Morris, Anneli Pouta, Amanda J. Bennett, Paul Scheet, Peter Schwarz, Jaakko Tuomilehto, Hugh Watkins, Johanna Kuusisto, Denis Rybin, Anna LiisaHartikainen, Maria GraziaFranzosi, Unnur Thorsteinsdottir, Rafn Benediktsson, Alan F. Wright, Colin N. Apalmer, Anuj Goel, Yavuz Ariyurek, Lars Lind, Robert Sladek, Stefan R. Bornstein, Reedik Mägi, Laila Simpson, Tim D. Spector, Paul W. Franks, Nicholas L. Smith, John R. B. Perry, Peter Vollenweider, Suzannah Bumpstead, Ruth E. Pakyz, Christa Meisinger, Alan R. Shuldiner, Josée Dupuis, Man Li, Eric J. Brunner, Francis S. Collins, Torben Hansen, James F. Wilson, Guangju Zhai, Igor Rudan, Nicole L. Glazer, Marco Orrù, Pierre Meneton, Knut Borch-Johnsen, Eleanor Wheeler, Gonçalo R. Abecasis, Mark I. McCarthy, Jouke JanHottenga, Inga Prokopenko, Ping An, Jérôme Delplanque, Albert Hofman, Andrew B. Singleton, Gabe Crawford, Thomas A. Buchanan, Avan Aihie Sayer, Richard M. Watanabe, David Schlessinger, A C Fedson, André G. Uitterlinden, Frank B. Hu, Jaqueline C. MWitteman, Dhiraj Varma, Ingrid B. Borecki, Sutapa Mukherjee, Murielle Bochud, Barbara Thorand, Christian Gieger, Lori L. Bonnycastle, Stephen J. Sharp, Markus Perola, Caroline Hayward, Kristin Ardlie, J. Graessler, Robert W. Mahley, Toby Johnson, Jian'an Luan, Joshua C. Randall, Cornelia M. van Duijn, Samuli Ripatti, Ko Willems van Dijk, Valgerdur Steinthorsdottir, Yurii S. Aulchenko, G. Mark Lathrop, Christian Dina, Eleftheria Zeggini, Cecilia M. Lindgren, Stavroula Kanoni, Timothy M. Frayling, Dawn M. Waterworth, Marika Kaakinen, Timo T. Valle, Diana Zelenika, Yii Der IdaChen, Angela Silveira, Nigel W. Rayner, Aimo Ruokonen, Yun Li, Cristian Pattaro, Annelli Sandbæk, Richa Saxena, Danielle Posthuma, Steven A. McCarroll, Niels Grarup, Samy Hadjadj, Pilar Galan, Xijing Han, Lyle J. Palmer, Ulf Gyllensten, Peter P. Pramstaller, Manuela Uda, Jarred B. McAteer, Brenda W.J.H. Penninx, Debbie A Lawlor, Torben Jørgensen, Beatrice Knight, Yvonne Böttcher, Claudia Langenberg, Nicole Soranzo, Ghislain Rocheleau, Erik Ingelsson, Mario A. Morken, Michael Roden, Felicity Payne, David R. Hillman, Michael Marmot, Karen L. Mohlke, Heather M. Stringham, Bruce M. Psaty, Gudmar Thorleifsson, Yoav Ben-Shlomo, Inês Barroso, W. H. Linda Kao, James S. Pankow, Valeriya Lyssenko, Nicholas J. Wareham, Tiinamaija Tuomi, Ann ChristineSyvänen, Braxton D. Mitchell, Alisa K. Manning, Mika Kivimäki, Peter Wagner, Praveen Sethupathy, G. BragiWalters, Jaakko Kaprio, Kijoung Song, Marjo Riitta-Järvelin, Michael A. Province, Andrew A. Hicks, Marilyn C. Cornelis, Sarah H. Wild, David Meyre, Guillaume Charpentier, Patrik K. E. Magnusson, David Melzer, Jennie Hui, Peter Shrader, Michael Stumvoll, Mark O. Goodarzi, Michael R. Erdos, Oluf Pedersen, Andreas Pfeiffer, Augustine Kong, Christian Herder, Laura J. Scott, John W. GYarnell, Kirsten Ohm Kyvik, Beverley Balkau, Antje Fischer-Rosinsky, Gonneke Willemsen, Thomas Illig, Neelam Hassanali, Markku Laakso, Michael Boehnke, John Beilby, Christopher S. Franklin, Fernando Rivadeneira, M. Carola Zillikens, Michael N. Weedon, Antonio Cao, Mark E. Cooper, Simon C. Potter, Eco J. C. de Geus, H.-Erich Wichmann, Amanda F. Elliott, Lachlan J. McOin, Sophie Visvikis-Siest, Thomas Sparsø, Laura J. McCulloch, Taina K. Lajunen, Peter S. Chines, Nabila Bouatia-Naji, Medical Research Council (MRC), Biological Psychology, Functional Genomics, Neuroscience Campus Amsterdam - Anxiety & Depression, Neuroscience Campus Amsterdam - Attention & Cognition, EMGO+ - Mental Health, Ophthalmology, Epidemiology, Clinical Genetics, Dermatology, Internal Medicine, DIAGRAM Consortium, GIANT Consortium, Global BPgen Consortium, Anders Hamsten on behalf of Procardis Consortium, MAGIC investigators, Human genetics, Psychiatry, EMGO - Mental health, NCA - Attention & Cognition, and NCA - Anxiety & Depression

Subjects
Blood Glucose, Netherlands Twin Register (NTR), Candidate gene, Genome-wide association study, Type 2 diabetes, CIRCADIAN CLOCK, TRIGLYCERIDE LEVELS, 0302 clinical medicine, Delta-5 Fatty Acid Desaturase, Databases, Genetic, Homeostasis, GENETICS & HEREDITY, Anders Hamsten on behalf of Procardis Consortium, Child, Genetics, PLASMA-GLUCOSE, 0303 health sciences, Glucokinase regulatory protein, COMMON VARIANTS, 11 Medical And Health Sciences, Fasting, MAGIC investigators, 3. Good health, MODEL ASSESSMENT, Life Sciences & Biomedicine, Adult, medicine.medical_specialty, ESSENTIAL COMPONENTS, Adolescent, DNA Copy Number Variations, Alleles, Blood Glucose/genetics, Blood Glucose/metabolism, DNA Copy Number Variations/genetics, Diabetes Mellitus, Type 2/genetics, Fasting/blood, Gene Expression Regulation, Genetic Loci/genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Homeostasis/genetics, Humans, Meta-Analysis as Topic, Polymorphism, Single Nucleotide/genetics, Quantitative Trait Loci/genetics, Quantitative Trait, Heritable, Reproducibility of Results, Quantitative Trait Loci, 030209 endocrinology & metabolism, Biology, DIAGRAM Consortium, INSULIN-SECRETION, Polymorphism, Single Nucleotide, Article, Fasting glucose, 03 medical and health sciences, Insulin resistance, SDG 3 - Good Health and Well-being, Diabetes mellitus, Internal medicine, genome wide association study, glucose, diabetes type 2, medicine, GIANT Consortium, Allele, GENOME-WIDE ASSOCIATION, Global BPgen Consortium, 030304 developmental biology, Glycemic, Science & Technology, genome-wide association beta-cell dysfunction plasma-glucose insulin-secretion triglyceride levels essential components model assessment common variants circadian clock disease risk, DISEASE RISK, 06 Biological Sciences, medicine.disease, Endocrinology, Diabetes Mellitus, Type 2, Genetic Loci, biology.protein, BETA-CELL DYSFUNCTION, Developmental Biology
Abstract

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46, 186 nondiabetic participants. Follow-up of 25 loci in up to 76, 558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

Published
2010
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20. Biological, clinical and population relevance of 95 loci for blood lipids

Author

Richard N. Bergman, Markku S. Nieminen, Peter Vollenweider, André G. Uitterlinden, Luigi Ferrucci, Iris M. Heid, Lynda M. Rose, Brenda W.J.H. Penninx, Nicholas G. Martin, Joshua C. Bis, Aaron Isaacs, Jaspal S. Kooner, Gavin Lucas, Caroline Hayward, Masahiro Koseki, Andrew A. Hicks, Maja Barbalić, Marju Orho-Melander, Xueling Sim, James Scott, Manjinder S. Sandhu, Damien C. Croteau-Chonka, Andreas Ziegler, Wilmar Igi, Igor Rudan, Aki S. Havulinna, Leslie A. Lange, Hilma Holm, James G. Wilson, Albert V. Smith, Chiara Sabatti, Candace Guiducci, Paul Elliott, A. Cecile J.W. Janssens, Dorret I. Boomsma, Harry Campbell, Lee M. Kaplan, Ruth J. F. Loos, Robert Luben, Veikko Salomaa, Kyunga Kim, James F. Wilson, Mark Seielstad, Ben A. Oostra, Robert Y.L. Zee, Talin Haritunians, Stacey Gabriel, Michael Boehnke, Ida Surakka, Alex N. Parker, Serena Sanna, Fabio Marroni, Leif Groop, Ingrid B. Borecki, Weihua Zhang, John R. Thompson, Paul M. Ridker, James P. Pirruccello, Nicole Soranzo, Ulf Gyllensten, G. Kees Hovingh, Jian'an Luan, Wendy L. McArdle, Alistair S. Hall, Yurii S. Aulchenko, Thomas Meitinger, John Whitfield, Gonçalo R. Abecasis, Yii-Der Ida Chen, Tien Yin Wong, Deborah A. Nickerson, Jaakko Tuomilehto, Kijoung Song, Reijo Laaksonen, Jeanette Erdmann, Daniel J. Rader, Jing Hua Zhao, Irene Pichler, Robert A. Hegele, Marjo-Riitta Järvelin, Guillaume Paré, Juha Sinisalo, Andrew C. Edmondson, Peter P. Pramstaller, E-Shyong Tai, Vilmundur Gudnason, Linda S. Adair, Min Jin Go, Heather M. Stringham, Nancy L. Pedersen, Bruce M. Psaty, Åsa Johansson, Guillaume Lettre, Tamara B. Harris, Christian Gieger, Toby Johnson, Cornelia M. van Duijn, Samuli Ripatti, Johannes H. Smit, Sigrid W. Fouchier, Gonneke Willemsen, Mark J. Rieder, Nicholas D. Hastie, Leena Peltonen, Jacqueline C. M. Witteman, David Schlessinger, Kiran Musunuru, Eric Boerwinkle, Kay-Tee Khaw, Massimo Mangino, Themistocles L. Assimes, Claudia Langenberg, Yoon Shin Cho, Elena Gonzalez, Eric J.G. Sijbrands, Toshiko Tanaka, Inês Barroso, Vincent Mooser, Eco J. C. de Geus, Karen L. Mohlke, Jaakko Kaprio, Eric E. Schadt, Gudmar Thorleifsson, Nelson B. Freimer, H.-Erich Wichmann, Francis S. Collins, Grant W. Montgomery, John J.P. Kastelein, Inke R. Koenig, Xiuqing Guo, Ruth McPherson, Benjamin F. Voight, Stefania Bandinelli, Sally L. Ricketts, S. Matthijs Boekholdt, Xin Yuan, David Altshuler, Marja-Liisa Lokki, Lori L. Bonnycastle, Aimo Ruokonen, Noël P. Burtt, Unnur Thorsteinsdottir, Markus Perola, Edward G. Lakatta, Serkalem Demissie, Kenechi Ejebe, Muredach P. Reilly, Florian Kronenberg, Panagiotis Deloukas, Gabriel Crawford, Lenore J. Launer, David P. Strachan, Xiaohui Li, Christian Hengstenberg, Olle Melander, Juha Saharinen, Ulf de Faire, Joshua D. Smith, Heribert Schunkert, Thomas Quertermous, Young Jin Kim, Alan R. Tall, Anna F. Dominiczak, Nicholas J. Wareham, Robert Roberts, Mark J. Caulfield, Tanya M. Teslovich, Daniel I. Chasman, Manuela Uda, Jong-Young Lee, Erik Ingelsson, Christopher W. Kuzawa, Jerome I. Rotter, Gina M. Peloso, Christie M. Ballantyne, Mingyao Li, Alan F. Wright, Albert Hofman, Angelo Scuteri, Rick Twee-Hee Ong, L. Adrienne Cupples, Taesung Park, Veronique Vitart, Kaisa Silander, Jouke-Jan Hottenga, Kari Stefansson, Christopher J. O'Donnell, Mary F. Feitosa, Tim D. Spector, Mark I. McCarthy, Nilesh J. Samani, Christopher T. Johansen, David Masson, Cristian Pattaro, Ioannis M. Stylianou, Angela Doering, Patricia B. Munroe, Herman A. Taylor, Patrik K. E. Magnusson, John C. Chambers, Claudia Lamina, Sekar Kathiresan, Dawn M. Waterworth, Jose M. Ordovas, Alan B. Feranil, Cristen J. Willer, Kirsten Ohm Kyvik, Gérard Waeber, Ronald M. Krauss, Medical Research Council (MRC), Psychiatry, EMGO - Mental health, NCA - Anxiety & Depression, Biological Psychology, Neuroscience Campus Amsterdam - Anxiety & Depression, EMGO+ - Mental Health, Experimental Vascular Medicine, Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Epidemiology, Internal Medicine, and Clinical Genetics

Subjects
Male, Netherlands Twin Register (NTR), genetics/metabolism, Blood lipids, Genome-wide association study, KLF14, Coronary Artery Disease, 030204 cardiovascular system & hematology, blood/genetics/therapy, DISEASE, chemistry.chemical_compound, Mice, African Americans, genetics, Animals, Asian Continental Ancestry Group, genetics, Cholesterol, HDL, blood, Cholesterol, LDL, blood, Coronary Artery Disease, blood/genetics/therapy, Europe, ethnology, European Continental Ancestry Group, genetics, Female, Genetic Loci, genetics, Genome-Wide Association Study, Genotype, Humans, Lipid Metabolism, genetics, Lipids, blood, Liver, metabolism, Male, Mice, N-Acetylgalactosaminyltransferases, genetics/metabolism, Phenotype, Polymorphism, Single Nucleotide, genetics, Protein Phosphatase 1, genetics/metabolism, Reproducibility of Results, Triglycerides, blood, 0302 clinical medicine, Protein Phosphatase 1, genetics, Genetics, RISK, 0303 health sciences, education.field_of_study, Multidisciplinary, CHOLESTEROL, Genomics, Lipids, 3. Good health, Multidisciplinary Sciences, Europe, Phenotype, Liver, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Science & Technology - Other Topics, N-Acetylgalactosaminyltransferases, Female, lipids (amino acids, peptides, and proteins), lipids, gwas, TRAITS, Asian Continental Ancestry Group, Genotype, General Science & Technology, Population, European Continental Ancestry Group, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, White People, 03 medical and health sciences, Asian People, SDG 3 - Good Health and Well-being, Animals, Humans, Polymorphism, GENOME-WIDE ASSOCIATION, education, Triglycerides, 030304 developmental biology, ethnology, Science & Technology, Cholesterol, Cholesterol, HDL, Reproducibility of Results, Lipid metabolism, Cholesterol, LDL, Lipid Metabolism, SCARB1, Black or African American, chemistry, Genetic Loci, metabolism, Genome-Wide Association Study
Abstract

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P-8), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD. © 2010 Macmillan Publishers Limited. All rights reserved.

Published
2010

21. Meta-analysis and imputation refines the association of 15q25 with smoking quantity

Author

Mark J. Caulfield, Paul Scheet, Ruth J. F. Loos, Ozren Polasek, Vincent Mooser, Michael Wittig, Stephen E. Epstein, James F. Wilson, Gonçalo R. Abecasis, Jennifer E. Huffman, Augusto D. Pichard, Mary Susan Burnett, Rajesh Rawal, Federica Tozzi, Nilesh J. Samani, Hans J. Grabe, Robert L. Wilensky, Miles Parkes, Jing Hua Zhao, Jaspal S. Kooner, Daniel J. Rader, Wade H. Berrettini, Per Bakke, Robert W. Mahley, Astrid Petersmann, Alan F. Wright, Kenneth M. Kent, Lowell F. Satler, Alistair S. Hall, Xin Yuan, Hakon Hakonarson, Henry Völzke, Peter Vollenweider, Xiangjun Xiao, John B. Vincent, Joseph M. Lindsay, Scott M. Grundy, Christopher G. Mathew, Caroline Hayward, Susan Campbell, John R. Thompson, Alexander Teumer, Ins Barroso, David Schlessinger, Jack Satsangi, Benjamin J. Wright, Carl A. Anderson, Fabio Busonero, James L. Kennedy, Harry Campbell, Dan Rujescu, Anne Barton, H.-Erich Wichmann, Philip J. Barter, Veronique Vitart, Antonio Terracciano, Ruth McPherson, S. Horstmann, Anna F. Dominiczak, Martin Preisig, Susanne Lucae, David St Clair, Lina Zgaga, Jane Worthington, Joseph M. Devaney, Wendy Thomson, Anne Farmer, Antero Kesäniemi, Ulrich John, Tariq Ahmad, William H. Matthai, Jason Z. Liu, Muredach P. Reilly, Ivana Kolcic, Igor Rudan, Norbert Dahmen, Martin Farrall, Anthony J. Balmforth, Nicholas J. Wareham, Steve Eyre, T. Brueckl, Kay-Tee Khaw, Liming Qu, Christopher W. Knouff, Sarah H. Wild, Patricia B. Munroe, Claudia Lamina, Dawn M. Waterworth, John Strauss, John C. Chambers, Marcus Ising, Richard O. Day, Amund Gulsvik, Gérard Waeber, Arne Schäfer, Andre Franke, Clyde Francks, Pierandrea Muglia, Mingyao Li, Peter McGuffin, Keith Matthews, Manuela Uda, Sreekumar G. Pillai, Jonathan Marchini, Lefkos T. Middleton, Ron Waksman, and Wellcome Trust Case Control Consortium

Subjects
Genetics, 0303 health sciences, education.field_of_study, Population, Single-nucleotide polymorphism, Genome-wide association study, Locus (genetics), Biology, Article, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Genome-Wide Association, Nicotine Dependence, Lung-Cancer, Susceptibility Locus, Risk-Factors, Disease, Genes, SNPS, Colaus Study, SNP, 1000 Genomes Project, Allele, education, 030217 neurology & neurosurgery, Imputation (genetics), genome-wide association study, smoking initiation, smoking quantity, 030304 developmental biology
Abstract

Smoking is a leading global cause of disease and mortality(1). We established the Oxford-GlaxoSmithKline study (Ox-GSK) to perform a genome-wide meta-analysis of SNP association with smoking-related behavioral traits. Our final data set included 41,150 individuals drawn from 20 disease, population and control cohorts. Our analysis confirmed an effect on smoking quantity at a locus on 15q25 (P = 9.45 x 10(-19)) that includes CHRNA5, CHRNA3 and CHRNB4, three genes encoding neuronal nicotinic acetylcholine receptor subunits. We used data from the 1000 Genomes project to investigate the region using imputation, which allowed for analysis of virtually all common SNPs in the region and offered a fivefold increase in marker density over HapMap2 (ref. 2) as an imputation reference panel. Our fine-mapping approach identified a SNP showing the highest significance, rs55853698, located within the promoter region of CHRNA5. Conditional analysis also identified a secondary locus (rs6495308) in CHRNA3.

Published
2010
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22. Genome-wide association study identifies eight loci associated with blood pressure

Author

Peter Holmans, Udo Seedorf, Beverley M. Shields, Peter McGruffin, Arne Pfeufer, Steve Eyre, Nathalie J. Prescott, Michael Boehnke, Valentina Moskovina, Abiodun Onipinla, Leena Peltonen, Nadira Yuldasheva, Peter M. Nilsson, Valeria Romanazzi, Vincent Mooser, Göran Berglund, Alistair S. Hall, Dominic P. Kwiatkowski, Barry Widmer, Benjamin F. Voight, Stefania Bandinelli, Mark M. Iles, Sven Bergmann, Thomas Meitinger, James P. Boorman, Simonetta Guarrera, Nazneen Rahman, Murielle Bochud, Graham A. Hitman, Emma Keniry, Nelson B. Freimer, Richard Dobson, Francis S. Collins, Gerjan Navis, Jennifer L. Pointon, Richard N. Bergman, Ruth J. F. Loos, Roberto Lorbeer, Carolina A. Braga Marcano, Christian Gieger, Florian Ernst, Xin Yuan, Catherine Potter, Hazel E. Drummond, Allan H. Young, George Kirov, John F. Peden, Helen Stevens, David Clayton, Mattijs E. Numans, Katherine Gordon-Smith, Anne Farmer, Alastair Forbes, M. Khalid Mohiuddin, John A. Todd, Christopher G. Mathew, David A. Collier, Mark I. McCarthy, Francesca Bredin, Clive M. Onnie, Dan Davidson, Markus Perola, Pamela Whittaker, Yvonne T. van der Schouw, Rathi Ravindrarajan, I. C.A. Spencer, Teresa Ferreira, Nilesh J. Samani, Serge Hercberg, Gonçalo R. Abecasis, Christopher J. Groves, Nicholas John Craddock, Angela Döring, Edward G. Lakatta, Muminatou Jallow, Wendy L. McArdle, David Bentley, Susana Eyheramendy, Uwe Völker, Christopher Newton-Cheh, Jaspal S. Kooner, Hugh Watkins, Gavin Lucas, H. T. Leung, Marjo Ritta Jarvelin, Johanna Kuusisto, Wiek H. van Gilst, Wendy Thomson, Lou R. Cardon, Harold Snieder, Marju Orho-Melander, Patricia B. Munroe, Toshiko Tanaka, Jeffrey C. Barrett, Azhar Maqbool, Henry Völzke, John M. C. Connell, Elaine R. Nimmo, John R. B. Perry, Michael R. Stratton, Ralph McGinnis, Pekka Jousilahti, Michiel L. Bots, Ian Jones, Elizabeth Meech, Matthew A. Brown, Johannie Gungadoo, Jian'an Luan, Jilur Ghori, Richard J. Dixon, N. Charlotte Onland-Moret, Fulvio Ricceri, Anthony J. Balmforth, Catherine E. Todhunter, Inês Barroso, Sheila Bingham, Timo T. Valle, Fredrik O. Vannberg, Diana Zelenika, Stephen Sawcer, Anneli Pouta, David M. Evans, Cuno S. P. M. Uiterwaal, Pilar Galan, Georg Homuth, Hannah Donovan, David J. Conway, Paul Elliott, Alessandra Allione, Paul E. de Jong, Miles Parkes, Amy Chaney, John C. Chambers, Toby Johnson, Isaac Subirana, Vesela Gateva, Cathryn M. Lewis, Christopher J. O'Donnell, Hana Lango, David Schlessinger, Mark J. Caulfield, Thorsten Reffelmann, Jamie Barbour, Karen L. Mohlke, Sarah E. Hunt, Thilo Winzer, Frances M K Williams, Christopher Mathew, I. Wallace, Anuj Goel, Jaakko Tuomilehto, Louise V. Wain, Gabriel Crawford, Samantha L. Hider, Detelinea Grozeva, Elaine K. Green, Paul D. Gilbert, Peter S. Braund, Jaume Marrugat, Rainer Rettig, Pim van der Harst, Yik Ying Teo, Andrew P. Morris, Guiseppe Matullo, Serena Sanna, Cristen J. Willer, Suzannah Bumpstead, Niall C. Taylor, Jacques S. Beckmann, Pierre Meneton, Elin Org, Luigi Ferrucci, Doug Easton, Sheila Seal, Joanne M. Heward, Anne U. Jackson, Eleftheria Zeggini, Rachel M. Freathy, Maris Laan, Paul Wordsworth, Sarah Nutland, Kerstin Koch, Sian Ceasar, Anders Hamsten, Judith M. Hussey, Tariq Ahmad, Derek P. Jewell, Paul Scheet, Charlie W. Lees, C Farrar, Christopher Prowse, Markku Laakso, David St Clair, Kate Downes, Diederick E. Grobbee, Paul Burton, Simon C. Potter, Ian N. Bruce, Tim D. Spector, Anne Barton, H.-Erich Wichmann, Matthew J. Simmonds, David Hadley, Cecilia M. Lindgren, Gérard Waeber, Nigel W. Rayner, Melanie J. Newport, Manjinder S. Sandhu, Audrey Duncanson, Guangju Zhai, Simon Heath, Susan M. Ring, Alessandra Di Gregorio, Richard Williamson, Nicholas J. Wareham, Zhan Su, Olle Melander, John R. Thompson, Alexander Teumer, Sheila A. Fisher, Lachlan J. M. Coin, Leif Groop, Giovanni Tognoni, Amanda Elkin, Alan J. Silman, Jack Satsangi, Jane Worthington, Martin Farrall, John Webster, Niall Cardin, Neil Walker, Anna F. Dominiczak, Jeremy D. Sanderson, Damjan Vukcevic, Bryan Howie, Silvia Polidoro, Stephen G. Ball, Mark Tremelling, Stephen Newhouse, Stephen M. Schwartz, Lori L. Bonnycastle, Chris Wallace, Kijoung Song, Mario A. Morken, I. Nicol Ferrier, Beverley Barke, Paolo Vineis, Manuela Uda, Deborah P M Symmons, Emily J. Lyons, Mingzhan Xue, Timothy M. Frayling, Stephen C.L. Cough, David Withers, Adrian V. S. Hill, Suzanne Stevens, Jennifer Jolley, Marcus Dörr, Kirk A. Rockett, David B. Dunger, Mark Walker, Jayne A. Franklyn, Lisa Jones, David S. Siscovick, Ann-Christine Syvänen, Laura J. Scott, Morris J. Brown, Barbera Cant, Michael Inouye, Feng Zhang, Carlotta Sacerdote, Katherine S. Elliott, Jonathan Marchini, Peter Donnely, Michael John Owen, An Goris, Marcus Prembey, Andrew T. Hattersley, Gerome Breen, Marian L. Hamshere, Thomas Illig, Samer S. Najjar, Nicole Soranzo, Kay-Tee Khaw, Graham R. Walters, Willem H. Ouwehand, David P. Strachan, Martin D. Tobin, Alastair Compston, John C. Mansfield, David Altshuler, Salvatore Panico, Sekar Kathiresan, Dawn M. Waterworth, Michael N. Weedon, D. Timothy Bishop, Claire Bryan, Alexandra S. Knight, Kate L. Lee, Paul F. O'Reilly, Massimo Mangino, Michael Conlon O'Donovan, Jing Hua Zhao, Konstantinos A. Papadakis, Jennifer H. Barrett, Joanne Pereira-Gale, N J Timpson, Stephan B. Felix, Panos Deloukas, Nicholas A. Watkins, Anna-Liisa Hartikainen, Peter Vollenweider, Richard Jones, Anne Hinks, Fraser Cummings, Noha Lim, Linda A. Bradbury, Rhian G. William, Nita G. Forouhi, Roberto Eluosa, Ingeleif B. Hallgrimsdottir, Giorgio Sirugo, Robert Luben, Veikko Salomaa, Robert Clarke, Sally John, Ursula Everson, Emma King, Ivan Nikolov, Heather M. Stringham, Antony P. Attwood, Angelo Scuteri, Wellcome Trust Case Control Consortium, Burton, PR., Clayton, DG., Cardon, LR., Craddock, N., Deloukas, P., Duncanson, A., Kwiatkowski, DP., McCarthy, MI., Ouwehand, WH., Samani, NJ., Todd, JA., Donnelly, P., Barrett, JC., Davison, D., Easton, D., Evans, D., Leung, HT., Marchini, JL., Morris, AP., Spencer, IC., Tobin, MD., Attwood, AP., Boorman, JP., Cant, B., Everson, U., Hussey, JM., Jolley, JD., Knight, AS., Koch, K., Meech, E., Nutland, S., Prowse, CV., Stevens, HE., Taylor, NC., Walters, GR., Walker, NM., Watkins, NA., Winzer, T., Jones, RW., McArdle, WL., Ring, SM., Strachan, DP., Pembrey, M., Breen, G., St Clair, D., Caesar, S., Gordon-Smith, K., Jones, L., Fraser, C., Green, EK., Grozeva, D., Hamshere, ML., Holmans, PA., Jones, IR., Kirov, G., Moskvina, V., Nikolov, I., O'Donovan, MC., Owen, MJ., Collier, DA., Elkin, A., Farmer, A., Williamson, R., McGuffin, P., Young, AH., Ferrier, IN., Ball, SG., Balmforth, AJ., Barrett, JH., Bishop, DT., Iles, MM., Maqbool, A., Yuldasheva, N., Hall, AS., Braund, PS., Dixon, RJ., Mangino, M., Stevens, S., Thompson, JR., Bredin, F., Tremelling, M., Parkes, M., Drummond, H., Lees, CW., Nimmo, ER., Satsangi, J., Fisher, SA., Forbes, A., Lewis, CM., Onnie, CM., Prescott, NJ., Sanderson, J., Mathew, CG., Barbour, J., Mohiuddin, MK., Todhunter, CE., Mansfield, JC., Ahmad, T., Cummings, FR., Jewell, DP., Webster, J., Brown, MJ., Lathrop, GM., Connell, J., Dominiczak, A., Braga Marcano, CA., Burke, B., Dobson, R., Gungadoo, J., Lee, KL., Munroe, PB., Newhouse, SJ., Onipinla, A., Wallace, I., Xue, M., Caulfield, M., Farrall, M., Barton, A., Bruce, IN., Donovan, H., Eyre, S., Gilbert, PD., Hider, SL., Hinks, AM., John, SL., Potter, C., Silman, AJ., Symmons, DP., Thomson, W., Worthington, J., Dunger, DB., Widmer, B., Frayling, TM., Freathy, RM., Lango, H., Perry, JR., Shields, BM., Weedon, MN., Hattersley, AT., Hitman, GA., Walker, M., Elliott, KS., Groves, CJ., Lindgren, CM., Rayner, NW., Timpson, NJ., Zeggini, E., Newport, M., Sirugo, G., Lyons, E., Vannberg, F., Hill, AV., Bradbury, LA., Farrar, C., Pointon, JJ., Wordsworth, P., Brown, MA., Franklyn, JA., Heward, JM., Simmonds, MJ., Gough, SC., Seal, S., Stratton, MR., Rahman, N., Ban, M., Goris, A., Sawcer, SJ., Compston, A., Conway, D., Jallow, M., Rockett, KA., Bryan, C., Bumpstead, SJ., Chaney, A., Downes, K., Ghori, J., Gwilliam, R., Hunt, SE., Inouye, M., Keniry, A., King, E., McGinnis, R., Potter, S., Ravindrarajah, R., Whittaker, P., Withers, D., Cardin, NJ., Ferreira, T., Pereira-Gale, J., Hallgrimsdóttir, IB., Howie, BN., Su, Z., Teo, YY., Vukcevic, D., Bentley, D., Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), and Medical Research Council (MRC)

Subjects
Hemodynamics, Genome-wide association study, Blood Pressure, 030204 cardiovascular system & hematology, 0302 clinical medicine, Diastole, 11 Medical and Health Sciences, POPULATION, Genetics, Genetics & Heredity, RISK, 0303 health sciences, education.field_of_study, Econometric and Statistical Methods: General, CELL-DIFFERENTIATION, biology, Intracellular Signaling Peptides and Proteins, Chromosome Mapping, Steroid 17-alpha-Hydroxylase, COMMON VARIANTS, 3. Good health, DNA-Binding Proteins, Europe, Cardiovascular Diseases, PUBLIC-HEALTH, BARTTERS-SYNDROME, Blood Pressure/genetics, Cardiovascular Diseases/genetics, Cardiovascular Diseases/physiopathology, Cytochrome P-450 CYP1A2/genetics, DNA-Binding Proteins/genetics, Diastole/genetics, European Continental Ancestry Group/genetics, Fibroblast Growth Factor 5/genetics, Genetic Variation, Genome-Wide Association Study, Humans, India, Methylenetetrahydrofolate Reductase (NADPH2)/genetics, Open Reading Frames/genetics, Phospholipase C delta/genetics, Polymorphism, Single Nucleotide, Proteins/genetics, Steroid 17-alpha-Hydroxylase/genetics, Systole/genetics, Wellcome Trust Case Control Consortium, Life Sciences & Biomedicine, hypertension, Fibroblast Growth Factor 5, Systole, Population, European Continental Ancestry Group, METHYLENETETRAHYDROFOLATE REDUCTASE GENE, Single-nucleotide polymorphism, LOW-RENIN HYPERTENSION, White People, Article, 03 medical and health sciences, Open Reading Frames, Fibroblast growth factor-5, Cytochrome P-450 CYP1A2, Geneeskunde(GENK), education, Methylenetetrahydrofolate Reductase (NADPH2), Adaptor Proteins, Signal Transducing, 030304 developmental biology, Genetic association, genome-wide association, Science & Technology, MUTATIONS, Proteins, 06 Biological Sciences, POLYMORPHISM, Blood pressure, Methylenetetrahydrofolate reductase, biology.protein, biology.gene, Phospholipase C delta, Developmental Biology
Abstract

Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N ≤ 71,225 European ancestry, N ≤ 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10(-24)), CYP1A2 (P = 1 × 10(-23)), FGF5 (P = 1 × 10(-21)), SH2B3 (P = 3 × 10(-18)), MTHFR (P = 2 × 10(-13)), c10orf107 (P = 1 × 10(-9)), ZNF652 (P = 5 × 10(-9)) and PLCD3 (P = 1 × 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.

Published
2009

23. Genome-wide linkage and association analyses to identify genes influencing adiponectin levels: the GEMS Study

Author

Robert W. Mahley, Gérard Waeber, Y. Antero Kesäniemi, Philip J. Barter, Scott M. Grundy, Vincent Mooser, Ruth McPherson, Toni I. Pollin, Dawn M. Waterworth, Heide A. Stirnadel, Thomas P. Bersot, Braxton D. Mitchell, Jonathan Cohen, and Hua Ling

Subjects
Adult, Male, medicine.medical_specialty, Turkey, Genetic Linkage, Endocrinology, Diabetes and Metabolism, Medicine (miscellaneous), 030209 endocrinology & metabolism, Genome-wide association study, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, Linkage Disequilibrium, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Polymorphism (computer science), Internal medicine, Genetic variation, medicine, SNP, Humans, 030304 developmental biology, Genetics, Metabolic Syndrome, Adiponectin/genetics, Cadherins/genetics, Europe, Female, Genome-Wide Association Study, Linkage (Genetics)/genetics, Linkage Disequilibrium/genetics, Metabolic Syndrome X/ethnology, Metabolic Syndrome X/genetics, Middle Aged, Polymorphism, Single Nucleotide/genetics, 0303 health sciences, Nutrition and Dietetics, Adiponectin, medicine.disease, Cadherins, Genetic epidemiology, Metabolic syndrome
Abstract

Adiponectin has a variety of metabolic effects on obesity, insulin sensitivity, and atherosclerosis. To identify genes influencing variation in plasma adiponectin levels, we performed genome-wide linkage and association scans of adiponectin in two cohorts of subjects recruited in the Genetic Epidemiology of Metabolic Syndrome Study. The genome-wide linkage scan was conducted in families of Turkish and southern European (TSE, n = 789) and Northern and Western European (NWE, N = 2,280) origin. A whole genome association (WGA) analysis (500K Affymetrix platform) was carried out in a set of unrelated NWE subjects consisting of approximately 1,000 subjects with dyslipidemia and 1,000 overweight subjects with normal lipids. Peak evidence for linkage occurred at chromosome 8p23 in NWE subjects (lod = 3.10) and at chromosome 3q28 near ADIPOQ, the adiponectin structural gene, in TSE subjects (lod = 1.70). In the WGA analysis, the single-nucleotide polymorphisms (SNPs) most strongly associated with adiponectin were rs3774261 and rs6773957 (P < 10(-7)). These two SNPs were in high linkage disequilibrium (r(2) = 0.98) and located within ADIPOQ. Interestingly, our fourth strongest region of association (P < 2 x 10(-5)) was to an SNP within CDH13, whose protein product is a newly identified receptor for high-molecular-weight species of adiponectin. Through WGA analysis, we confirmed previous studies showing SNPs within ADIPOQ to be strongly associated with variation in adiponectin levels and further observed these to have the strongest effects on adiponectin levels throughout the genome. We additionally identified a second gene (CDH13) possibly influencing variation in adiponectin levels. The impact of these SNPs on health and disease has yet to be determined.

Published
2009
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24. Pharmacological effects of lipid-lowering drugs recapitulate with a larger amplitude the phenotypic effects of common variants within their target genes

Author

Peter Vollenweider, Christopher W. Knouff, Max C. Walker, Dawn M. Waterworth, Noha Lim, Vincent Mooser, Gérard Waeber, Xin Yuan, Paul M. Matthews, Kijoung Song, and Raymond R. Townsend

Subjects
Adult, Blood Glucose, Male, Genotype, Population, Blood Pressure, Single-nucleotide polymorphism, Genome-wide association study, 030204 cardiovascular system & hematology, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Genetics, Humans, SNP, General Pharmacology, Toxicology and Pharmaceutics, education, Molecular Biology, CETP inhibitor, Genetics (clinical), Aged, Oligonucleotide Array Sequence Analysis, 030304 developmental biology, Genetic association, 0303 health sciences, education.field_of_study, Middle Aged, Lipids, Cholesterol Ester Transfer Proteins, SNP genotyping, Phenotype, Cardiovascular Diseases, Pharmacogenetics, Molecular Medicine, Female, lipids (amino acids, peptides, and proteins), Hydroxymethylglutaryl-CoA Reductase Inhibitors
Abstract

Background A major expectation underlying the search for novel susceptibility genes for common diseases using genome-wide association studies (GWAS) is that these discoveries will lead to new drug targets. This claim has not been verified yet. Here, we tested the hypothesis that common single nucleotide polymorphisms (SNPs) within drug target genes are associated with the corresponding phenotypes, using a population-based GWAS dataset and lipid-lowering drugs as a test case. Methods We examined the association between 36 genotyped and 193 imputed SNPs within four lipid-lowering drug target genes (HMGCR, PPARA, HM74A/GPR109A and CETP) and four non-lipid drug target genes (ACE, AGTR1, P2RY12, and ATP4B) and lipid phenotypes, blood pressure, and coronary artery disease in 5635 adult participants of the Lausanne, Switzerland, CoLaus study, genotyped using the Affymetrix 500K SNP chip technology. Results The phenotypes associated with SNPs within drug target genes recapitulated to a certain extent the pharmacological effects of the drug. The amplitude of the SNP effect was about 10 times smaller than the pharmacological effect of the corresponding drug. In particular, several CETP SNPs were associated with an elevation in HDL-cholesterol levels, yet a lower diastolic blood pressure, providing evidence that the blood pressure elevation induced by the CETP inhibitor torcetrapib is more likely compound specific than class specific. Conclusion Pharmacological modulation of lipid-lowering drug targets recapitulates, and markedly amplifies, the phenotypic effects of common SNPs within these target genes. This data provides indirect evidence that, with certain limitations, large-scale GWAS represent a new tool for the discovery and the development of innovative drugs.

Published
2008

25. Genetic and phenotypic architecture of metabolic syndrome-associated components in dyslipidemic and normolipidemic subjects: the GEMS Study

Author

Xiwu Lin, Y. Antero Kesäniemi, Gérard Waeber, Scott M. Grundy, Hua Ling, Philip J. Barter, Ruth McPherson, Kijoung Song, Thomas P. Bersot, Jonathan Cohen, Dawn M. Waterworth, Heide A. Stirnadel, Robert W. Mahley, Braxton D. Mitchell, and Vincent Mooser

Subjects
Adult, medicine.medical_specialty, Adolescent, Apolipoprotein B, Adipokine, Hyperlipidemias, 030209 endocrinology & metabolism, Biology, 03 medical and health sciences, Quantitative Trait, Heritable, 0302 clinical medicine, Internal medicine, Hyperlipidemia, medicine, Cluster Analysis, Humans, Genetic Predisposition to Disease, Aged, 030304 developmental biology, Metabolic Syndrome, 0303 health sciences, Adiponectin, nutritional and metabolic diseases, Middle Aged, medicine.disease, Phenotype, Genetic architecture, Endocrinology, Adipose Tissue, Case-Control Studies, biology.protein, lipids (amino acids, peptides, and proteins), Metabolic syndrome, Cardiology and Cardiovascular Medicine, Lipoprotein
Abstract

Atherogenic dyslipidemia, manifest by low HDL-cholesterol and high TG levels, is an important component of ATP-III defined metabolic syndrome. Here, we dissected the phenotypic and genetic architecture of these traits by assessing their relationships with other metabolically relevant measures, including plasma adipo-cytokines, highly sensitive C-reactive protein (hsCRP) and LDL particle size, in a large family data set (n = 2800) and in an independent set of dyslipidemic cases (n = 716) and normolipidemic controls (n = 1073). We explored the relationships among these phenotypes using variable clustering and then estimated their genetic heritabilities and cross-trait correlations. In families, four clusters explained 61% of the total variance, with one adiposity-related cluster (including hsCRP), one BP-related cluster, and two lipid-related clusters (HDL-C, TG, adiponectin and LDL particle size; apoB and non-HDL-C). A similar structure was observed in dyslipidemic cases and normolipidemic controls. The genetic correlations in the families largely paralleled the phenotype clustering results, suggesting that common genes having pleiotropic effects contributed to the correlations observed. In summary, our analyses support a model of metabolic syndrome with two major components, body fat and lipids, each with two subcomponents, and quantifies their degree of overlap with each other and with metabolic-syndrome related measures (adipokines, LDL particle size and hsCRP).

Published
2008
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26. Interaction between insulin (VNTR) and hepatic lipase (LIPC−514C>T) variants on the response to an oral glucose tolerance test in the EARSII group of young healthy men

Author

Philippa J. Talmud, Steve E. Humphries, Hans Jansen, Dawn M. Waterworth, Viviane Nicaud, and Clinical Chemistry

Subjects
Adult, Male, medicine.medical_specialty, medicine.medical_treatment, Minisatellite Repeats, Type 2 diabetes, Biology, Insulin resistance, Gene interaction, Polymorphism (computer science), Internal medicine, medicine, Humans, Insulin, Genetic Predisposition to Disease, Apolipoproteins C, Exercise, Molecular Biology, Apolipoprotein C-III, Glucose tolerance test, medicine.diagnostic_test, Genetic Variation, Hepatic lipase, Lipase, Glucose Tolerance Test, medicine.disease, Europe, Variable number tandem repeat, Glucose, Endocrinology, Molecular Medicine, Insulin Resistance
Abstract

Insulin resistance is polygenic in origin, and can be observed at an early age. We have shown that variations in APOC3−482T>C and hepatic lipase (LIPC)-514C>T), individually (APOC3 alone) and interactively, modulate insulin and glucose levels after an OGTT in young healthy men participating in the European Atherosclerosis Research Study II (EARSII). Variation in the insulin gene (INS) variable number tandem repeat (VNTR) has been found to predispose to type 1 and type 2 diabetes. We have evaluated the HphI site 23 bp upstream of the INS gene (a surrogate marker for the VNTR) in EARSII (n=822), to determine if variation in INS contributes to insulin resistance. Carriers of the INS VNTR class III (HphI−) allele (frequency=0.29 (95%CI 0.27, 0.31)) had significantly higher 60-min insulin concentrations after the OGTT (P=0.014) and a marginally higher AUC insulin (P=0.07), compared to class I (HphI+) homozygotes. However, this effect on AUC insulin was modified by the level of physical activity, displaying significant gene:environment interaction (P=0.03). We tested for gene:gene interaction between the INS VNTR and both the LIPC−514C>T and APOC3−482T>C. While there was a significant interaction between INS VNTR and LIPC−514C>T on AUC glucose (P=0.013) and on AUC insulin (P=0.015), there was no interaction with APOC3−482T>C. Thus, despite a modest effect of the INS VNTR alone, the influence of this variant on insulin sensitivity was modified by gene:environment and gene:gene interactions, illustrating the biological complexity of insulin resistance.

Published
2005

27. Cardiovascular pharmacogenetics in the SNP era

Author

Lefkos T. Middleton, T. Isenhour, Dawn M. Waterworth, and Vincent Mooser

Subjects
Genetics, Candidate gene, education.field_of_study, Linkage disequilibrium, Genome, Human, Population, Single-nucleotide polymorphism, Hematology, Biology, Bioinformatics, Polymorphism, Single Nucleotide, Pharmacogenetic Study, Linkage Disequilibrium, Haplotypes, Pharmacogenetics, Risk Factors, Chromosomal region, Humans, education, Genotyping
Abstract

In the past pharmacological agents have contributed to a significant reduction in age-adjusted incidence of cardiovascular events. However, not all patients treated with these agents respond favorably, and some individuals may develop side-effects. With aging of the population and the growing prevalence of cardiovascular risk factors worldwide, it is expected that the demand for cardiovascular drugs will increase in the future. Accordingly, there is a growing need to identify the 'good' responders as well as the persons at risk for developing adverse events. Evidence is accumulating to indicate that responses to drugs are at least partly under genetic control. As such, pharmacogenetics - the study of variability in drug responses attributed to hereditary factors in different populations - may significantly assist in providing answers toward meeting this challenge. Pharmacogenetics mostly relies on associations between a specific genetic marker like single nucleotide polymorphisms (SNPs), either alone or arranged in a specific linear order on a certain chromosomal region (haplotypes), and a particular response to drugs. Numerous associations have been reported between selected genotypes and specific responses to cardiovascular drugs. Recently, for instance, associations have been reported between specific alleles of the apoE gene and the lipid-lowering response to statins, or the lipid-elevating effect of isotretinoin. Thus far, these types of studies have been mostly limited to a priori selected candidate genes due to restricted genotyping and analytical capacities. Thanks to the large number of SNPs now available in the public domain through the SNP Consortium and the newly developed technologies (high throughput genotyping, bioinformatics software), it is now possible to interrogate more than 200,000 SNPs distributed over the entire human genome. One pharmacogenetic study using this approach has been launched by GlaxoSmithKline to identify the approximately 4% of patients who are predisposed to developing a hypersensitivity reaction to abacavir, an anti-HIV agent. Data collected thus far on the HLA locus on chromosome 6 indicate that this approach is feasible. Extended linkage disequilibrium can be detected readily, even across several haplotype blocks, thus potentially reducing the number of SNPs for future whole-genome scans. Finally, a modest number of cases and controls appears to be sufficient to detect genetic associations. There is little doubt that this type of approach will have an impact on the way cardiovascular drugs will be developed and prescribed in the future.

Published
2003

28. Polymorphisms in CYP-7A1, not APOE, influence the change in plasma lipids in response to population dietary change in an 8 year follow-up; results from the Czech MONICA study

Author

Zdena Škodová, Jaroslav A. Hubacek, Vera Lánská, Rudolf Poledne, Dawn M. Waterworth, Jan Pitha, Philippa J. Talmud, and Steve E. Humphries

Subjects
Adult, Male, Apolipoprotein E, medicine.medical_specialty, Genotype, Apolipoprotein E2, Apolipoprotein E4, Clinical Biochemistry, Population, Apolipoprotein E3, Follow up results, Biology, Cholesterol 7 alpha-hydroxylase, Diet Surveys, chemistry.chemical_compound, Apolipoproteins E, Internal medicine, Plasma lipids, medicine, Humans, Cholesterol 7-alpha-Hydroxylase, education, Triglycerides, Aged, Apolipoproteins B, Czech Republic, education.field_of_study, Polymorphism, Genetic, Cholesterol, Cholesterol, HDL, Cholesterol, LDL, General Medicine, Metabolism, Middle Aged, Lipids, Diet, Endocrinology, chemistry, lipids (amino acids, peptides, and proteins), Follow-Up Studies
Abstract

Objectives: To evaluate the influence of variation in the genes for apolipoprotein E (APOE; epsilon2, epsilon3, epsilon4) and cholesterol-7alpha hydroxylase (CYP-7A1; -204A-->C) on plasma lipid level changes.Design and methods: 131 males for whom dietary composition markedly changed and total cholesterol decreased (from 6.21 +/- 1.31 mmol/L in 1988 - 5.43 +/- 1.06 mmol/L in 1996). over an 8 yr follow-up study. Polymorphisms were investigated using PCR.Results: APOE genotype influenced plasma total and LDL cholesterol, with carriers of the epsilon4 having the highest and epsilon2 carriers the lowest levels, this reached borderline significance for cholesterol in 1988 (p = 0.06) and strongly affected the 1996 levels of LDL cholesterol (p = 0.008). However, APOE did not influence the change in these measures over time. In contrast, the CYP-7A1 -204A-->C polymorphism did not affect lipid measures per se but was strongly associated with a dec tease in plasma total cholesterol [AA -0.38 (+/- 0.20) mmol/L, AC -0.65 +/- (0.08), CC -1.33 (+/- 0.3) mmol/L, p = 0.01] over the 8 yr time period.Conclusions: Variation in the CYP-7A1 gene may play an important role in an individual's sensitivity to dietary composition. (C) 2003 The Canadian Society of Clinical Chemists. All rights reserved.

Published
2003

29. Variants in the APOC3 promoter insulin responsive element modulate insulin secretion and lipids in middle-aged men

Author

Dawn M. Waterworth, P.J. Talmud, David M. Flavell, Jian'an Luan, Nicholas J. Wareham, Christopher D. Byrne, and S.E. Humphries

Subjects
Blood Glucose, Male, medicine.medical_specialty, Time Factors, medicine.medical_treatment, Type 2 diabetes, Biology, Glucose homeostasis, Response Elements, chemistry.chemical_compound, NEFA, Sex Factors, Internal medicine, medicine, Humans, Insulin, Apolipoproteins C, Promoter Regions, Genetic, Triglyceride metabolism, Molecular Biology, Triglycerides, Proinsulin, Apolipoprotein C-III, Triglyceride, Hypertriglyceridemia, Smoking, Nonesterified fatty acid, Fasting, Middle Aged, Atherosclerosis, medicine.disease, Endocrinology, chemistry, Diabetes Mellitus, Type 2, Multivariate Analysis, Mutation, Molecular Medicine, Female, Lipoprotein
Abstract

Variation in the insulin responsive element (IRE) of the APOC3 promoter has been shown to be associated with insulin and glucose concentrations after an oral glucose tolerance test (OGTT) in young healthy men. We evaluated two variants in the IRE (−455T>C and −482C>T) in the Ely study, a prospective cohort study of middle-aged men (n=223) and women (n=279), to determine if the effect of these variants on glucose homeostasis could be explained by altered nonesterified fatty acid (NEFA) levels and if these effects are modulated by age and gender. Both variants had significant effects on the 30-min insulin incremental response in men alone (−482C>T, P=0.007; −455T>C, P=0.0155), with rare allele homozygotes having a 33.3% and 23.3% lower insulin increment as compared to common allele homozygotes, respectively. Thirty-minute NEFA concentrations were also significantly associated with genotype in men and levels were approximately 10% higher in carriers homozygous for the rare alleles as compared to subjects homozygous for the common alleles (−482C>T, P=0.04; −455T>C, P=0.006). In addition, there was a strong interaction between both variants and cigarette smoking affecting fasting triglyceride levels in both men (interaction: −455T>C, P=0.02; −482C>T, P=0.008) and women (interaction: −455T>C, P=0.007; −482C>T, P=0.013). Taken together, the data shows that men who carry the rare alleles of the IRE variants have disturbed glucose homeostasis and an unfavourable lipid phenotype. The finding of an elevated 30-min NEFA may be an important mechanistic link between triglyceride-rich lipoprotein (TRL) metabolism and glucose homeostasis.

Published
2003
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30. Variation in the promoter of the human hormone sensitive lipase gene shows gender specific effects on insulin and lipid levels: results from the Ely study

Author

Jutta Palmen, Dave Flavell, Dawn M. Waterworth, Nicholas J. Wareham, Philippa J. Talmud, Christopher D. Byrne, and Jian'an Luan

Subjects
Male, medicine.medical_specialty, Heterozygote, medicine.medical_treatment, Adipose tissue, Hormone-sensitive lipase, Biology, chemistry.chemical_compound, NEFA, Insulin resistance, Sex Factors, Diabetes mellitus, Internal medicine, medicine, Lipolysis, Humans, Insulin, Prospective Studies, Fasting insulin levels, Promoter Regions, Genetic, Molecular Biology, Genetic polymorphism, Polymorphism, Genetic, Triglyceride, Genetic Variation, Glucose Tolerance Test, Middle Aged, Sterol Esterase, medicine.disease, Lipids, Hormone sensitive lipase, Endocrinology, chemistry, Diabetes Mellitus, Type 2, Molecular Medicine, Female, Insulin Resistance
Abstract

We previously identified a hormone sensitive lipase (HSL) promoter variant, −60C>G, which in vitro exhibits 40% reduced promoter activity. In this study we examined the effect of the −60C>G on glycemic and lipid measures in the population based Ely study of metabolic function and insulin resistance in 218 middle-aged men and 276 middle-aged women. Adipose tissue HSL is the rate-limiting step in triglyceride lipolysis, generating free fatty acids for energy utilization. HSL is also expressed in pancreatic β-cells where its activity therefore may affect insulin secretion. In the women, carriers of the HSL −60G allele had significantly lower fasting insulin levels (P=0.0005) and a lower total area under the curve for insulin during the oral glucose tolerance test (P=0.005). There was no demonstrable association in men with these measures of insulin sensitivity but carriers of the −60G allele had significantly lower fasting non-esterified fatty acid (NEFA) levels (P=0.025) and higher low density lipoprotein cholesterol levels (P=0.02) than men who were non-carriers. This study provides additional evidence for a role for HSL in the development of insulin resistance, from which carriers of the −60G allele, associated here with markers of insulin sensitivity in women, and with lower NEFA levels in men, might be protected.

Published
2001
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31. Plasma levels of remnant particles are determined in part by variation in the APOC3 gene insulin response element and the APOCI–APOE cluster

Author

P.J. Talmud, Jaroslav A. Hubacek, J. Kovar, Jan Pitha, Dawn M. Waterworth, Steve E. Humphries, and Rudolf Poledne

Subjects
Apolipoprotein E, medicine.medical_specialty, Apolipoprotein B, lipoprotein lipase, QD415-436, Biochemistry, insulin response element, chemistry.chemical_compound, Endocrinology, Chylomicron remnant, Internal medicine, Genotype, medicine, apolipoprotein B, remnant-like cholesterol, Lipoprotein lipase, biology, Triglyceride, Cholesterol, Cell Biology, remnant-like triglyceride, hepatic lipase, chemistry, biology.protein, lipids (amino acids, peptides, and proteins), Hepatic lipase
Abstract

Remnant particles of triglyceride-rich lipoproteins (RLP) are known to be a strong predictor of atherogenicity. The serum concentrations of remnant-like particle triglyceride (RLPTG) and remnant-like particle cholesterol (RLPC) have been determined in a representative sample of the Czech MONICA study (n = 285). The relationship was investigated between remnant particle triglyceride/cholesterol concentrations and polymorphisms in the genes APOC3 (−482C→T/3238C→G), APOE (ε2/ε3/ε4), APOCI (−317-321ins), APOB (signal peptide), hepatic lipase (LIPE, −480C→T), and lipoprotein lipase (LPL, S447X). Univariate analysis showed significant effects on RLPTG associated only with the APOE genotype (P = 0.009), the APOC3 −482C→T genotype (P = 0.018), and the APOCI −317-321ins (P = 0.014) genotype and significant effects on RLPC with APOE (P = 0.01) and APOCI −317-321ins (P = 0.021). The raising effect of the APOE genotype for both remnant cholesterol and triglyceride was confined to the ε2/4 (n = 6) and ε4/4 (n = 3) groups, and thus when the ε2/4 group was omitted in order to analyze by allele (ε2+/ε3+/ε4+), significance was lost (P = 0.6). There was strong linkage disequilibrium between the APOE and APOCI alleles (χ2, P < 0.001) and a multivariate ANOVA of RLPTG with all three significantly associated variants as factors demonstrated that while the APOC3 −482C→T effect was independent of the others (P = 0.003), the APOCI −317-321ins and APOE effects were not. This was also true for the APOCI −317-321ins and APOE effects on RLPC. To assess whether APOE-CI effects on RLPC were independent of their effects on total cholesterol and triglyceride levels, multiple linear regression was used. Using multiple linear regression, it appeared that the APOE-CI effects on RLPC were independent of their effects on plasma cholesterol, but the effects of APOC3 and APOE-CI on RLPTG could not be separated from their effects on plasma Tg levels.Further characterization of this remnant particle phenotype and its genetic determinants may lead to a better understanding of its metabolism and contribution to atherosclerosis.

Published
2000

32. In-vivo and in-vitro nutrient-gene interactions

Author

Philippa J. Talmud and Dawn M. Waterworth

Subjects
Apolipoprotein B, Endocrinology, Diabetes and Metabolism, Apolipoprotein A-IV, Fatty acid-binding protein, Cholesterol, Dietary, Gene expression, Genetics, Animals, Humans, Nutritional Physiological Phenomena, RNA, Messenger, Apolipoproteins C, Molecular Biology, Gene, Apolipoproteins A, chemistry.chemical_classification, Apolipoprotein C-III, Nutrition and Dietetics, Apolipoprotein A-I, biology, Genetic Variation, Fatty acid, Cell Biology, Lipids, Fatty acid synthase, Biochemistry, chemistry, biology.protein, lipids (amino acids, peptides, and proteins), Apolipoprotein C2, Cardiology and Cardiovascular Medicine
Abstract

Association studies of gene variants and response to dietary challenges represent one way of investigating gene-nutrient interactions. Several studies reported in the present review concentrate on evaluating variation at the apolipoprotein AI-CIII-AIV and apolipoprotein E gene loci, as well as the fatty acid binding protein gene. In addition, the effect of nutrients can be directly evaluated at the level of gene expression, and reports of in-vitro studies of control of fatty acid and triglycerides synthesis are discussed in the present review.

Published
2000

33. ApoCIII Gene Variants Modulate Postprandial Response to Both Glucose and Fat Tolerance Tests

Author

Jean Dallongeville, Viviane Nicaud, Josep Ribalta, Dawn M. Waterworth, Philippa J. Talmud, and Steve E. Humphries

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, Apolipoprotein B, Genetic Linkage, Offspring, medicine.medical_treatment, Eating, chemistry.chemical_compound, Gene Frequency, Physiology (medical), Internal medicine, Humans, Medicine, Apolipoproteins C, Alleles, Triglycerides, Apolipoprotein C-III, Glucose tolerance test, Lipoprotein lipase, Triglyceride, biology, medicine.diagnostic_test, business.industry, Insulin, Hypertriglyceridemia, Genetic Variation, Glucose Tolerance Test, medicine.disease, Dietary Fats, Glucose, Endocrinology, Postprandial, chemistry, biology.protein, Cardiology and Cardiovascular Medicine, business
Abstract

Background —We investigated the relationship between variation in the apolipoprotein (apo) AI-CIII-AIV gene cluster and response to an oral glucose test (OGTT) and oral fat load test (OFTT) in the EARSII group of young, healthy male offspring whose fathers had had a myocardial infarction before the age of 55 years (cases, n=407) compared with age-matched controls (n=415). The apoCIII variations examined were C3238G ( Sst I) in the 3′-UTR, C1100T in exon 3, C-482T in the insulin response element (IRE), and T-2854G in the apoCIII-AIV intergenic region. Methods and Results —The postprandial response was regulated by variation at the T-2854G and C3238G sites. After the OFTT, carriers of the rare alleles had delayed clearance of triglyceride (Tg) levels; G-2854 carriers showed the largest effect on Tg (AUC, 24% greater, P P P P =0.03). However, after adjustment for fasting level of Tg, only the effect with the T-2854G remained significant. Variation at the C-482T (IRE) determined response to the OGTT, with carriers of the rare T-482 having significantly elevated glucose (28.7% AUC, P =0.013) and insulin (20.5% AUC, P Conclusions —These data suggest that specific genetic variants at the apoCIII gene locus differentially affect postprandial and response to OGTT and suggest a novel mechanism for the effects of variation at this locus on risk for atherosclerosis.

Published
1999

34. Male-pattern baldness susceptibility locus at 20p11

Author

Peter Vollenweider, Vincent Mooser, Panos Deloukas, Nicole Soranzo, Frank Geller, Gérard Waeber, Unnur Thorsteinsdottir, Bragi Walters, Dawn M. Waterworth, Katja K.H. Aben, Hreinn Stefansson, J. Brent Richards, Augustine Kong, Patrick Sulem, Tim D. Spector, Daniel Glass, Kari Stefansson, Kijoung Song, Lambertus A. Kiemeney, Veronique Bataille, Thorunn Rafnar, and Xin Yuan

Subjects
Male, medicine.medical_specialty, Chromosomes, Human, Pair 20, Locus (genetics), Aetiology, screening and detection [ONCOL 5], Biology, Polymorphism, Single Nucleotide, Article, Molecular epidemiology [NCEBP 1], 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Translational research [ONCOL 3], Internal medicine, Genetics, medicine, Humans, Genetic Predisposition to Disease, Molecular diagnosis, prognosis and monitoring [UMCN 1.2], 030304 developmental biology, 0303 health sciences, Hereditary cancer and cancer-related syndromes [ONCOL 1], Genome, Human, Chromosome, Alopecia, biology.organism_classification, medicine.disease, Human genetics, Female, Androgen receptor, Endocrinology, Risk allele, Susceptibility locus, Male-pattern baldness, Cabello
Abstract

Contains fulltext : 69120.pdf (Publisher’s version ) (Closed access) We conducted a genome-wide association study for androgenic alopecia in 1,125 men and identified a newly associated locus at chromosome 20p11.22, confirmed in three independent cohorts (n = 1,650; OR = 1.60, P = 1.1 x 10(-14) for rs1160312). The one man in seven who harbors risk alleles at both 20p11.22 and AR (encoding the androgen receptor) has a sevenfold-increased odds of androgenic alopecia (OR = 7.12, P = 3.7 x 10(-15)).

Published
2008

35. Erratum to: The epigenetic signature of systemic insulin resistance in obese women

Author

Indranil Sinha, Deepak K. Rajpal, Peter Arner, Huan Xu, Toby Johnson, Mikael Rydén, Ingrid Dahlman, Anders Thorell, Xiang Yao, Anna-Stina Sahlqvist, A. Katrina Loomis, Dawn M. Waterworth, Erik Näslund, and Johannes M. Freudenberg

Subjects
0301 basic medicine, 03 medical and health sciences, 030104 developmental biology, Insulin resistance, Endocrinology, Diabetes and Metabolism, Internal Medicine, medicine, Human physiology, Epigenetics, Biology, Bioinformatics, medicine.disease, Signature (logic)
Published
2016

36. Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways

Author

Andrew A. Hicks, Han Chen, Anders Franco-Cereceda, Vilmundur Gudnason, David M. Evans, May E. Montasser, Ulf de Faire, Jeanette S. Andrews, Rainer Rauramaa, Ching-Ti Liu, Michael Boehnke, Panos Deloukas, Naveed Sattar, Jacques S. Beckmann, Marcus E. Kleber, Hanneke Basart, Bruna Gigante, Göran Hallmans, Francis S. Collins, Toshiko Tanaka, Stella Trompet, Kathleen Stirrups, Jula Antti, Ryan P. Welch, Sirkka Keinänen-Kiukaanniemi, Jaakko Kaprio, T. Saaristo, Jeffrey R. O'Connell, Bernhard O. Boehm, Eleanor Wheeler, Kijoung Song, John Beilby, Michael A. Province, Inga Prokopenko, Ping An, Dawn M. Waterworth, Nita G. Forouhi, Nicholas J. Timpson, George Dedoussis, Fernando Rivadeneira, Winfried Maerz, Anneli Pouta, Anuj Goel, Jackie F. Price, Sarah Edkins, Markus Perola, Inês Barroso, Albertine J. Oldehinkel, Igor Rudan, Peter Vollenweider, Philippe Froguel, Richard M. Watanabe, Kari E. North, Dorret I. Boomsma, Harry Campbell, G. Kees Hovingh, Paul C. D. Johnson, Cécile Lecoeur, Vasiliki Lagou, Denis Rybin, Pierre Meneton, Soumya Raychaudhuri, Jian'an Luan, Neil Robertson, Andrew P. Morris, Veikko Salomaa, Anubha Mahajan, Beate St Pourcain, Robert A. Scott, Evelin Mihailov, Gerard R Fowkes, Nancy L. Pedersen, Susan Campbell, Sonia Shah, Veronique Vitart, Mustafa Atalay, Richard N. Bergman, Ross M. Fraser, Anders Hamsten, Benjamin F. Voight, Wolfgang Rathmann, Christian Gieger, James F. Wilson, Wieland Kiess, Marcel Bruinenberg, Serge Hercberg, Ian Ford, James B. Meigs, Tibor V. Varga, George Davey Smith, Josée Dupuis, Stefania Bandinelli, John F. Peden, Mika Kivimäki, J. Wouter Jukema, Michael Stumvoll, Caroline Hayward, Emil Rehnberg, Ozren Polasek, Letizia Marullo, Andrew D. Morris, Brenda W.J.H. Penninx, Lori L. Bonnycastle, Jouke-Jan Hottenga, Martin Farrall, Albert V. Smith, Rona J. Strawbridge, Ingrid B. Borecki, Kari Stefansson, Kirsten Ohm Kyvik, Harald Grallert, Alan James, Tim D. Spector, Paul W. Franks, Lasse Folkersen, Sara M. Willems, Stephan J. L. Bakker, Iva Miljkovic, Nigel W. Rayner, Tamara B. Harris, Momoko Horikoshi, Linda S. Adair, Christian Herder, Tõnu Esko, Thomas Illig, Alan R. Shuldiner, Ruth J. F. Loos, Serena Sanna, Massimo Mangino, Alex S. F. Doney, Hugh Watkins, Erik Ingelsson, Colin N. A. Palmer, Pau Navarro, Claudia Langenberg, Mark I. McCarthy, Johanna Kuusisto, Anne U. Jackson, Martina Müller-Nurasyid, Perttu Salo, Ying Wu, Alan F. Wright, Lars Lind, Johannes H. Smit, Gonneke Willemsen, Stefan R. Bornstein, Jennie Hui, Peter Schwarz, Anke Toenjes, Albert Hofman, Markku Laakso, Maria Dimitriou, Marjo-Riitta Järvelin, Aaron Isaacs, Hyun Min Kang, James S. Pankow, Annette Peters, André G. Uitterlinden, Loic Yengo, Beverley Balkau, Augustine Kong, Toby Johnson, Cornelia M. van Duijn, Luigi Ferrucci, Samuli Ripatti, Mulas Antonella, Aroon D. Hingorani, Meena Kumari, Nicholas J. Wareham, Sarah H. Wild, Patricia B. Munroe, Nicholas D. Hastie, Stefan Gustafsson, Kerrin S. Small, Cecilia M. Lindgren, Jennifer L. Bolton, Matti Uusitupa, Peter P. Pramstaller, Tove Fall, Patricia A. Peyser, Dmitry Shungin, Yongmei Liu, Patrik K. E. Magnusson, Jaakko Tuomilehto, Francesco Cucca, Reedik Mägi, Karen L. Mohlke, Gudmar Thorleifsson, Hanneke Jansen, Mark J. Caulfield, Tanya M. Teslovich, Timo A. Lakka, Heather M. Stringham, Bruce M. Psaty, Niek Verweij, Heikki Oksa, Wei Zhao, Andres Metspalu, Jaana Lindström, Stavroula Kanoni, Bengt Sennblad, Carlo Sidore, Eco J. C. de Geus, Ben A. Oostra, Lawrence F. Bielak, Peter Kovacs, Laura J. Rasmussen-Torvik, Tatijana Zemunik, Jose C. Florez, Antje Körner, Pim van der Harst, Ramaiah Nagaraja, Peter S. Chines, Nabila Bouatia-Naji, Addenbrooke's Hospital, Wellcome Trust Ctr Human Genet, University of Oxford [Oxford], Michigan State University [East Lansing], Michigan State University System, Wellcome Trust Sanger Inst, Partenaires INRAE, University of Maryland [College Park], University of Maryland System, University of Tartu, Karolinska Institutet [Stockholm], Karolinska University Hospital [Stockholm], The Wellcome Trust Sanger Institute [Cambridge], Northwestern University [Evanston], Université Lille Nord de France (COMUE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Lund University [Lund], Umeå University, Consiglio Nazionale delle Ricerche (CNR), Istituto di Virologia Vegetale, Università degli studi di Torino (UNITO), Università degli Studi di Sassari, University of Glasgow, Netherlands Heart Institute, Leiden University, Queen Mary University of London (QMUL), University of Groningen, deCODE genetics [Reykjavik], Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), (IGE3 Inst Genet & Genom Geneva), University College of London [London] (UCL), Icelandic Heart Association, Heart Preventive Clinic and Research Institute, University of Iceland, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Natl Inst Hlth & Welf, University of Helsinki, University of Bristol [Bristol], North Carolina State University, Center for High Performance Simulation and Department of Chemical and Biomolecular Engineering, Wake Forest School of Medicine, Sir Charles Gairdner Hospital, University of Western Australia, PathW Lab Med WA, University of Edinburgh, Centre for Medical Systems Biology, Erasmus University Rotterdam, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], University of Pennyslvania, Brigham and Women's Hospital, Boston University [Boston] (BU), Dept Med Genet, Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Centre Hospitalier Universitaire Vaudois (CHUV), National Human Genome Research Institute (NHGRI), GlaxoSmithKline, National Institute on Aging, Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA), National Institutes of Health [N01-AG-1-2100], National Institute on Aging Intramural Research Program, Hjartavernd (the Icelandic Heart Association), Althingi (the Icelandic Parliament), Psychiatry, EMGO - Lifestyle, overweight and diabetes, Other departments, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Medical Research Council (MRC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Epidemiology, Medical Microbiology & Infectious Diseases, Clinical Chemistry, Child and Adolescent Psychiatry / Psychology, Dermatology, Internal Medicine, Clinical Genetics, and VU University Amsterdam

Subjects
Netherlands Twin Register (NTR), Blood Glucose, Male, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Genome-wide association study, Type 2 diabetes, Fasting/blood, Mice, 0302 clinical medicine, DIAbetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium, Gene Frequency, Insulin, GENETICS & HEREDITY, Genetics, 0303 health sciences, INSULIN-RESISTANCE, Metabolic Networks and Pathways/genetics, gene, glucose, glycemic, GLUCOSE-METABOLISM, 11 Medical And Health Sciences, Fasting, CARDIOVASCULAR-DISEASE, SKELETAL-MUSCLE, Female, Life Sciences & Biomedicine, Metabolic Networks and Pathways, Adult, SUSCEPTIBILITY LOCI, Quantitative Trait Loci, 030209 endocrinology & metabolism, Blood Glucose/genetics, KAPPA-B, Quantitative trait locus, Biology, Article, 03 medical and health sciences, Insulin resistance, SDG 3 - Good Health and Well-being, Diabetes mellitus, Genome-Wide Association Study/statistics & numerical data, Quantitative Trait Loci/physiology, KLOTHO GENE POLYMORPHISMS, medicine, Animals, Humans, GENOME-WIDE ASSOCIATION, Allele frequency, 030304 developmental biology, Glycemic, Science & Technology, Osmolar Concentration, 06 Biological Sciences, medicine.disease, BODY-MASS INDEX, BINDING-PROTEIN-ALPHA, Insulin/blood, Developmental Biology, Genome-Wide Association Study
Abstract

Seuls les auteurs INRA et les 100 premiers auteurs figurent sur la notice. Group Authors : DIAbet Genetics Replication traits and provide insight into the underlying biological pathways La liste complète des auteurs et de leurs affiliations des auteurs est disponible sur la publication, p. 1004-1005, à l'adresse suivante : https://www.nature.com/articles/ng.2385.pdf; International audience; Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.

Published
2012

37. Abdominal Aortic Aneurysm Is Associated with a Variant in Low-Density Lipoprotein Receptor-Related Protein 1

Author

Wolfgang Lieb, Bruna Gigante, Thodur M. Vasudevan, Georg Homuth, Joseph B. Muhlestein, Mark J. Daly, Andrew P. Morris, Jacqueline de Graaf, Peter Kraft, Ann-Kristin Petersen, André G. Uitterlinden, Jaqueline C M Witteman, Valgerdur Steinthorsdottir, Jutta Palmen, Amanda L. Elliott, Cecilia M. Lindgren, Richard N. Bergman, Benjamin D. Horne, Tony R. Merriman, Robert W. Davies, Jaspal S. Kooner, Gavin Lucas, Carl G. P. Platou, Diederick E. Grobbee, Ruth J. F. Loos, Fulvio Ricceri, Karin Leander, Wen H. L. Kao, Torsten Lauritzen, Qi Sun, Narisu Narisu, Stephan B. Felix, N. William Rayner, Aaron R. Folsom, Robert D. Sayers, Ross D. Blair, John F. Carlquist, Jing Hua Zhao, L. Vicky Phillips, Gabe Crawford, Anne Johnson, Chris Wallace, Paul F. O'Reilly, Jose C. Florez, Andreas Ziegler, Salvatore Panico, Neil R. Robertson, Ruth Frikke-Schmidt, Leif Groop, Pier Mannuccio Mannucci, Stanley L. Hazen, Gerjan Navis, Peter P. Pramstaller, Laura J. Scott, Niels Grarup, Klaus Berger, Christian Gieger, Stephen E. Epstein, Cornelia Huth, Stephanie Tennstedt, Morris J. Brown, Timothy A. Barnes, Naomi Hammond, Ulf de Faire, Vilmundur Gudnason, Marcus Fischer, Nita G. Forouhi, Paolo Vineis, Thomas Quertermous, Christopher Patterson, W.H. Wilson Tang, Konstantinos A. Papadakis, Lincoln Stein, Maciej Tomaszewski, Suthesh Sivapalaratnam, M. S. Sandhu, Feng Zhang, Christa Meisinger, David R. Lewis, Norman Klopp, Roza Blagieva, Gonçalo R. Abecasis, Jeffrey L. Anderson, Lu Qi, Amy J. Swift, Albert Hofman, George Dedoussis, Robert Luben, Daniel J. Rader, Thomas Münzel, Bert Bravenboer, Christopher J. O'Donnell, Elin Org, Veikko Salomaa, Philipp S. Wild, Stephen G. Ellis, Dawn M. Waterworth, Vesela Gateva, Loukianos S. Rallidis, Joseph M. Devaney, kevin Burnand, Robert Clarke, George A. Wells, Harold Snieder, Kay-Tee Khaw, Panos Deloukas, Jaakko Tuomilehto, Louise V. Wain, Eric Boerwinkle, Inke R. König, Amanda J. Bennett, Uwe Völker, Florian Ernst, Markus M. Nöthen, Thomas Sparsø, Jean Tichet, Inga Prokopenko, Paul Johnson, Jaume Marrugat, Marju Orho-Melander, Aloysius G Lieverse, Ian Thomson, Vincent Mooser, Teresa Ferreira, Man Li, Benjamin J. Wright, Ryan P. Welch, Alessandra Allione, Stefan Blankenberg, Veryan Codd, Philippe Froguel, James C. Engert, Pekka Jousilahti, Klaus Stark, Toby Johnson, Cornelia M. van Duijn, Ivo Gut, John J.P. Kastelein, Thomas M. Morgan, Noël P. Burtt, Laura J. McCulloch, Tim D. Spector, Peter S. Chines, Timo T. Valle, Peter Shrader, Christian Dina, Diana Zelenika, Monika Stoll, Peter S. Braund, Harry Campbell, Rainer Rettig, Joep A.W. Teijink, Thomas Illig, Anne Tybjærg-Hansen, Peter Vollenweider, Guangju Zhai, Frits R. Rosendaal, Pau Navarro, James B. Meigs, Ghislain Rocheleau, Li Chen, Pilar Galan, Giuseppe Matullo, Henry Völzke, Samer S. Najjar, Christina Loley, N. Charlotte Onland-Moret, Alison H. Goodall, Riyaz S. Patel, S. Matthijs Boekholdt, Pim van der Harst, John R. B. Perry, Angela Doering, James S. Pankow, Gudmundur Thorgeirsson, Xin Yuan, Patricia B. Munroe, Abbas Dehghan, Tamara B. Smith, Valeriya Lyssenko, Mark I. McCarthy, Andrew T. Hattersley, Simon Futers, Barbara Thorand, Andre G. Uitterlinden, Simon J. Griffin, Winfried März, Nilesh J. Samani, Frank B. Hu, Valeria Romanazzi, Michael N. Weedon, Zouhair Aherrahrou, Ruth McPherson, Benjamin F. Voight, Wolfgang Rathmann, Markus Perola, Stefania Bandinelli, Kathy Stirrups, Hilma Holm, Maja Barbalić, Kiran Musunuru, David Couper, David S. Siscovick, Guillaume Charpentier, Alexandre F.R. Stewart, Patrick Diemert, Leena Peltonen, Serge Hercberg, Robert Roberts, Michael Roden, Rhian Gwilliam, Guillaume Lettre, Eric J.G. Sijbrands, Lambertus A. Kiemeney, Martha Ganser, Silvia Polidoro, Kristin G. Ardlie, Stephen G. Ball, Kristina Bengtsson Boström, Katharine R. Owen, Paul E. de Jong, Felicity Payne, Wendy L. McArdle, Frances M K Williams, Paul Elliott, Roberto Elosua, Devin Absher, Kristian Midthjell, Jan D. Blankensteijn, Nelson B. Freimer, John C. Chambers, G. Kolovou, Karl Andersen, John Webster, Nicholas J. Wareham, Eric E. Schadt, Simon Heath, Diana Rubin, Solveig Gretarsdottir, Willem H. Ouwehand, Oluf Pedersen, Liming Qu, Sandra Eifert, Mary Susan Burnett, Paul Burton, Frank M. van Bockxmeer, Eleftheria Zeggini, Stephen M. Schwartz, Simon C. Potter, Tiinamaija Tuomi, Jeffrey R. Gulcher, David Altshuler, Harald Grallert, Hooman Allayee, Kari Stefansson, Anne H. Child, Sekar Kathiresan, Torben Hansen, Unnur Thorsteinsdottir, Isaac Subirana, Serena Sanna, Muredach P. Reilly, J. Wouter Jukema, H.-Erich Wichmann, François Cambien, Pier Angelica Merlini, Wiek H. van Gilst, Caroline S. Fox, Andrew Smith, Oliviero Olivieri, S Sohrabi, James F. Wilson, Gillian W. Cockerill, Guanming Wu, Andrew D. Morris, Carlos Iribarren, Joshua W. Knowles, Angelo Scuteri, Göran Berglund, Marilyn C. Cornelis, Pascal P. McKeown, Thorsten Reffelmann, Gérard Waeber, Les McNoe, Maris Laan, Dilip K. Naik, Karen L. Mohlke, Matthew Waltham, Rachel E. Clough, Claudia Langenberg, Seamus C. Harrison, Hany Hafez, Timon W. van Haeften, Carlotta Sacerdote, Robert Sladek, Nicola Martinelli, Declan Bradley, Cristen J. Willer, Sarah E. Hunt, Sven Cichon, Udo Seedorf, Winston Hide, Arne Schillert, Cuno S.P.M. Uiterwaal, Steve E. Humphries, Andre A van Rij, Stéphane Cauchi, Michael Boehnke, Beverley M. Shields, Suzannah Bumpstead, Diane M. Becker, Ron Do, Heribert Schunkert, Jacques S. Beckmann, Alistair S. Hall, Mike Sampson, Christine Proença, Lachlan J. M. Coin, Rob M. van Dam, Mohan U. Sivananthan, Martin Farrall, B. Gerry Hill, Simonetta Guarrera, Thijs T. W. van Herpt, Sonia S. Anand, Peter M. Nilsson, Arne Pfeufer, Rafn Benediktsson, Candace Guiducci, Lee M. Kaplan, Michel Marre, Thomas Meitinger, Annette F. Baas, Graham A. Hitman, Roberto Lorbeer, Flora Peyvandi, David J. Hunter, Seraya Maouche, G. Mark Lathrop, Michael R. Erdos, Thomas W. Mühleisen, L. Adrienne Cupples, Anne E. Hughes, Ayellet V. Segrè, Igor Rudan, Kijoung Song, Reijo Laaksonen, G. Bragi Walters, Christopher P. Nelson, Christopher S. Franklin, Richard M. Watanabe, Mattijs E. Numans, Christina Willenborg, Jeanette Erdmann, Alessandra Di Gregorio, John M. C. Connell, Soumya Raychaudhuri, Jian'an Luan, Anthony J. Balmforth, Yurii S. Aulchenko, Arne Schäfer, Catherine M. Rice, Tanja Zeller, Grace Yu, Augustine Kong, Matthew M Thompson, Diego Ardissino, Oliver Hofmann, John R. Thompson, J.B. Wild, Alexander Teumer, Ulf Gyllensten, David P. Strachan, Martin D. Tobin, Michael A. Kaiser, Steve McCarroll, Beverley Balkau, Stephen J. Newhouse, Michael Preuss, John A. Spertus, Janja Nahrstaedt, Neelam Hassanali, Gunnar Sigurdsson, Jaapjan D. Snoep, Angela Döring, Todd Green, D. Julian A. Scott, Christian Herder, Bo Isomaa, Anne U. Jackson, David Hadley, Domenico Girelli, Jes S. Lindholt, Toshiko Tanaka, Ruth Topless, Bernhard O. Boehm, Jana V. van Vliet-Ostaptchouk, Anna-Liisa Hartikainen, Anneli Pouta, Anuj Goel, Stefan Schreiber, Kristian Hveem, Gabriel Crawford, Pierre Meneton, Jürgen Schrezenmeir, Andre M. van Rij, Markku Laakso, Richa Saxena, Joshua C. Bis, Samy Hadjadj, Anders Franco-Cereceda, Noha Lim, Christopher J. Groves, Klaus Strassburger, Stefan E Matthiasson, M. Lourdes Sampietro, Josée Dupuis, Morris J. Bown, Cisca Wijmenga, Shu Ye, Jennifer Freyer, Anders Hamsten, Christian Hengstenberg, Olle Melander, Sarah Edkins, Alberto Smith, Luigi Ferrucci, Murielle Bochud, Lori L. Bonnycastle, Gregory T. Jones, Manuela Uda, Lasse Folkersen, Timothy M. Frayling, Giovanni Tognoni, Torben Jørgensen, Anna F. Dominiczak, Michiel L. Bots, Mario A. Morken, Ian Buysschaert, Colin N. A. Palmer, Andrew Hill, Mark J. Caulfield, Nicolas Sylvius, Nicole Soranzo, Susana Eyheramendy, Christopher Newton-Cheh, Eran Halperin, Mandy van Hoek, Stephen A. Badger, Paul Scheet, Gudmar Thorleifsson, Themistocles L. Assimes, Inês Barroso, Sheila Bingham, Nour Eddine El Mokhtari, Yvonne T. van der Schouw, Andrew J. Lotery, Heather M. Stringham, Marcus Dörr, Per Eriksson, Mark Walker, Mette Refstrup, Anna L. Gloyn, Ann-Christine Syvänen, John F. Peden, Diether Lambrechts, Arshed A. Quyyumi, Katherine S. Elliott, Jonathan Golledge, Edward G. Lakatta, Serkalem Demissie, Lewis C. Becker, Alex S. F. Doney, Najaf Amin, Hugh Watkins, Johanna Kuusisto, Paul Norman, Marjo-Riitta Järvelin, Annette Peters, David Schlessinger, Janet T. Powell, Surgery, ICaR - Ischemia and repair, and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)

Subjects
Male, VASCULAR WALL, Genome-wide association study, 030204 cardiovascular system & hematology, Bioinformatics, Aortic aneurysm, 0302 clinical medicine, Risk Factors, Odds Ratio, Genetics(clinical), Genetics (clinical), Aorta, 0303 health sciences, Cardiovascular diseases [NCEBP 14], Homozygote, Abdominal aortic aneurysm, Organ Specificity, Data Interpretation, Statistical, CORONARY-ARTERY-DISEASE, Female, METALLOPROTEINASE, Sterol Regulatory Element Binding Protein 1, Low Density Lipoprotein Receptor-Related Protein-1, medicine.medical_specialty, SUSCEPTIBILITY LOCI, Locus (genetics), Biology, Polymorphism, Single Nucleotide, DISSECTIONS, Article, Molecular epidemiology [NCEBP 1], 03 medical and health sciences, SDG 3 - Good Health and Well-being, Genome-wide associaton, Coronary-artery-disease, Susceptibility loci, Sequence variant, Vascular wall, Metalloproteinase, Atherosclerosis, Identification, Metaanalysis, Dissections, medicine.artery, Internal medicine, Cell Line, Tumor, medicine, Genetics, Humans, Genetic Predisposition to Disease, ddc:610, GENOME-WIDE ASSOCIATION, METAANALYSIS, 030304 developmental biology, Genetic association, Molecular epidemiology Aetiology, screening and detection [NCEBP 1], Aged, IDENTIFICATION, Case-control study, Odds ratio, medicine.disease, Endocrinology, ATHEROSCLEROSIS, SEQUENCE VARIANT, Genetic Loci, Case-Control Studies, Aortic Aneurysm, Abdominal, Follow-Up Studies, Genome-Wide Association Study
Abstract

Contains fulltext : 97601.pdf (Publisher’s version ) (Closed access) Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 x 10(-5)) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 x 10(-5)). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 x 10(-10), odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression. 9 p.

Published
2011

38. The association between inflammatory biomarkers and metabolically healthy obesity depends of the definition used

Author

S Velho, Pedro Marques-Vidal, Peter Vollenweider, Gérard Waeber, R von Känel, and Dawn M. Waterworth

Subjects
Adult, Male, Interleukin-1beta, Medicine (miscellaneous), 030209 endocrinology & metabolism, Inflammation, Body Mass Index, 03 medical and health sciences, 0302 clinical medicine, Metabolically healthy obesity, Prevalence, Medicine, Humans, 030212 general & internal medicine, Obesity, Interleukin 6, Triglycerides, Aged, 2. Zero hunger, Nutrition and Dietetics, biology, business.industry, Interleukin-6, Tumor Necrosis Factor-alpha, C-reactive protein, Middle Aged, medicine.disease, Inflammatory biomarkers, 3. Good health, Lipoproteins, LDL, C-Reactive Protein, Adipose Tissue, Immunology, Multivariate Analysis, biology.protein, Linear Models, Female, medicine.symptom, business, Lipoproteins, HDL, Body mass index, Biomarkers
Abstract

Background/Objectives:To assess the distribution of interleukin (IL) 1ß IL 6 tumour necrosis factor (TNF) a and C reactive protein (CRP) according to the different definitions of metabolically healthy obesity (MHO).Subjects/Methods:A total of 881 obese (body mass index (BMI) ?30?kg/m(2)) subjects derived from the population based CoLaus Study participated in this study. MHO was defined using six sets of criteria including different combinations of waist blood pressure total high density lipoprotein cholesterol or low density lipoprotein cholesterol triglycerides fasting glucose homeostasis model high sensitivity CRP and personal history of cardiovascular respiratory or metabolic diseases. IL 1ß IL 6 and TNF a were assessed by multiplexed flow cytometric assay. CRP was assessed by immunoassay.Results:On bivariate analysis some but not all definitions of MHO led to significantly lower levels of IL 6 TNF a and CRP compared with non MH obese subjects. Most of these differences became nonsignificant after multivariate analysis. An posteriori analysis showed a statistical power between 9 and 79 depending on the inflammatory biomarker and MHO definition considered. Further increasing sample size to overweight+obese individuals (BMI?25?kg/m(2) n=2917) showed metabolically healthy status to be significantly associated with lower levels of CRP while no association was found for IL 1ß. Significantly lower IL 6 and TNF a levels were also found with some but not all MHO definitions the differences in IL 6 becoming nonsignificant after adjusting for abdominal obesity or percent body fat.Conclusions:MHO individuals present with decreased levels of CRP and depending on MHO definition also with decreased levels in IL 6 and TNF a. Conversely no association with IL 1ß levels was found.European Journal of Clinical Nutrition advance online publication 28 September 2011; doi:10.1038/ejcn.2011.170.

Published
2011

39. Sequencing of Lp-PLA2-encoding PLA2G7 gene in 2000 Europeans reveals several rare loss-of-function mutations

Author

Dawn M. Waterworth, John C. Whittaker, Manas Es, Xin Yuan, Matthew R. Nelson, Silviu-Alin Bacanu, Kijoung Song, Jennifer L. Aponte, Vincent Mooser, Lon R. Cardon, and Xiangyang Kong

Subjects
Phospholipase A2 Inhibitors, Lp-PLA2, Coronary Disease, Biology, Polymorphism, Single Nucleotide, White People, Exon, Genetics, Humans, Allele, Enzyme Inhibitors, rare variant, Gene, Allele frequency, Loss function, Alleles, Pharmacology, Homozygote, Sequence Analysis, DNA, Null allele, Enzyme assay, enzyme activity, Minor allele frequency, Phospholipases A2, Genetics, Population, Amino Acid Substitution, 1-Alkyl-2-acetylglycerophosphocholine Esterase, Mutation, biology.protein, Molecular Medicine, Original Article, re-sequencing
Abstract

Elevated plasma levels of lipoprotein-associated phospholipase A(2) (Lp-PLA2) activity have been shown to be associated with increased risk of coronary heart disease and an inhibitor of this enzyme is under development for the treatment of that condition. A Val279Phe null allele in this gene, that may influence patient eligibility for treatment, is relatively common in East Asians but has not been observed in Europeans. We investigated the existence and functional effects of low frequency alleles in a Western European population by re-sequencing the exons of PLA2G7 in 2000 samples. In all, 19 non-synonymous single-nucleotide polymorphisms (nsSNPs) were found, 14 in fewer than four subjects (minor allele frequency

Published
2011

40. Pathway-Wide Association Study Implicates Multiple Sterol Transport and Metabolism Genes in HDL Cholesterol Regulation

Author

Kai eWang, Andrew C Edmondson, Mingyao eLi, Fan eGao, Atif N Qasim, Joseph M Devaney, Mary Susan eBurnett, Dawn M Waterworth, Vincent eMooser, Struan F.A. Grant, Stephen E Epstein, Muredach P Reilly, Hakon eHakonarson, and Daniel J Rader

Subjects
Candidate gene, lcsh:QH426-470, sterol metabolism, genetic association, Genome-wide association study, 030204 cardiovascular system & hematology, Quantitative trait locus, Biology, 03 medical and health sciences, 0302 clinical medicine, lipid, Genetics, GWAS, HDL-C, Gene, Genetics (clinical), 030304 developmental biology, Genetic association, Original Research, 0303 health sciences, SOAT1, cholesterol, sterol transport, Sterol transport, Phenotype, pathway analysis, lcsh:Genetics, Molecular Medicine
Abstract

Pathway-based association methods have been proposed to be an effective approach in identifying disease genes, when single-marker association tests do not have sufficient power. The analysis of quantitative traits may be benefited from these approaches, by sampling from two extreme tails of the distribution. Here we tested a pathway association approach on a small genome-wide association study (GWAS) on 653 subjects with extremely high high-density lipoprotein cholesterol (HDL-C) levels and 784 subjects with low HDL-C levels. We identified 102 genes in the sterol transport and metabolism pathways that collectively associate with HDL-C levels, and replicated these association signals in an independent GWAS. Interestingly, the pathways include 18 genes implicated in previous GWAS on lipid traits, suggesting that genuine HDL-C genes are highly enriched in these pathways. Additionally, multiple biologically relevant loci in the pathways were not detected by previous GWAS, including genes implicated in previous candidate gene association studies (such as LEPR, APOA2, HDLBP, SOAT2), genes that cause Mendelian forms of lipid disorders (such as DHCR24), and genes expressing dyslipidemia phenotypes in knockout mice (such as SOAT1, PON1). Our study suggests that sampling from two extreme tails of a quantitative trait and examining genetic pathways may yield biological insights from smaller samples than are generally required using single-marker analysis in large-scale GWAS. Our results also implicates that functionally related genes work together to regulate complex quantitative traits, and that future large-scale studies may benefit from pathway-association approaches to identify novel pathways regulating HDL-C levels.

Published
2011

41. Genetic Architecture of Ambulatory Blood Pressure in the General Population Insights From Cardiovascular Gene-Centric Array

Author

Veryan Codd, Christopher P. Nelson, Radoslaw Debiec, Paraskevi Christofidou, John R. Thompson, Vincent Mooser, Gérard Waeber, Fadi J. Charchar, Dawn M. Waterworth, Kijoung Song, Suzanne Rafelt, Maciej Tomaszewski, Peter S. Braund, Martin D. Tobin, Matthew Denniff, Peter Vollenweider, Nilesh J. Samani, Pim van der Harst, Robert J. Hardwick, Paul Burton, Ewa Zukowska-Szczechowska, Faculteit Medische Wetenschappen/UMCG, and Cardiovascular Centre (CVC)

Subjects
Male, 030204 cardiovascular system & hematology, heritability, Cohort Studies, 0302 clinical medicine, Gene Frequency, single nucleotide polymorphism, Prevalence, genetics, Promoter Regions, Genetic, Oligonucleotide Array Sequence Analysis, Genetics, 0303 health sciences, education.field_of_study, biology, blood pressure, Blood Pressure Monitoring, Ambulatory, Middle Aged, Colaus Study, Hypertension, Cardiology, Female, medicine.medical_specialty, Ambulatory blood pressure, Genotype, Population, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, White People, Article, Young Adult, 03 medical and health sciences, Chloride Channels, Internal medicine, Internal Medicine, medicine, Humans, Allele, education, gene, Allele frequency, Genetic Association Studies, Methylenetetrahydrofolate Reductase (NADPH2), 030304 developmental biology, association, United Kingdom, Minor allele frequency, Blood pressure, Genetic Loci, Methylenetetrahydrofolate reductase, biology.protein
Abstract

Genetic determinants of blood pressure are poorly defined. We undertook a large-scale, gene-centric analysis to identify loci and pathways associated with ambulatory systolic and diastolic blood pressure. We measured 24-hour ambulatory blood pressure in 2020 individuals from 520 white European nuclear families (the Genetic Regulation of Arterial Pressure of Humans in the Community Study) and genotyped their DNA using the Illumina HumanCVD BeadChip array, which contains ≈50 000 single nucleotide polymorphisms in >2000 cardiovascular candidate loci. We found a strong association between rs13306560 polymorphism in the promoter region of MTHFR and CLCN6 and mean 24-hour diastolic blood pressure; each minor allele copy of rs13306560 was associated with 2.6 mm Hg lower mean 24-hour diastolic blood pressure ( P =1.2×10 −8 ). rs13306560 was also associated with clinic diastolic blood pressure in a combined analysis of 8129 subjects from the Genetic Regulation of Arterial Pressure of Humans in the Community Study, the CoLaus Study, and the Silesian Cardiovascular Study ( P =5.4×10 −6 ). Additional analysis of associations between variants in gene ontology-defined pathways and mean 24-hour blood pressure in the Genetic Regulation of Arterial Pressure of Humans in the Community Study showed that cell survival control signaling cascades could play a role in blood pressure regulation. There was also a significant overrepresentation of rare variants (minor allele frequency

Published
2010

42. FGF21 signalling pathway and metabolic traits - genetic association analysis

Author

Christian Hengstenberg, Gérard Waeber, Fadi J. Charchar, Maciej Tomaszewski, Dawn M. Waterworth, Klaus Stark, Peter Vollenweider, Ewa Zukowska-Szczechowska, Kijoung Song, Vincent Mooser, Timothy A. Barnes, William Y.S. Wang, Nilesh J. Samani, and Bernhard M. Kaess

Subjects
Adult, Male, Molecular Sequence Data, Genome-wide association study, Single-nucleotide polymorphism, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Genetic determinism, Article, 03 medical and health sciences, 0302 clinical medicine, Quantitative Trait, Heritable, Genotype, Genetic variation, Genetics, Humans, Allele, Receptor, Fibroblast Growth Factor, Type 2, Genetics (clinical), 030304 developmental biology, 2. Zero hunger, 0303 health sciences, Base Sequence, Reproducibility of Results, Middle Aged, 3. Good health, Fibroblast Growth Factors, stomatognathic diseases, Phenotype, 030220 oncology & carcinogenesis, Hypertension, Female, Body mass index, Metabolic Networks and Pathways, Genome-Wide Association Study, Signal Transduction
Abstract

Fibroblast growth factor 21 (FGF21) is a novel master regulator of metabolic profile. The biological actions of FGF21 are elicited upon its klotho beta (KLB)-facilitated binding to FGF receptor 1 (FGFR1), FGFR2 and FGFR3. We hypothesised that common polymorphisms in the FGF21 signalling pathway may be associated with metabolic risk. At the screening stage, we examined associations between 63 common single-nucleotide polymorphisms (SNPs) in five genes of this pathway (FGF21, KLB, FGFR1, FGFR2, FGFR3) and four metabolic phenotypes (LDL cholesterol - LDL-C, HDL-cholesterol - HDL-C, triglycerides and body mass index) in 629 individuals from Silesian Hypertension Study (SHS). Replication analyses were performed in 5478 unrelated individuals of the Swiss CoLaus cohort (imputed genotypes) and in 3030 directly genotyped individuals of the German Myocardial Infarction Family Study (GerMIFS). Of 54 SNPs that met quality control criteria after genotyping in SHS, 4 (rs4733946 and rs7012413 in FGFR1; rs2071616 in FGFR2 and rs7670903 in KLB) showed suggestive association with LDL-C (P=0.0006, P=0.0013, P=0.0055, P=0.011, respectively) and 1 (rs2608819 in KLB) was associated with body mass index (P=0.011); all with false discovery rate q

Published
2010

43. A new highly penetrant form of obesity due to deletions on chromosome 16p11.2

Author

Peter Vollenweider, Leena Peltonen, Audrey Labalme, Jessica L. Buxton, Alessandra Ferrarini, Dawn M. Waterworth, Sven Bergmann, Gérard Waeber, Marie Pigeyre, Sébastien Jacquemont, Vincent Mooser, Audrey Guilmatre, C. Lecoeur, Muriel Holder-Espinasse, Bettina Blaumeiser, Elena G. Bochukova, Ni Huang, Andrew Walley, Danielle Martinet, Peter Jacobson, B. Leheup, Marie-Pierre Lemaitre, A. Brioschi, Julia M. Keogh, Damien Sanlaville, Stephen O'Rahilly, Robert Sladek, Bruno Delobel, Fanny Stutzmann, Sophie Dupuis-Girod, Philippe Froguel, Muriel Gaillard, Anne Philippe, Katrin Männik, Jean-Marie Cuisset, M. Béri-Dexheimer, Lachlan J. M. Coin, Fei Chen, François Pattou, Katrin Õunap, Mari Nelis, A.-L. Hartikainen, Jean-Claude Chèvre, Philippe Jonveaux, Alice Goldenberg, Kay D. MacDermot, Elana Henning, Odile Boute, Sonia Bouquillon, Armand Valsesia, Valérie Malan, Stéphane Lobbens, R. F. Kooy, Alexandra I. F. Blakemore, Marie-Pierre Cordier, Lena M. S. Carlsson, Marjo-Riitta Järvelin, Lars Sjöström, Paul Elliott, C Le Caignec, Florence Fellmann, Nadège Calmels, Dominique Campion, M. M. van Haelst, Vincent Vatin, B. Balkau, Jacques S. Beckmann, Mark I. McCarthy, Robert Caiazzo, Jean-Louis Mandel, Joris Andrieux, Nouchine Hadjikhani, Catherine Vincent-Delorme, David Meyre, Ants Kurg, J. S. El-Sayed Moustafa, Johanna C. Andersson, Jean Chiesa, Michèle Mathieu-Dramard, R. Touraine, Tõnu Esko, Albert David, Alexandre Reymond, Priit Palta, Ghislaine Plessis, Andres Metspalu, Robin G. Walters, Vittorio Giusti, Richard J. Ellis, Bertrand Isidor, Anne-Emmanuelle Ambresin, A J de Smith, I. S. Farooqi, Matthew E. Hurles, Mario Falchi, Medical Research Council (MRC), Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), and Other departments

Subjects
Male, Aging, SAMPLE, Inheritance Patterns, Genome-wide association study, Penetrance, MC4R, Body Mass Index, Cohort Studies, 0302 clinical medicine, SH2B1, Missing heritability problem, Age of Onset, Child, 2. Zero hunger, Genetics, 0303 health sciences, education.field_of_study, Sex Characteristics, Multidisciplinary, Mental-Retardation, Adolescent Adult Age of Onset Aging Body Mass Index Case-Control Studies Child *Chromosome Deletion Chromosomes, Human, Pair 16/*genetics Cognition Disorders/complications/genetics Cohort Studies Europe Female Genome-Wide Association Study Heterozygote Humans Inheritance Patterns/genetics Male Mutation/genetics Obesity/complications/*genetics/*physiopathology *Penetrance Reproducibility of Results Sex Characteristics Young Adult, 3. Good health, Multidisciplinary Sciences, Europe, Adolescent, Adult, Case-Control Studies, Chromosome Deletion, Chromosomes, Human, Pair 16/genetics, Cognition Disorders/complications, Cognition Disorders/genetics, Female, Genome-Wide Association Study, Heterozygote, Humans, Inheritance Patterns/genetics, Mutation/genetics, Obesity/complications, Obesity/genetics, Obesity/physiopathology, Reproducibility of Results, Young Adult, Medical genetics, Science & Technology - Other Topics, CHILDHOOD OBESITY, medicine.medical_specialty, Childhood Obesity, BIRTH, General Science & Technology, Population, Single-nucleotide polymorphism, Biology, Article, Childhood obesity, 03 medical and health sciences, medicine, MICRODELETION, Obesity, GENOME-WIDE ASSOCIATION, AUTISM, education, 030304 developmental biology, COPY NUMBER VARIATION, Science & Technology, MULTIDISCIPLINARY SCIENCES, FRAMESHIFT MUTATION, Individuals, medicine.disease, RISK LOCI, INDIVIDUALS, CIRCULAR BINARY SEGMENTATION, Mutation, Human medicine, Cognition Disorders, MENTAL-RETARDATION, 030217 neurology & neurosurgery, Chromosomes, Human, Pair 16
Abstract

Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western 'obesogenic' environment and a strong genetic contribution. Recent extensive genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms associated with obesity, but these loci together account for only a small fraction of the known heritable component. Thus, the 'common disease, common variant' hypothesis is increasingly coming under challenge. Here we report a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from eight European cohorts. These deletions were absent from healthy non-obese controls and accounted for 0.7% of our morbid obesity cases (body mass index (BMI) >or= 40 kg m(-2) or BMI standard deviation score >or= 4; P = 6.4 x 10(-8), odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with strong effects. This highlights a promising strategy for identifying missing heritability in obesity and other complex traits: cohorts with extreme phenotypes are likely to be enriched for rare variants, thereby improving power for their discovery. Subsequent analysis of the loci so identified may well reveal additional rare variants that further contribute to the missing heritability, as recently reported for SIM1 (ref. 3). The most productive approach may therefore be to combine the 'power of the extreme' in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.

Published
2010

44. Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge

Author

François Pattou, Thomas Sparsø, Eleftheria Zeggini, Michael N. Weedon, J. Graessler, Mandy van Hoek, Suzette J. Bielinski, Amy J. Swift, David S. Siscovick, Michael R. Erdos, Kenneth Rice, Nabila Bouatia-Naji, Benjamin F. Voight, Wolfgang Rathmann, Jarred B. McAteer, Caroline S. Fox, Kari Stefansson, Vincent Mooser, Philippe Froguel, Gordon H. Williams, Mike Sampson, Annelli Sandbæk, Jeffrey R. O'Connell, Stefan R. Bornstein, Robert Sladek, Andrew D. Morris, Torben Jørgensen, Suzannah Bumpstead, Ruth E. Pakyz, James B. Meigs, Denis Rybin, Peter Vollenweider, Valle Tt, Andrew T. Hattersley, Amélie Bonnefond, Knut Krohn, Kijoung Song, Erik Ingelsson, Mario A. Morken, Laura J. Scott, Richard M. Watanabe, Eric J.G. Sijbrands, David Altshuler, Harald Grallert, Vladimir Mayor, Yii-Der Ida Chen, Heather M. Stringham, Bruce M. Psaty, Andrew B. Singleton, Nicole L. Glazer, Peter Schwarz, Jaakko Tuomilehto, Mathieu Firmann, Yvonne Böttcher, Knut Borch-Johnsen, Josée Dupuis, Unnur Thorsteinsdottir, Thomas A. Buchanan, Avan Aihie Sayer, Inga Prokopenko, Thomas Illig, Inês Barroso, Aroon D. Hingorani, Daniel S. Pearson, Luigi Ferrucci, Anna Köttgen, H.-Erich Wichmann, Peter Shrader, Yurii S. Aulchenko, Lu Qi, Olivier Le Bacquer, Eric J. Brunner, Meena Kumari, Karen L. Mohlke, Valgerdur Steinthorsdottir, Laura Pascoe, Lori L. Bonnycastle, Francis S. Collins, Jérôme Delplanque, Guillaume Charpentier, Michael Stumvoll, Mark O. Goodarzi, Felicity Payne, Ruth J. F. Loos, Richard N. Bergman, Gudmar Thorleifsson, Beverley Balkau, Jing Hua Zhao, Timothy M. Frayling, Josephine M. Egan, Kristin Ardlie, Stephen J. Sharp, Jalal Taneera, Mark Walker, W. H. Linda Kao, Nicholas L. Smith, Niels Grarup, Nita G. Forouhi, Oluf Pedersen, Cécile Lecoeur, Andrew Walley, Ann-Christine Syvänen, Eric Boerwinkle, Toby Johnson, Camilla H. Andreasen, Jian Anluan, Dawn M. Waterworth, Toshiko Tanaka, Braxton D. Mitchell, Alisa K. Manning, James S. Pankow, Valeriya Lyssenko, Mika Kivimäki, David Couper, Alex S. F. Doney, Nicholas J. Wareham, Tiinamaija Tuomi, Johanna Kuusisto, Torben Hansen, Christine Cavalcanti-Proença, Richa Saxena, Markku Laakso, James F. Wilson, Bo Isomaa, Marilyn C. Cornelis, David Meyre, Anne U. Jackson, Holly E. Syddall, Alan R. Shuldiner, Michael Boehnke, Peter M. Nilsson, Gabriel Crawford, Claudia Langenberg, Jerome I. Rotter, Peter S. Chines, Cyrus Cooper, Peter Kovacs, Torsten Lauritzen, Christian Dina, Gerard Waeber, Man Li, Anke Tönjes, Narisu Narisu, Jose C. Florez, David M. Nathan, Leif Groop, Claire Levy-Marchal, Cornelia M. van Duijn, Mark I. McCarthy, Frank B. Hu, Trine Welløv Boesgaard, Colin N. Apalmer, Michael Marmot, GIANT consortium, MAGIC investigators, Ophthalmology, Internal Medicine, and Epidemiology

Subjects
Adenylate Cyclase, Male, medicine.medical_specialty, medicine.medical_treatment, Denmark, Incretin, 030209 endocrinology & metabolism, Type 2 diabetes, Biology, Carbohydrate metabolism, Incretins, Polymorphism, Single Nucleotide, Article, Body Mass Index, Receptors, Gastrointestinal Hormone, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Meta-Analysis as Topic, Internal medicine, Diabetes mellitus, medicine, Genetics, Humans, Insulin, RNA, Messenger, 030304 developmental biology, 0303 health sciences, Glucose tolerance test, medicine.diagnostic_test, Gene Expression Profiling, Genetic Variation, Proteins, Glucose Tolerance Test, medicine.disease, Adenylate Cyclase/genetics, Denmark%22">Type="Geographic">Denmark, Diabetes Mellitus, Type 2/genetics, Female, Gene Expression Regulation, Genetic Loci/genetics, Genome-Wide Association Study, Glucose/metabolism, Incretins/genetics, Insulin/metabolism, Polymorphism, Single Nucleotide/genetics, Proteins/genetics, RNA, Messenger/genetics, RNA, Messenger/metabolism, Receptors, Gastrointestinal Hormone/genetics, Receptors, Gastrointestinal Hormone/metabolism, Colaus Study, Glucagon-like peptide-1, Endocrinology, Glucose, Diabetes Mellitus, Type 2, Genetic Loci, TCF7L2, Adenylyl Cyclases
Abstract

Udgivelsesdato: 2010-Feb Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958-30,620). We identify variants at the GIPR locus associated with 2-h glucose level (rs10423928, beta (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 x 10(-15)). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 x 10(-17); ratio of insulin to glucose area under the curve, P = 1.3 x 10(-16)) and diminished incretin effect (n = 804; P = 4.3 x 10(-4)). We also identified variants at ADCY5 (rs2877716, P = 4.2 x 10(-16)), VPS13C (rs17271305, P = 4.1 x 10(-8)), GCKR (rs1260326, P = 7.1 x 10(-11)) and TCF7L2 (rs7903146, P = 4.2 x 10(-10)) associated with 2-h glucose. Of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09-1.15, P = 4.8 x 10(-18)).

Published
2010

45. A genome-wide association study of neuroticism in a population-based sample

Author

Peter Vollenweider, Vincent Mooser, Pierandrea Muglia, Dawn M. Waterworth, Federica Tozzi, Athos Antoniades, Nicholas Galwey, David J. Balding, Federico C. F. Calboli, Martin Preisig, Gérard Waeber, and Marvin Johnson

Subjects
Male, Neurotic Disorders, Genome-wide association study, GENERALIZED ANXIETY DISORDER, 0302 clinical medicine, CARDIOVASCULAR RISK-FACTORS, Big Five personality traits, Genetics and Genomics/Genetics of Disease, media_common, 0303 health sciences, education.field_of_study, Multidisciplinary, HERITABILITY, Middle Aged, Neuroticism, Multidisciplinary Sciences, ALZHEIMERS-DISEASE, Anxiety, Science & Technology - Other Topics, Medicine, Female, medicine.symptom, Research Article, Adult, medicine.medical_specialty, GENES, Genotype, General Science & Technology, media_common.quotation_subject, Science, Population, TWIN, Biology, PERSONALITY-TRAIT NEUROTICISM, Genetics and Genomics/Complex Traits, Population stratification, Polymorphism, Single Nucleotide, Personality-Trait Neuroticism, Generalized Anxiety Disorder, Cardiovascular Risk-Factors, Major Depression, Linkage Analysis, Alzheimers-Disease, 1st Onset, Twin, Heritability, Genes, Colaus Study, 03 medical and health sciences, Glypicans, MD Multidisciplinary, mental disorders, medicine, Personality, Humans, Genetic Predisposition to Disease, Psychiatry, education, 030304 developmental biology, Aged, Science & Technology, LINKAGE ANALYSIS, Membrane Proteins, MAJOR DEPRESSION, Eysenck Personality Questionnaire, Cyclic Nucleotide Phosphodiesterases, Type 3, Cyclic Nucleotide Phosphodiesterases, Type 4, 030217 neurology & neurosurgery, 1ST ONSET, Demography, Genome-Wide Association Study, Neuroscience
Abstract

Neuroticism is a moderately heritable personality trait considered to be a risk factor for developing major depression, anxiety disorders and dementia. We performed a genome-wide association study in 2,235 participants drawn from a population-based study of neuroticism, making this the largest association study for neuroticism to date. Neuroticism was measured by the Eysenck Personality Questionnaire. After Quality Control, we analysed 430,000 autosomal SNPs together with an additional 1.2 million SNPs imputed with high quality from the Hap Map CEU samples. We found a very small effect of population stratification, corrected using one principal component, and some cryptic kinship that required no correction. NKAIN2 showed suggestive evidence of association with neuroticism as a main effect (p < 10(-6)) and GPC6 showed suggestive evidence for interaction with age (p approximately = 10(-7)). We found support for one previously-reported association (PDE4D), but failed to replicate other recent reports. These results suggest common SNP variation does not strongly influence neuroticism. Our study was powered to detect almost all SNPs explaining at least 2% of heritability, and so our results effectively exclude the existence of loci having a major effect on neuroticism.

Published
2010

46. Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy

Author

Peter Vollenweider, Joan Santamaria, Antonio Benetó, Stine Knudsen, Vincent Mooser, Michel Lecendreux, Hyun Hor, Sven Bergmann, Corinne Pfister, Isabelle Arnulf, Yves Dauvilliers, Peter Geisler, Claire E H M Donjacour, Gert J. Lammers, Johannes Mathis, Sebastiaan Overeem, Jacques S. Beckmann, Julie Vienne Bürki, Alex Iranzo, Mehdi Tafti, Claudio L. Bassetti, Frans H.J. Claas, Armand Valsesia, Geert Mayer, Dawn M. Waterworth, Brice Petit, Rosa Peraita Adrados, Gérard Waeber, Zoltán Kutalik, Raphael Heinzer, Gérard Didelot, Ioannis Theodorou, Michel Billiard, Guadalupe Ercilla, Poul Jennum, Willem Verduijn, and José L. Vicario

Subjects
Adult, Male, musculoskeletal diseases, Population, Genome-wide association study, Human leukocyte antigen, Biology, White People, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, immune system diseases, Genetics, medicine, Humans, Genetic Predisposition to Disease, copy number variation sleep-disorders cataplexy genetics diseases risk 2nd, education, skin and connective tissue diseases, Allele frequency, Aged, Narcolepsy, 030304 developmental biology, HLA-D Antigens, 0303 health sciences, education.field_of_study, Haplotype, Case-control study, Odds ratio, Middle Aged, medicine.disease, 3. Good health, Haplotypes, Case-Control Studies, Immunology, Female, Functional Neurogenomics [DCN 2], 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Contains fulltext : 88508.pdf (Publisher’s version ) (Closed access) Narcolepsy is a rare sleep disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1*1501-DQB1*0602 haplotype is common in the general population (15-25%), it has been suggested that it is almost necessary but not sufficient for developing narcolepsy. To further define the genetic basis of narcolepsy risk, we performed a genome-wide association study (GWAS) in 562 European individuals with narcolepsy (cases) and 702 ethnically matched controls, with independent replication in 370 cases and 495 controls, all heterozygous for DRB1*1501-DQB1*0602. We found association with a protective variant near HLA-DQA2 (rs2858884; P < 3 x 10(-8)). Further analysis revealed that rs2858884 is strongly linked to DRB1*03-DQB1*02 (P < 4 x 10(-43)) and DRB1*1301-DQB1*0603 (P < 3 x 10(-7)). Cases almost never carried a trans DRB1*1301-DQB1*0603 haplotype (odds ratio = 0.02; P < 6 x 10(-14)). This unexpected protective HLA haplotype suggests a virtually causal involvement of the HLA region in narcolepsy susceptibility. 01 september 2010

Published
2010

47. Genome-wide meta-analysis for serum calcium identifies significantly associated SNPs near the calcium-sensing receptor (CASR) gene

Author

Gérard Waeber, Andrew B. Singleton, Toby Johnson, Daniel F. Gudbjartsson, Gudmundur I. Eyjolfsson, Peter Vollenweider, Yuri Milaneschi, Vincent Mooser, Diana Marek, Jacques S. Beckmann, Noam D. Beckmann, John C. Chambers, Unnur Styrkarsdottir, Kari Stefansson, Hilma Holm, Gunnar Sigurdsson, Stefania Bandinelli, Toshiko Tanaka, Joban Sehmi, Yun Li, Sven Bergmann, Dawn M. Waterworth, Murielle Bochud, Jack M. Guralnik, Paul Elliott, Unnur Thorsteinsdottir, Karen Kapur, Ranil DeSilva, Jaspal S. Kooner, James Scott, Weihua Zhang, Zoltán Kutalik, Unnur S. Bjornsdottir, Angelo DiIorio, Dena G. Hernandez, Luigi Ferrucci, and Medical Research Council (MRC)

Subjects
Cancer Research, Candidate gene, Linkage disequilibrium, CARDIOVASCULAR MORTALITY, LOCI, Genome-wide association study, 0302 clinical medicine, PRIMARY HYPERPARATHYROIDISM, Genetics (clinical), Genetics, Genetics & Heredity, 0303 health sciences, education.field_of_study, A986S POLYMORPHISM, 030220 oncology & carcinogenesis, Calcium-sensing receptor, BONE-MINERAL DENSITY, Life Sciences & Biomedicine, Research Article, medicine.medical_specialty, lcsh:QH426-470, Population, European Continental Ancestry Group, Public Health and Epidemiology, chemistry.chemical_element, Single-nucleotide polymorphism, Biology, Calcium, HYPOCALCIURIC HYPERCALCEMIA, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, ADULT, Internal medicine, medicine, Humans, CORONARY-HEART-DISEASE, education, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Calcium metabolism, 0604 Genetics, Science & Technology, Genome, Human, Genetics and Genomics, Calcium/blood, European Continental Ancestry Group/statistics & numerical data, Genome-Wide Association Study/statistics & numerical data, Receptors, Calcium-Sensing/genetics, COMMON VARIANT, lcsh:Genetics, Endocrinology, chemistry, MYOCARDIAL-INFARCTION, Computational Biology/Population Genetics, Receptors, Calcium-Sensing, Computational Biology/Genomics, Genome-Wide Association Study, Developmental Biology
Abstract

Calcium has a pivotal role in biological functions, and serum calcium levels have been associated with numerous disorders of bone and mineral metabolism, as well as with cardiovascular mortality. Here we report results from a genome-wide association study of serum calcium, integrating data from four independent cohorts including a total of 12,865 individuals of European and Indian Asian descent. Our meta-analysis shows that serum calcium is associated with SNPs in or near the calcium-sensing receptor (CASR) gene on 3q13. The top hit with a p-value of 6.3×10-37 is rs1801725, a missense variant, explaining 1.26% of the variance in serum calcium. This SNP had the strongest association in individuals of European descent, while for individuals of Indian Asian descent the top hit was rs17251221 (p = 1.1×10-21), a SNP in strong linkage disequilibrium with rs1801725. The strongest locus in CASR was shown to replicate in an independent Icelandic cohort of 4,126 individuals (p = 1.02×10-4). This genome-wide meta-analysis shows that common CASR variants modulate serum calcium levels in the adult general population, which confirms previous results in some candidate gene studies of the CASR locus. This study highlights the key role of CASR in calcium regulation., Author Summary Calcium levels in blood serum play an important role in many biological processes. The regulation of serum calcium is under strong genetic control. This study describes the first meta-analysis of a genome-wide association study from four cohorts totaling 12,865 participants of European and Indian Asian descent. Confirming previous results in some candidate gene studies, we find that common polymorphisms at the calcium-sensing receptor (CASR) gene locus are associated with serum calcium concentrations. We show that CASR variants give rise to the strongest signals associated with serum calcium levels in both European and Indian Asian populations, while no other locus reaches genome-wide significance. Our results show that CASR is a key player in genetic regulation of serum calcium in the adult general population.

Published
2010
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48. Genetic loci influencing kidney function and chronic kidney disease

Author

Thomas Eggermann, James Scott, Graham M. Lord, L.J. Ubink-Veltmaat, Weihua Zhang, Gérard Waeber, Georg Schlieper, Michael J.E. Sternberg, Brenda W.J.H. Penninx, Stephan J. L. Bakker, Elina Hyppönen, Toshiko Tanaka, Bo Hedblad, Xijin Han, Peter Vollenweider, Johannes H. Smit, Anneli Pouta, Yun Li, Olle Melander, Nita G. Forouhi, Morris J. Brown, Joban Sehmi, George Davey Smith, Ruth J. F. Loos, Vincent Mooser, Jaap J. Homan van der Heide, Manuela Uda, Mark N. Wass, Debbie A Lawlor, Gonçalo R. Abecasis, Klaus Zerres, Nicole Soranzo, Leena Peltonen, Maria P. Hernandez-Fuentes, Marketa Sjögren, Dawn M. Waterworth, Ron T. Gansevoort, Mark J. Caulfield, Nada Dimkovic, Shah Ebrahim, Louise Nordfors, Harold Snieder, Ranil de Silva, Céline Maréchal, Olivier Devuyst, Ioana Cotlarciuc, Toby Johnson, John M. C. Connell, Jian'an Luan, Martin Schalling, R. Swaminathan, Peter Stenvinkel, Nanne Kleefstra, Henk J. G. Bilo, Guohong Deng, Patrick H. Maxwell, Bouke G. Hepkema, Inga Prokopenko, Karin Luttropp, Luigi Ferrucci, Murielle Bochud, Gerjan Navis, Kourosh R. Ahmadi, Anna F. Dominiczak, Paul Elliott, H. Terence Cook, Serena Sanna, Mark Dockrell, Chris Wallace, Marc A. Seelen, Esperanza Perucha, Marta Lapsley, Marjo-Riitta Järvelin, Jürgen Floege, David Schlessinger, Afshin Parsa, Vasiliki Lagou, Liz Lightstone, Patricia B. Munroe, Daniel P. Gale, Paul E. de Jong, John C. Chambers, Martin Farrall, Tim D. Spector, Alan R. Shuldiner, Pim van der Harst, Mark I. McCarthy, Jacqui Beckmann, Lambert D Dikkeschei, Nilesh J. Samani, Paul Roderick, Jaspal S. Kooner, Aimo Ruokonen, Nicholas J. Wareham, Psychiatry, NCA - Anxiety & Depression, EMGO - Mental health, Other departments, Chambers, John C, Zhang, Weihua, Lord, Graham M, Van der Harst, Pim, Hypponen, Elina, Kooner, Jaspal S, Cardiovascular Centre (CVC), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Neuroscience Campus Amsterdam - Anxiety & Depression, and EMGO+ - Mental Health

Subjects
Genetic Markers, medicine.medical_specialty, Genotype, Urinary system, 030232 urology & nephrology, Renal function, Genome-wide association study, Kidney, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Genetics, medicine, Humans, Genetic Predisposition to Disease, Cystatin C, oct2, 030304 developmental biology, 0303 health sciences, Creatinine, biology, Models, Genetic, Genetic Variation, Biological Transport, medicine.disease, 3. Good health, Europe, Endocrinology, medicine.anatomical_structure, chemistry, Gene Expression Regulation, Genetic marker, biology.protein, Kidney Failure, Chronic, Kidney disease, Genome-Wide Association Study, Glomerular Filtration Rate
Abstract

Using genome-wide association, we identify common variants at 2p12-p13, 6q26, 17q23 and 19q13 associated with serum creatinine, a marker of kidney function (P = 10−10 to 10−15). Of these, rs10206899 (near NAT8, 2p12-p13) and rs4805834 (near SLC7A9, 19q13) were also associated with chronic kidney disease (P = 5.0 × 10−5 and P = 3.6 × 10−4, respectively). Our findings provide insight into metabolic, solute and drug-transport pathways underlying susceptibility to chronic kidney disease. Refereed/Peer-reviewed

Published
2010

49. Clear detection of ADIPOQ locus as the major gene for plasma adiponectin: results of genome-wide association analyses including 4659 European individuals

Author

James B. Meigs, George Davey Smith, Kijoung Song, Stefan Coassin, Ben A. Oostra, Olga D. Carlson, Florian Kronenberg, Dawn M. Waterworth, Cornelia M. van Duijn, Ko Willems van Dijk, Toshiko Tanaka, Yurii S. Aulchenko, David M. Evans, Christian Fuchsberger, Peter P. Pramstaller, Josephine M. Egan, Keith Burling, Nicole Soranzo, Andrew A. Hicks, Vincent Mooser, Marie-France Hivert, Beate Glaser, Stefania Bandinelli, Iris M. Heid, Barbara Kollerits, Jack M. Guralnik, Timothy M. Frayling, John R. B. Perry, Peter Henneman, Thomas Illig, Josée Dupuis, Rune R. Frants, Jose C. Florez, J. Brent Richards, Tim D. Spector, Peter Vollenweider, Luigi Ferrucci, Najaf Amin, Thomas W. Winkler, Irene Pichler, Nicholas J. Timpson, Barbara Thorand, Epidemiology, and Clinical Genetics

Subjects
Male, medicine.medical_specialty, Genotype, Genome-wide association study, Locus (genetics), Type 2 diabetes, Biology, ADIPOQ Gene, Polymorphism, Single Nucleotide, Article, Sex Factors, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Humans, Metabolic Syndrome, Genetics, Polymorphism, Genetic, Adiponectin, Adiponectin Genome-wide association study Polymorphism Cardiovascular disease Metabolic syndrome metabolic syndrome insulin-resistance apm1 gene risk promoter disease obesity prevalence caucasians contribute, Computational Biology, nutritional and metabolic diseases, medicine.disease, Colaus Study, Major gene, Europe, Phenotype, Endocrinology, Gene Expression Regulation, Cardiovascular Diseases, Female, Metabolic syndrome, Cardiology and Cardiovascular Medicine, hormones, hormone substitutes, and hormone antagonists, Genome-Wide Association Study
Abstract

Objective: Plasma adiponectin is strongly associated with various components of metabolic syndrome, type 2 diabetes and cardiovascular outcomes. Concentrations are highly heritable and differ between men and women. We therefore aimed to investigate the genetics of plasma adiponectin in men and women. Methods: Wecombined genome-wide association scans of three population-based studies including 4659 persons. For the replication stage in 13795 subjects, we selected the 20 top signals of the combined analysis, as well as the 10 top signals with p-values less than 1.0 x 10(-4) for each the men-and the women-specific analyses. We further selected 73 SNPs that were consistently associated with metabolic syndrome parameters in previous genome-wide association studies to check for their association with plasma adiponectin. Results: The ADIPOQ locus showed genome-wide significant p-values in the combined (p = 4.3 x 10(-24)) as well as in both women-and men-specific analyses (p = 8.7 x 10(-17) and p = 2.5 x 10(-11), respectively). None of the other 39 top signal SNPs showed evidence for association in the replication analysis. None of 73 SNPs from metabolic syndrome loci e x hibited association with plasma adiponectin (p > 0.01). Conclusions: We demonstrated the ADIPOQ gene as the only major gene for plasma adiponectin, which e x plains 6.7% of the phenotypic variance. We further found that neither this gene nor any of the metabolic syndrome loci e x plained the se x differences observed for plasma adiponectin. Larger studies are needed to identify more moderate genetic determinants of plasma adiponectin. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Published
2010

50. Genome-Wide Association Scan Shows Genetic Variants in the FTO Gene Are Associated with Obesity-Related Traits

Author

Karol Estrada, Thomas Meitinger, Christopher J. Groves, Tim D. Spector, Paul W. Franks, Weihua Zhang, Nicholas J. Timpson, Leena Peltonen, M. Carola Zillikens, Alexander W. Drong, Leonie C. Jacobs, Massimo Mangino, Nita G. Forouhi, Fredrik Karpe, Inga Prokopenko, Amanda J. Bennett, G. Mark Lathrop, Cornelia M. van Duijn, Albert Hofman, Michael Boehnke, Inês Barroso, Veikko Salomaa, Lu Qi, John F. Peden, Fernando Rivadeneira, Mark I. McCarthy, Jaakko Tuomilehto, Joel N. Hirschhorn, Nilesh J. Samani, Frank B. Hu, Edward G. Lakatta, Alex S. F. Doney, Najaf Amin, Anders Hamsten, Hugh Watkins, Johanna Kuusisto, Elizabeth K. Speliotes, Narisu Narisu, Guido Fischer, Wendy L. McArdle, David Hadley, Manjinder S. Sandhu, Francis S. Collins, Paul Elliott, Vincent Mooser, Luigi Ferrucci, Leif Groop, H.-Erich Wichmann, Serena Sanna, Xin Yuan, Anna F. Dominiczak, Peter S. Chines, Lachlan J. M. Coin, Lynn Cherkas, Cyrus Cooper, Mario A. Morken, Colin N. A. Palmer, Frida Renström, Blanca M. Herrera, Kijoung Song, Markku Laakso, Marjo-Riitta Järvelin, Kaisa Silander, David Schlessinger, Kari Stefansson, Peter Nordström, David P. Strachan, Angelo Scuteri, Michael N. Weedon, Jia N.an Luan, Rolf Holle, Joshua C. Randall, Yurii S. Aulchenko, Aimo Ruokonen, Stefania Bandinelli, Andrew D. Morris, Shah Ebrahim, Noha Lim, Nicholas J. Wareham, Tiinamaija Tuomi, Mark J. Caulfield, Paul Scheet, Karen L. Mohlke, Gudmar Thorleifsson, Debbie A Lawlor, Karen A. Jameson, Peter Almgren, Lori L. Bonnycastle, Candace Guiducci, Timothy M. Frayling, David J. Hunter, Amy J. Swift, Peter Vollenweider, Iris M. Heid, Stephen J. Chanock, Felicity Payne, Ruth J. F. Loos, George Davey Smith, Gonçalo R. Abecasis, Jaana Laitinen, Andrew T. Hattersley, Cristen J. Willer, Suzannah Bumpstead, G. Bragi Walters, Pekka Jousilahti, Harald Grallert, Laura J. Scott, Panos Deloukas, Cuilin Zhang, Ben A. Oostra, Thomas Illig, Claudia Lamina, Dawn M. Waterworth, Angela Doering, Patricia B. Munroe, Toshiko Tanaka, Chris Wallace, Unnur Thorsteinsdottir, Gabriel Crawford, John C. Chambers, John W. Holloway, Christian Gieger, Gérard Waeber, Jacqueline C.M. Witteman, Ian N. M. Day, Michael R. Erdos, Augustine Kong, Bo Isomaa, Anne U. Jackson, Scott M. Grundy, Andrew P. Morris, Hua Zhao Jing, Aki S. Havulinna, André G. Uitterlinden, Valgerdur Steinthorsdottir, Cecilia M. Lindgren, Richard N. Bergman, Anna Nordström, Manuela Uda, Jaspal S. Kooner, Nicole Soranzo, Heather M. Stringham, Helen N. Lyon, Broad Institute of MIT and Harvard, Peltonen, Leena, Hunter, David J., Guiducci, Candace, Crawford, Gabriel, Hirschhorn, Joel N., Lyon, Helen N., Speliotes, Elizabeth K., and Medical Research Council (MRC)

Subjects
Male, Cancer Research, Genome-wide association study, Giant Consortium, QH426-470, FTO gene, Body Mass Index, Cohort Studies, Diabetes and Endocrinology/Obesity, 0302 clinical medicine, Waist–hip ratio, Germany, Body Fat Distribution, Environmental conditions, Age of Onset, Procardis Consortia, Child, Genetics and Genomics/Genetics of Disease, Genetics (clinical), Adiposity, Genetics & Heredity, Genetics and Genomics/Medical Genetics, Genetics, 0303 health sciences, 3. Good health, Diabetes and Endocrinology, Wellcome Trust Case Control Consortium, Female, France, Waist Circumference, Lysophospholipase, Oxidoreductases, Life Sciences & Biomedicine, Research Article, Adult, Waist, Adolescent, Single-nucleotide polymorphism, Genetics and Genomics/Complex Traits, Biology, Polymorphism, Single Nucleotide, Sequence variants, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, Humans, Genetic Predisposition to Disease, Obesity, Diabetes and Endocrinology/Type 2 Diabetes, Molecular Biology, Alleles, Ecology, Evolution, Behavior and Systematics, Imputation, 030304 developmental biology, Genetic association, waist circumference, adult obesity, fto gene, environmental-conditions, insulin-resistance, sequence variants, common variants, expression, imputation, height, 0604 Genetics, Science & Technology, Height, Genome, Human, Waist-Hip Ratio, Common variants, Body Weight, Genetics and Genomics, Insulin-resistance, medicine.disease, Transcription Factor AP-2, Genetic Loci, Methionine Sulfoxide Reductases, Adult obesity, Body mass index, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study
Abstract

To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist–hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9×10[superscript −11]) and MSRA (WC, P = 8.9×10[superscript −9]). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6×10[superscript −8]). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity., Vandervell Foundation and Wellcome Trust (068545/Z/02, GR072960, GR076113, GR069224, 086596/Z/08/Z), University of Oxford, UK Department of Health Policy Research Programme, UK National Institute of Health Research, Swedish Medical Research Council (8691), Swedish Heart-Lung Foundation, Support for Science Funding (UK), Stockholm County Council (560183), Scottish Executive Chief Scientist's Office, Peninsula Medical School, Novartis, Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) (050-060-810), Netherlands Center of Medical Systems Biology, Netherlands Organization for Scientific Research, National Human Genome Research Institute (HG02651), National Institute of Diabetes and Digestive and Kidney Diseases (DK062370; DK072193; DK075787; DK079466; DK080145; DK067288; DK07191), National Heart, Lung and Blood Institute (HL087679 [STAMPEED], HL084729), National Institute on Aging, National Institutes of Health (US: intramural programs (1Z01-HG000024), Munich Center of Health Sciences, MedStar Research Institute, Medical Research Council UK (G0000934, G0000649, G0601261, G0500539, G9521010D, G0600705), Knut and Alice Wallenberg Foundation, Kings College London, Karolinska Institute, Sigrid Juselius Foundation, GlaxoSmithKline, German National Genome Research Net, Folkhälsan Research Foundation, Finnish Cultural Foundation, Finnish Heart Association, Swiss National Science Foundation (Grant 33CSCO-122661), Faculty of Biology and Medicine of Lausanne, Switzerland, European Commission (Framework VI: LSHG-CT-2004-518153 [EURODIA]; LSHG-CT-2004-512066 [MolPAGE]; LSHM-CT-2006-037197; LSHM-CT-2003-503041; QL46-CT-2002-02629 [GENOMOS]; LSHM-CT-2007-037273; Framework VII: HEALTH-F4-2007- 201413 [ENGAGE]), Diabetes UK, Cancer Research UK, CIDR (NIH Contract Number N01-HG-65403), Camstrad, British Heart Foundation, Biotechnology and Biological Sciences Research Council (UK), Biocentrum Helsinki, The Barts and The London Charity, AstraZeneca AB, Arthritis Research Campaign, American Diabetes Association, ADA Smith Family Foundation Pinnacle Program, Academy of Finland (104781, 124243)

Published
2009

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