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1. 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

2. Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations

Author

Cindy G. Boer, Konstantinos Hatzikotoulas, Lorraine Southam, Lilja Stefánsdóttir, Yanfei Zhang, Rodrigo Coutinho de Almeida, Tian T. Wu, Jie Zheng, April Hartley, Maris Teder-Laving, Anne Heidi Skogholt, Chikashi Terao, Eleni Zengini, George Alexiadis, Andrei Barysenka, Gyda Bjornsdottir, Maiken E. Gabrielsen, Arthur Gilly, Thorvaldur Ingvarsson, Marianne B. Johnsen, Helgi Jonsson, Margreet Kloppenburg, Almut Luetge, Sigrun H. Lund, Reedik Mägi, Massimo Mangino, Rob R.G.H.H. Nelissen, Manu Shivakumar, Julia Steinberg, Hiroshi Takuwa, Laurent F. Thomas, Margo Tuerlings, George C. Babis, Jason Pui Yin Cheung, Jae Hee Kang, Peter Kraft, Steven A. Lietman, Dino Samartzis, P. Eline Slagboom, Kari Stefansson, Unnur Thorsteinsdottir, Jonathan H. Tobias, André G. Uitterlinden, Bendik Winsvold, John-Anker Zwart, George Davey Smith, Pak Chung Sham, Gudmar Thorleifsson, Tom R. Gaunt, Andrew P. Morris, Ana M. Valdes, Aspasia Tsezou, Kathryn S.E. Cheah, Shiro Ikegawa, Kristian Hveem, Tõnu Esko, J. Mark Wilkinson, Ingrid Meulenbelt, Ming Ta Michael Lee, Joyce B.J. van Meurs, Unnur Styrkársdóttir, Eleftheria Zeggini, John Loughlin, Nigel Arden, Fraser Birrell, Andrew Carr, Panos Deloukas, Michael Doherty, Andrew W. McCaskie, William E.R. Ollier, Ashok Rai, Stuart H. Ralston, Tim D. Spector, Gillian A. Wallis, Amy E. Martinsen, Cristen Willer, Egil Andreas Fors, Ingunn Mundal, Knut Hagen, Kristian Bernhard Nilsen, Marie Udnesseter Lie, Sigrid Børte, Ben Brumpton, Jonas Bille Nielsen, Lars G. Fritsche, Wei Zhou, Ingrid Heuch, Kjersti Storheim, Evangelos Tyrpenou, Athanasios Koukakis, Dimitrios Chytas, Dimitrios Stergios Evangelopoulos, Chronopoulos Efstathios, Spiros Pneumaticos, Vasileios S. Nikolaou, Konstantinos Malizos, Lydia Anastasopoulou, Goncalo Abecasis, Aris Baras, Michael Cantor, Giovanni Coppola, Andrew Deubler, Aris Economides, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Alan Shuldiner, Katia Karalis, Katherine Siminovitch, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, Thomas D. Schleicher, Maria Sotiropoulos Padilla, Louis Widom, Sarah E. Wolf, Manasi Pradhan, Kia Manoochehri, Xiaodong Bai, Suganthi Balasubramanian, Boris Boutkov, Gisu Eom, Lukas Habegger, Alicia Hawes, Olga Krasheninina, Rouel Lanche, Adam J. Mansfield, Evan K. Maxwell, Mona Nafde, Sean O’Keeffe, Max Orelus, Razvan Panea, Tommy Polanco, Ayesha Rasool, William Salerno, Jeffrey C. Staples, Dadong Li, Deepika Sharma, Ilanjana Banerjee, Jonas Bovijn, Adam Locke, Niek Verweij, Mary Haas, George Hindy, Tanima De, Parsa Akbari, Olukayode Sosina, Manuel A.R. Ferreira, Marcus B. Jones, Jason Mighty, Michelle G. LeBlanc, Lyndon J. Mitnaul, and Internal Medicine

Subjects
Resource, genome-wide association meta-analysis, Disease, Osteoarthritis, effector genes, Biology, Bioinformatics, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Drug Targets, Effector Genes, Functional Genomics, Genetic Architecture, Genome-wide Association Meta-analysis, Spine osteoarthritis, Risk Factors, drug targets, medicine, Humans, Genetic Predisposition to Disease, Sex Characteristics, Cartilage, Correction, medicine.disease, Phenotype, genetic architecture, Genetic architecture, ddc, osteoarthritis, Genetics, Population, medicine.anatomical_structure, Subchondral bone, Female, Functional genomics, functional genomics, Genome-Wide Association Study, Signal Transduction
Abstract

Summary Osteoarthritis affects over 300 million people worldwide. Here, we conduct a genome-wide association study meta-analysis across 826,690 individuals (177,517 with osteoarthritis) and identify 100 independently associated risk variants across 11 osteoarthritis phenotypes, 52 of which have not been associated with the disease before. We report thumb and spine osteoarthritis risk variants and identify differences in genetic effects between weight-bearing and non-weight-bearing joints. We identify sex-specific and early age-at-onset osteoarthritis risk loci. We integrate functional genomics data from primary patient tissues (including articular cartilage, subchondral bone, and osteophytic cartilage) and identify high-confidence effector genes. We provide evidence for genetic correlation with phenotypes related to pain, the main disease symptom, and identify likely causal genes linked to neuronal processes. Our results provide insights into key molecular players in disease processes and highlight attractive drug targets to accelerate translation., Graphical abstract, Highlights • A multicohort study identifies 52 previously unknown osteoarthritis genetic risk variants • Similarities and differences in osteoarthritis genetic risk depend on joint sites • Osteoarthritis genetic components are associated with pain-related phenotypes • High-confidence effector genes highlight potential targets for drug intervention, A multicohort genome-wide association meta-analysis of osteoarthritis highlights the impact of joint site types on the features of genetic risk variants and the link between osteoarthritis genetics and pain-related phenotypes, pointing toward potential targets for therapeutic intervention.

Published
2021

3. Genome-wide analysis of 944 133 individuals provides insights into the etiology of haemorrhoidal disease

Author

Wolfgang Lieb, Johannes Jongen, Mauro D'Amato, Ulrike Nowak-Göttl, François Cossais, Peter R. Strege, Tenghao Zheng, Verena Limperger, Volker Kahlke, Ralf Junker, Tom H. Karlsen, Olga V. Sazonova, Fabian H. Leendertz, Jochen Hampe, Gabriele Mayr, Matthias Laudes, Go Ito, Christian Datz, Frank Bokelmann, Eivind Ness-Jensen, Karina Banasik, Maris Teder-Laving, Brett Vanderwerff, Anne Heidi Skogholt, Anita Pandit, Philip Rosenstiel, Georg Hemmrich-Stanisak, Henrik Ullum, Hans Günter Peleikis, Sebastian Hinz, Malte C. Rühlemann, Justus Gross, Kerstin Mätz-Rensing, Henry Völzke, Andre Franke, Cristina Leal Rodríguez, Thomas Becker, Isabella Friis Jørgensen, Andrea Gsur, Nikolaos Margetis, Christopher Georg Németh, Sisi Chen, Sebastian Zeissig, Martin Schulzky, Witigo von Schönfels, Florian Uellendahl-Werth, Gianrico Farrugia, Tobias Gräßle, Alexander Hendricks, David Ellinghaus, Lars G. Fritsche, Julia Wilking, Vladimir Vacic, Norbert Frey, Jurgita Skieceviciene, Bodo Schniewind, Thilo Wedel, Hartmut Clausnitzer, Michael Forster, Michael Wittig, Arthur Beyder, Laurent F. Thomas, Greta Burmeister, Juozas Kupcinskas, Kristian Hveem, Ilka Vogel, Elizabeth S. Noblin, Jürgen Tepel, Myrko Zobel, Søren Brunak, Matthew Zawistowski, Tilman Laubert, Wolfgang Kruis, Ole Birger Pedersen, Tõnu Esko, Kenneth Peuker, Simonas Juzenas, Maiken Elvestad Gabrielsen, Marek Doniec, Clemens Schafmayer, Christoph Röcken, Christian Erikstrup, Frauke Degenhardt, Stephan Buch, and Lorenzo von Fersen

Subjects
Genetics, inorganic chemicals, Candidate gene, education.field_of_study, integumentary system, Colon, Population, Gastroenterology, anal canal histopathology, Genome-wide association study, Disease, anorectal disorders, genetics, Biology, Genetic correlation, Transcriptome, Genetic predisposition, polycyclic compounds, heterocyclic compounds, education, Gene
Abstract

ObjectiveHaemorrhoidal disease (HEM) affects a large and silently suffering fraction of the population but its aetiology, including suspected genetic predisposition, is poorly understood. We report the first genome-wide association study (GWAS) meta-analysis to identify genetic risk factors for HEM to date.DesignWe conducted a GWAS meta-analysis of 218 920 patients with HEM and 725 213 controls of European ancestry. Using GWAS summary statistics, we performed multiple genetic correlation analyses between HEM and other traits as well as calculated HEM polygenic risk scores (PRS) and evaluated their translational potential in independent datasets. Using functional annotation of GWAS results, we identified HEM candidate genes, which differential expression and coexpression in HEM tissues were evaluated employing RNA-seq analyses. The localisation of expressed proteins at selected loci was investigated by immunohistochemistry.ResultsWe demonstrate modest heritability and genetic correlation of HEM with several other diseases from the GI, neuroaffective and cardiovascular domains. HEM PRS validated in 180 435 individuals from independent datasets allowed the identification of those at risk and correlated with younger age of onset and recurrent surgery. We identified 102 independent HEM risk loci harbouring genes whose expression is enriched in blood vessels and GI tissues, and in pathways associated with smooth muscles, epithelial and endothelial development and morphogenesis. Network transcriptomic analyses highlighted HEM gene coexpression modules that are relevant to the development and integrity of the musculoskeletal and epidermal systems, and the organisation of the extracellular matrix.ConclusionHEM has a genetic component that predisposes to smooth muscle, epithelial and connective tissue dysfunction.

Published
2021

4. Genome-wide analysis of 944,133 individuals provides insights into the etiology of hemorrhoidal disease

Author

Brett Vanderwerff, Maiken Elvestad Gabrielsen, Hans Günter Peleikis, Isabella Friis Jørgensen, Mauro D'Amato, Jurgita Skieceviciene, Nikolaos Margetis, Anne Heidi Skogholt, Juozas Kupcinskas, Anita Pandit, Lars G. Fritsche, Tilman Laubert, Andrea Gsur, Justus Gross, Michael Forster, Fabian H. Leendertz, Olga V. Sazonova, Simonas Juzenas, Christian Datz, Karina Banasik, François Cossais, Witigo von Schoenfels, Jochen Hampe, Thomas Becker, Ulrike Nowak-Göttl, Malte C. Rühlemann, Marek Doniec, Henry Völzke, Ralf Junker, Cristina Leal Rodríguez, Christopher Georg Németh, Julia Wilking, Thilo Wedel, Tom H. Karlsen, Michael Wittig, Jürgen Tepel, Alexander Hendricks, Volker Kahlke, Matthew Zawistowski, Laurent F. Thomas, Bodo Schniewind, Gabriele Mayr, Greta Burmeister, Matthias Laudes, Kerstin Mätz-Rensing, Maris Teder-Laving, Georg Hemmrich-Stanisak, Vladimir Vacic, Hartmut Clausnizer, Tobias Gräßle, David Ellinghaus, Frank Bokelmann, Eivind Ness-Jensen, Clemens Schafmayer, Andre Franke, Martin Schulzky, Norbert Frey, Tenghao Zheng, Verena Limperger, Henrik Ullum, Sebastian Hinz, Sebastian Zeissig, Elizabeth S. Noblin, Myrko Zobel, Kristian Hveem, Ilka Vogel, Florian Uellendahl-Werth, Søren Brunak, Lorenzo von Fersen, Wolfgang Lieb, Johannes Jongen, Tõnu Esko, Christian Erikstrup, Frauke Degenhardt, Kenneth Peuker, Stephan Buch, Wolfgang Kruis, and Ole Birger Pedersen

Subjects
education.field_of_study, integumentary system, Population, Connective tissue, Genome-wide association study, Biology, Bioinformatics, Extracellular matrix, Transcriptome, medicine.anatomical_structure, polycyclic compounds, Genetic predisposition, medicine, Etiology, education, Gene
Abstract

Hemorrhoidal disease (HEM) affects a large fraction of the population but its etiology including suspected genetic predisposition is poorly understood. We conducted a GWAS meta-analysis of 218,920 HEM patients and 725,213 controls of European ancestry, demonstrating modest heritability and genetic correlation with several other diseases from the gastrointestinal, neuroaffective and cardiovascular domains. HEM polygenic risk scores validated in 180,435 individuals from independent datasets allowed the identification of those at risk and correlated with younger age of onset and recurrent surgery. We identified 102 independent HEM risk loci harboring genes whose expression is enriched in blood vessels and gastrointestinal tissues, and in pathways associated with smooth muscles, epithelial and endothelial development and morphogenesis. Network transcriptomic analyses of affected tissue from HEM patients highlighted HEM gene co-expression modules that are relevant to the development and integrity of the musculoskeletal and epidermal systems, and the organization of the extracellular matrix. We conclude HEM has a genetic component that predisposes to smooth muscle, epithelial and connective tissue dysfunction.

Published
2020

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. Multi-ethnic genome-wide association study for atrial fibrillation

Author

Marcus E. Kleber, Raji P. Grewal, Yingchang Lu, Sanghamitra Mohanty, Harry J.G.M. Crijns, Han Sun, Ilkka Seppälä, Jonathan D. Smith, Albert Hofman, Yii-Der Ida Chen, Diane Fatkin, Patrik K. E. Magnusson, Pil Sung Yang, Jari Laurikka, Saman Nazarian, Peter W. Macfarlane, Natalia S. Rost, Sekar Kathiresan, Heribert Schunkert, Sandosh Padmanabhan, Tõnu Esko, Bruno H. Stricker, Rebecca Gutmann, Alfredo José Mansur, Jonathan Rosand, Jesper Hastrup Svendsen, Alvaro Alonso, J. Gustav Smith, Benjamin Neumann, John Barnard, Christopher D. Anderson, Joanna Pera, Samir Saba, Lynne J. Hocking, Siew-Kee Low, Daniel I. Chasman, Patrick T. Ellinor, Nancy L. Pedersen, Stephan B. Felix, Vilmundur Gudnason, Kjell Nikus, Kahraman Tanriverdi, David J. Porteous, Samuel C. Dudley, Clive R. Pullinger, Tamara B. Harris, Barry London, Lorenz Risch, Ruth J. F. Loos, Rainer Malik, Isabelle C. Van Gelder, John F. Carlquist, Lena Refsgaard, Carolina Roselli, Albert Y. Sun, Man Li, Lenore J. Launer, Anders Hamsten, Svati H. Shah, Lin Y. Chen, Martina Müller-Nurasyid, Michiel Rienstra, Kent D. Taylor, Katharina Schramm, Jennifer A. Brody, Honghuang Lin, Eric Boerwinkle, Rozenn N. Lemaitre, Olle Melander, Hugh Calkins, Elsayed Z. Soliman, Moritz F. Sinner, Heather L. Bloom, Nicholas L. Smith, Nada Esa, John W. Cole, Maartje N. Niemeijer, David R. Van Wagoner, Anubha Mahajan, Roopinder K. Sandhu, Henry J. Lin, Jordi Jimenez-Conde, Ian Ford, Eue Keun Choi, Stacey Knight, Scott M. Damrauer, Markku Eskola, Claudia Schurman, Stuart A. Scott, Sara L. Pulit, Raymond Noordam, Mika Kähönen, Jay A. Montgomery, Agnieszka Slowik, Esra Gucuk Ipek, Joylene E. Siland, Lingyao Zeng, Andrew P. Morris, Oscar H. Franco, Bas L.J.H. Kietselaer, Adnan Kastrati, Dan E. Arking, José Eduardo Krieger, J. Wouter Jukema, Stefan Gustafsson, Nathan R. Tucker, Zachary T. Yoneda, Daniel Woo, Winfried März, Lauren Margolin, Uwe Völker, Stefan Kääb, Marju Orho-Melander, Lars Lind, Yoichiro Kamatani, Maris Teder-Laving, Paul M. Ridker, Bradford B. Worrall, Jaemin Shim, Bob Weijs, Ingrid E. Christophersen, Kenneth B. Margulies, James P. Cook, Graciela Delgado, Andrea Natale, Stefan Weiss, Gustav Ahlberg, Jie Huang, Guillaume Paré, M. Benjamin Shoemaker, Marcus Dörr, Arnljot Tveit, Elton A. M. P. Dudink, Thomas P. Cappola, Bruce M. Psaty, Alaa Shalaby, Gregory M. Marcus, Sébastien Thériault, Niek Verweij, Traci M. Bartz, Thorsten Kessler, Michael Morley, Xiuqing Guo, Alexandre C. Pereira, Efthymia Vlachopoulou, Albert V. Smith, Andrea R. V. R. Horimoto, David Conen, Erik Ingelsson, Jie Yao, Raul Weiss, David D. McManus, Michiaki Kubo, Lu-Chen Weng, Michael A. Rosenberg, Nona Sotoodehnia, Jennifer E. Huffman, Hui Nam Pak, Dan M. Roden, Peter Weeke, Joshua C. Bis, Archie Campbell, Marta Ribasés, Renee Johnson, Renate B. Schnabel, Christian M. Shaffer, Krishna G. Aragam, Seung Hoan Choi, André G. Uitterlinden, Morten S. Olesen, Toshihiro Tanaka, Daniel J. Rader, Mina K. Chung, Stella Trompet, Steven A. Lubitz, Martin Dichgans, Peter Almgren, Christine M. Albert, Blair H. Smith, Petra Katschnig-Winter, Joshua C. Denny, Christopher Newton-Cheh, Paulus Kirchhof, Namrata Gupta, Emelia J. Benjamin, Stefanie Aeschbacher, Marja-Liisa Lokki, Jorge A. Wong, Quinn S. Wells, Jussi Hernesniemi, Cecilia M. Lindgren, Mark Chaffin, Kaoru Ito, Jerome I. Rotter, Michael J. Cutler, Kerri L. Wiggins, Maryam Kavousi, Nathan A. Bihlmeyer, Bastiaan Geelhoed, Susan R. Heckbert, Caroline Hayward, Alexander Teumer, Paul L. Huang, Terho Lehtimäki, Juha Sinisalo, John P. Kane, Kirsten Leineweber, Tanja Zeller, Hong Euy Lim, Kathryn L. Lunetta, Brian R. Daniels, Heidi Oellers, Biqi Wang, Pim van der Harst, Peter M. Nilsson, Dawood Darbar, Erwin B. Bottinger, Leo-Pekka Lyytikäinen, Epidemiology, Internal Medicine, RS: Carim - H01 Clinical atrial fibrillation, Cardiologie, MUMC+: MA Cardiologie (3), RS: CARIM - R2.01 - Clinical atrial fibrillation, RS: CARIM - R3.11 - Imaging, MUMC+: MA Med Staf Spec Cardiologie (9), MUMC+: MA Med Staf Artsass Cardiologie (9), Cardiovascular Centre (CVC), and MUMC+: MA Cardiologie (9)

Subjects
0301 basic medicine, medicine.medical_specialty, Identification, Annotation, Quantitative Trait Loci, Genome-wide association study, 030204 cardiovascular system & hematology, Quantitative trait locus, Biology, methods [Genome-Wide Association Study], Gene, genetics [Ethnic Groups], Article, DISEASE, 03 medical and health sciences, COMPONENTS-ANALYSIS, 0302 clinical medicine, ddc:570, Atrial Fibrillation, Cardiac conduction, Ethnicity, Genetics, medicine, Humans, Genetic Predisposition to Disease, genetics [Atrial Fibrillation], Genetic association, Imputation, ethnology [Atrial Fibrillation], Loci, Case-control study, Variants, METANÁLISE, Polymorphic ventricular-tachycardia, 030104 developmental biology, GWAS CATALOG, Susceptibility, Case-Control Studies, Expression quantitative trait loci, genetics [Ethnicity], Medical genetics, Transcriptome, Imputation (genetics), Mutations, Genome-Wide Association Study
Abstract

Atrial fibrillation (AF) affects more than 33 million individuals worldwide 1 and has a complex heritability 2 . We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

Published
2018

7. Identifying pathways modulating sleep duration : from genomics to transcriptomics

Author

Rosa Maria Levandovski, Rodolfo Costa, Paola Cusumano, Karla V. Allebrandt, Andreas Ruepp, Maris Teder-Laving, Goar Frishman, Cristiano De Pittà, Andres Metspalu, Maria Paz Loayza Hidalgo, and Till Roenneberg

Subjects
0301 basic medicine, K-ATP CHANNELS, WIDE ASSOCIATION, DROSOPHILA, DISEASE, ACTIVATION, HOMOLOG, Science, Biology, Polymorphism, Single Nucleotide, Article, ABCC9, Transcriptome, 03 medical and health sciences, ErbB Receptors, Meta-Analysis as Topic, ErbB, Cronobiologia, Genômica, Animals, Humans, Gene Regulatory Networks, Regulation of gene expression, Genetics, Gene knockdown, Multidisciplinary, Gene Expression Profiling, Computational Biology, Genomics, Sleep in non-human animals, Gene expression profiling, Phenotype, 030104 developmental biology, Gene Expression Regulation, Medicine, Sleep, Genome-Wide Association Study, Signal Transduction, Sono
Abstract

Recognizing that insights into the modulation of sleep duration can emerge by exploring the functional relationships among genes, we used this strategy to explore the genome-wide association results for this trait. We detected two major signalling pathways (ion channels and the ERBB signalling family of tyrosine kinases) that could be replicated across independent GWA studies meta-analyses. To investigate the significance of these pathways for sleep modulation, we performed transcriptome analyses of short sleeping flies’ heads (knockdown for the ABCC9 gene homolog; dSur). We found significant alterations in gene-expression in the short sleeping knockdowns versus controls flies, which correspond to pathways associated with sleep duration in our human studies. Most notably, the expression of Rho and EGFR (members of the ERBB signalling pathway) genes was down- and up-regulated, respectively, consistently with the established role of these genes for sleep consolidation in Drosophila. Using a disease multifactorial interaction network, we showed that many of the genes of the pathways indicated to be relevant for sleep duration had functional evidence of their involvement with sleep regulation, circadian rhythms, insulin secretion, gluconeogenesis and lipogenesis.

Published
2017

8. Multi-ethnic fine-mapping of 14 central adiposity loci

Author

Eco De Geus, Michael Weedon, Joyce Van Meurs, Torben Jørgensen, Kirsi Pietiläinen, Patricia Munroe, Amanda Bennett, Michael Stumvoll, Andrew Hattersley, Vilmundur Gudnason, Dale Nyholt, Mary Feitosa, Mariano Dei, Marcus Dörr, Terho Lehtimäki, Anette P Gjesing, Daniel Witte, Adebowale Adeyemo, Eleanor Wheeler, Peter Kovacs, Hana Lango Allen, Philippe Froguel, Panos Deloukas, Cornelia Van Duijn, Tiinamaija Tuomi, Daniel Shriner, Struan Grant, Tonu Esko, Reedik Mägi, Lyle John Palmer, L. Adrienne Cupples, Claes Ohlsson, Krina Zondervan, Thomas Meitinger, Sarah Nyante, Lina Zgaga, Themistocles Assimes, Paul Elliott, Robert Luben, Albert Vernon Smith, MANUELA UDA, Rona Strawbridge, Richard Bergman, Gonneke Willemsen, Igor Rudan, Maris Teder-Laving, Liesbeth Vandenput, Mary Cushman, Allan Linneberg, Biological Psychology, and EMGO+ - Lifestyle, Overweight and Diabetes

Subjects
Netherlands Twin Register (NTR), Linkage disequilibrium, Ethnic group, Churg-strauss syndrome, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, waist-to-hip ratio, multi-ethnic fine-mapping, Genetics, medicine, Ethnicity, Humans, Molecular Biology, Genetics (clinical), Adiposity, Anthropometry, Association Studies Articles, Physical Chromosome Mapping, Computational Biology, Molecular Sequence Annotation, General Medicine, medicine.disease, Carotid sinus syncope, Genetic Loci, Central Adiposity, Allelic heterogeneity
Abstract

The Genetic Investigation of Anthropometric Traits (GIANT) consortium identified 14 loci in European Ancestry (EA) individuals associated with waist-to-hip ratio (WHR) adjusted for body mass index. These loci are wide and narrowingthe signalsremains necessary. Twelve of 14 loci identified inGIANTEA samples retained strong associations with WHR in our joint EA/individuals of African Ancestry (AA) analysis (log-Bayes factor >6.1). Transethnic analysesatfiveloci (TBX15-WARS2, LYPLAL1, ADAMTS9, LY86andITPR2-SSPN)substantially narrowed the signals to smaller sets of variants, some of which are in regions that have evidence of regulatory activity. By leveraging varying linkage disequilibrium structures across different populations, single-nucleotide polymorphisms (SNPs) with strong signals and narrower credible sets from trans-ethnic meta-analysis of central obesity provide more precise localizations of potential functional variants and suggest a possible regulatory role. Meta-analysis results for WHR were obtained from 77 167 EA participants from GIANT and 23 564 AA participants from the AfricanAncestry Anthropometry Genetics Consortium. For fine mapping we interrogatedSNPs within ±250 kbflanking regionsof 14 previously reported indexSNPsfrom loci discovered in EApopulations by performing trans-ethnic meta-analysis of results from the EA and AA meta-analyses. We applied a Bayesian approach that leverages allelic heterogeneity across populations to combine meta-analysis results and aids in fine-mapping shared variants at these locations. We annotated variants using information from the ENCODE Consortium and Roadmap Epigenomics Project to prioritize variants for possible functionality. © The Author 2014. Published by Oxford University Press. All rights reserved.

Published
2014

9. A K-ATP channel gene effect on sleep duration: from genome-wide association studies to function in Drosophila

Author

Charalambos P. Kyriacou, Caroline Hayward, C M van Duijn, Till Roenneberg, Karla V. Allebrandt, Nicole Vogelzangs, Tõnu Esko, A. C. J. W. Janssens, J. van Mill, James F. Wilson, Peter Lichtner, Harry Campbell, Igor Rudan, R. V. D. M. Azevedo, Bertram Mueller-Myhsok, Edward W. Green, Zoran Dogas, Andres Metspalu, Martha Merrow, H-E Wichmann, Scott A. Melville, Ben A. Oostra, Brenda W.J.H. Penninx, Maris Teder-Laving, Najaf Amin, Thomas Meitinger, Andrew A. Hicks, Peter P. Pramstaller, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Mental Health, Epidemiology, Clinical Genetics, Psychiatry, NCA - Neurobiology of mental health, and EMGO - Mental health

Subjects
Male, Gerontology, Receptors, Drug, ABCC9, chronotype, Munich Chrono Type Questionnaire, seasonality, sleep duration, SUR, Genome-wide association study, Sulfonylurea Receptors, Animals, Genetically Modified, Cohort Studies, Drosophila Proteins, Aged, 80 and over, Kv1.3 Potassium Channel, Middle Aged, Sleep in non-human animals, Phenotype, Potassium channel, Cell biology, Psychiatry and Mental health, Drosophila, Female, RNA Interference, Adult, Sleep Wake Disorders, Adolescent, Genotype, Photoperiod, Biology, Polymorphism, Single Nucleotide, White People, Young Adult, Cellular and Molecular Neuroscience, Animals, Humans, Genetic Predisposition to Disease, sleep, Potassium Channels, Inwardly Rectifying, Molecular Biology, Aged, Genetic association, Myocardium, Repressor Proteins, Munich ChronoType Questionnaire, Sulfonylurea receptor, ATP-Binding Cassette Transporters, Plakophilins, Function (biology), Genome-Wide Association Study
Abstract

Humans sleep approximately a third of their lifetime. The observation that individuals with either long or short sleep duration show associations with metabolic syndrome and psychiatric disorders suggests that the length of sleep is adaptive. Although sleep duration can be influenced by photoperiod (season) and phase of entrainment (chronotype), human familial sleep disorders indicate that there is a strong genetic modulation of sleep. Therefore, we conducted high-density genome-wide association studies for sleep duration in seven European populations (N=4251). We identified an intronic variant (rs11046205; P=3.99 x 10(-8)) in the ABCC9 gene that explains approximate to 5% of the variation in sleep duration. An influence of season and chronotype on sleep duration was solely observed in the replication sample (N=5949). Meta-analysis of the associations found in a subgroup of the replication sample, chosen for season of entry and chronotype, together with the discovery results showed genome-wide significance. RNA interference knockdown experiments of the conserved ABCC9 homologue in Drosophila neurons renders flies sleepless during the first 3 h of the night. ABCC9 encodes an ATP-sensitive potassium channel subunit (SUR2), serving as a sensor of intracellular energy metabolism. Molecular Psychiatry (2013) 18, 122-132; doi:10.1038/mp.2011.142; published online 22 November 2011

Published
2013

10. Genetic variants in RBFOX3 are associated with sleep latency

Author

Igor Rudan, Tõnu Esko, Wilfred F. J. van IJcken, Alan F. Wright, Caroline Hayward, Nathaniel F. Watson, Ben A. Oostra, Karla V. Allebrandt, Scott A. Melville, Steven R. Cummings, Aaron Isaacs, Gonneke Willemsen, Yurii S. Aulchenko, Albert Hofman, Fran Borovečki, Maris Teder-Laving, Sina A. Gharib, Brenda W.J.H. Penninx, Cornelia M. van Duijn, Josine G. van Mill, Dorret I. Boomsma, Harry Campbell, James F. Wilson, Katie L. Stone, Rutger W W Brouwer, Philip R. Gehrman, Annemarie I. Luik, Ozren Polasek, Naresh M. Punjabi, Jouke-Jan Hottenga, Jennifer E. Huffman, Daniel S. Evans, Martina Müller-Nurasyid, Ashley van der Spek, Andrew A. Hicks, Susan Redline, Peter P. Pramstaller, Fabiola M. Del Greco, Rudolf S N Fehrmann, Bertram Müller-Myhsok, Nicole Vogelzangs, Man Li, Lude Franke, Edwin Oole, Ayse Demirkan, Lina Zgaga, Karin Hek, Mirjam C G N van den Hout, Wen Hong Linda Kao, Gregory J. Tranah, Enda M. Byrne, Bruce M. Psaty, Hamdi Mbarek, Martha Merrow, Kristin D. Marciante, Josef Coresh, Henning Tiemeier, Grant W. Montgomery, Till Roenneberg, Susan Campbell, Ivana Kolcic, Juha Karjalainen, Zoran Dogas, Andres Metspalu, Ting Hsu Chen, Najaf Amin, André G. Uitterlinden, Nicholas G. Martin, Daniel J. Gottlieb, Andrew C. Heath, Thomas Meitinger, Heinz Erich Wichmann, Jacqueline M. Vink, Evelin Mihailov, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Biochemie, RS: FHML MaCSBio, RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, Psychiatry, EMGO - Mental health, Epidemiology, Cell biology, Internal Medicine, Clinical Genetics, Child and Adolescent Psychiatry / Psychology, and Biological Psychology

Subjects
0301 basic medicine, Netherlands Twin Register (NTR), EXPRESSION, Candidate gene, medicine.medical_specialty, Single-nucleotide polymorphism, Genome-wide association study, Delayed sleep phase, Nerve Tissue Proteins, DETERMINANTS, Biology, RECORDED SLEEP, Polymorphism, Single Nucleotide, Synaptic Transmission, Article, ONSET INSOMNIA, SELF-REPORT, sleep latency, gene, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Genetic linkage, Molecular genetics, Genetics, medicine, Insomnia, IMPUTATION, Humans, GENOME-WIDE ASSOCIATION, Genetics (clinical), Genetic association, LINKAGE ANALYSIS, Brain, Antigens, Nuclear, medicine.disease, FAMILY, 030104 developmental biology, CANDIDATE-GENE, medicine.symptom, Sleep, Developmental Psychopathology, 030217 neurology & neurosurgery
Abstract

Time to fall asleep (sleep latency) is a major determinant of sleep quality. Chronic, long sleep latency is a major characteristic of sleep-onset insomnia and/or delayed sleep phase syndrome. In this study we aimed to discover common polymorphisms that contribute to the genetics of sleep latency. We performed a meta-analysis of genome-wide association studies (GWAS) including 2 572 737 single nucleotide polymorphisms (SNPs) established in seven European cohorts including 4242 individuals. We found a cluster of three highly correlated variants (rs9900428, rs9907432 and rs7211029) in the RNA-binding protein fox-1 homolog 3 gene (RBFOX3) associated with sleep latency (P-values=5.77 × 10(-08), 6.59 × 10(-)(08) and 9.17 × 10(-)(08)). These SNPs were replicated in up to 12 independent populations including 30 377 individuals (P-values=1.5 × 10(-)(02), 7.0 × 10(-)(03) and 2.5 × 10(-)(03); combined meta-analysis P-values=5.5 × 10(-07), 5.4 × 10(-07) and 1.0 × 10(-07)). A functional prediction of RBFOX3 based on co-expression with other genes shows that this gene is predominantly expressed in brain (P-value=1.4 × 10(-316)) and the central nervous system (P-value=7.5 × 10(-)(321)). The predicted function of RBFOX3 based on co-expression analysis with other genes shows that this gene is significantly involved in the release cycle of neurotransmitters including gamma-aminobutyric acid and various monoamines (P-values

Published
2016

11. Chronotype and sleep duration: The influence of season of assessment

Author

Thomas Kantermann, Harry Campbell, Till Roenneberg, Annette Peters, Igor Rudan, Karla V. Allebrandt, Andres Metspalu, Maris Teder-Laving, James F. Wilson, and Beersma lab

Subjects
Adult, Male, Gerontology, Time Factors, Light, Physiology, Photoperiod, Population, Biology, Young Adult, Sex Factors, Sleep debt, Physiology (medical), Zeitgeber, medicine, Humans, Wakefulness, education, education.field_of_study, Age Factors, Chronotype, Middle Aged, Seasonality, medicine.disease, Adaptation, Physiological, Circadian Rhythm, Europe, Cross-Sectional Studies, Phenotype, Cohort, Female, Seasons, Sleep, Body mass index, Daylight saving time, Demography
Abstract

Little is known about human entrainment under natural conditions, partly due to the complexity of human behavior, torn between biological and social time and influenced by zeitgebers (light-dark cycles) that are progressively "polluted" (and thereby weakened) by artificial light. In addition, data about seasonal variations in sleep parameters are scarce. We, therefore, investigated seasonal variation in cross-sectional assessments of sleep/wake times of 9765 subjects from four European populations (EGCUT = Estonian Genome Centre, University of Tartu in Estonia; KORA = Cooperative Health Research in the Region of Augsburg in Germany; KORCULA = The Korcula study in Croatia; and ORCADES = The Orkney Complex Disease Study in Scotland). We identified time-of-year dependencies for the distribution of chronotype (phase of entrainment assessed as the mid-sleep time point on free days adjusted for sleep deficit of workdays) in cohorts from Estonia (EGCUT) and Germany (KORA). Our results indicate that season (defined as daylight saving time - DST and standard zonetime periods - SZT) specifications of photoperiod influence the distribution of chronotype (adjusted for age and sex). Second, in the largest investigated sample, from Estonia (EGCUT; N = 5878), we could detect that seasonal variation in weekly average sleep duration was dependent on individual chronotype. Later chronotypes in this cohort showed significant variation in their average sleep duration across the year, especially during DST (1 h advance in social time from the end of March to end of October), while earlier chronotypes did not. Later chronotypes not only slept less during the DST period but the average chronotype of the population assessed during this period was earlier than during the SZT (local time for a respective time zone) period. More in detail, hierarchical multiple regression analyses showed that, beyond season of assessment (DST or SZT), social jetlag (SJl; the discrepancy between the mid sleep on free and work days - which varied with age and sex) contributed to a greater extent to the variation in sleep duration than chronotype (after taking into account factors that are known to influence sleep duration, i.e. age, sex and body mass index). Variation in chronotype was also dependent on age, sex, season of assessment and SJl (which is highly correlated with chronotype - SJl was larger among later chronotypes). In summary, subjective assessments of sleep/wake times are very reliable to assess internal time and sleep duration (e.g. reproducing sleep duration and timing tendencies related to age and sex across the investigated populations), but season of assessment should be regarded as a potential confounder. We identified in this study photoperiod (seasonal adaptation) and SJl as two main factors influencing seasonal variation in chronotype and sleep duration. In conclusion, season of assessment, sex and age have an effect on epidemiological variation in sleep duration, chronotype and SJl, and should be included in studies investigating associations between these phenotypes and health parameters, and on the development of optimal prevention strategies.

Published
2014

12. Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts

Author

Benjamin Voight, Guillaume Pare, Ruth Loos, Michael Preuss, Åsa Johansson, Eco De Geus, Michael Weedon, Marjo-Riitta Jarvelin, Joyce Van Meurs, Torben Jørgensen, Kirsi Pietiläinen, Nicole Glazer, Mattias Lorentzon, Braxton Mitchell, Nicole Soranzo, Patricia Munroe, Ozren Polasek, Elisabeth Thiering, Marika Kaakinen, Carla Vogel, Jennie Hui, Elina Hypponen, ROBERTO ELOSUA, Amanda Bennett, Michael Stumvoll, Andrew Hattersley, Peter P Pramstaller, Lambertus Kiemeney, Sophie Visvikis-Siest, Vilmundur Gudnason, John Whittaker, Aroon Hingorani, Thor Aspelund, Dale Nyholt, Mary Feitosa, Vimal Karani, Mika Kähönen, Lachlan Coin, Malcolm Dunlop, Josee Dupuis, Terho Lehtimäki, Peter Visscher, Katja Aben, Daniel Witte, Cyrus Cooper, Stefan Pilz, Willem Ouwehand, Eleanor Wheeler, Peter Kovacs, Debbie A Lawlor, Kevin Jacobs, Evropi Theodoratou, Hana Lango Allen, Rosanda Mulic, Rui Li, Stephen Kritchevsky, Philippe Froguel, Soumya Raychaudhuri, Cornelia Van Duijn, Andrew Wood, Chiara Lanzani, Tonu Esko, Sadaf Farooqi, Reedik Mägi, Gerard Waeber, Claes Ohlsson, André Scherag, Marcus Kleber, Thomas Meitinger, Lina Zgaga, Denise Houston, Karl Michaëlsson, Robert Weyant, Thomas Wang, Paul Elliott, Robert Luben, Albert Vernon Smith, MANUELA UDA, Gonneke Willemsen, Mark McCarthy, Cecilia Lindgren, Olle Melander, Igor Rudan, Maris Teder-Laving, Liesbeth Vandenput, Vimaleswaran, K, Berry, Dj, Lu, C, Tikkanen, E, Pilz, S, Hiraki, Lt, Cooper, Jd, Dastani, Z, Li, R, Houston, Dk, Wood, Ar, Michaëlsson, K, Vandenput, L, Zgaga, L, YERGES ARMSTRONG, Lm, Mccarthy, Mi, Dupuis, J, Kaakinen, M, Kleber, Me, Jameson, K, Arden, N, Raitakari, O, Viikari, J, Lohman, Kk, Ferrucci, L, Melhus, H, Ingelsson, E, Byberg, L, Lind, L, Lorentzon, M, Salomaa, V, Campbell, H, Dunlop, M, Mitchell, Bd, Herzig, Kh, Pouta, A, Hartikainen, Al, Manunta, Paolo, Streeten, Ea, Theodoratou, E, Jula, A, Wareham, Nj, Ohlsson, C, Frayling, Tm, Kritchevsky, Sb, Spector, Td, Richards, Jb, Lehtimäki, T, Ouwehand, Wh, Kraft, P, Cooper, C, März, W, Power, C, Loos, Rj, Wang, Tj, Järvelin, Mr, Whittaker, Jc, Hingorani, Ad, Hyppönen, E., Council, Medical Research, Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Institute for Molecular Medicine Finland, Haartman Institute (-2014), Transplantation Laboratory, Vimaleswaran, Karani S, Berry, Diane J, Lu, Chen, Tikkanen, Emmi, Hyppönen, Elina, Genetic Investigation of Anthropometric Traits (GIANT) Consortium, Hinney, Anke (Beitragende*r), Scherag, Susann (Beitragende*r), Hebebrand, Johannes (Beitragende*r), Epidemiology and Data Science, Psychiatry, EMGO - Lifestyle, overweight and diabetes, Genetic Investigation of Anthropometric Traits-GIANT Consortium, Speliotes, E.K., Willer, C.J., Berndt, S.I., Monda, K.L., Thorleifsson, G., Jackson, A.U., Allen, H.L., Lindgren, C.M., Jian'an, L., Mägi, R., Randall, J.C., Vedantam, S., Winkler, T.W., Qi, L., Workalemahu, T., Heid, I.M., Steinthorsdottir, V., Stringham, H.M., Weedon, M.N., Wheeler, E., Wood, A.R., Ferreira, T., Weyant, R.J., Segrè, A.V., Estrada, K., Liang, L., Nemesh, J., Park, J.H., Gustafsson, S., Kilpeläinen, T.O., Yang, J., Bouatia-Naji, N., Tõnu, E., Feitosa, M.F., Kutalik, Z., Mangino, M., Raychaudhuri, S., Scherag, A., Smith, A.V., Welch, R., Zhao, J.H., Aben, K.K., Absher, D.M., Amin, N., Dixon, A.L., Fisher, E., Glazer, N.L., Goddard, M.E., Heard-Costa, N.L., Hoesel, V., Hottenga, J.J., Johansson, Å., Johnson, T., Ketkar, S., Lamina, C., Li, S., Moffatt, M.F., Myers, R.H., Narisu, N., Perry, J.R., Peters, M.J., Preuss, M., Ripatti, S., Rivadeneira, F., Sandholt, C., Scott, L.J., Timpson, N.J., Tyrer, J.P., van Wingerden, S., Watanabe, R.M., White, C.C., Wiklund, F., Barlassina, C., Chasman, D.I., Cooper, M.N., Jansson, J.O., Lawrence, R.W., Pellikka, N., Prokopenko, I., Shi, J., Thiering, E., Alavere, H., Alibrandi, M.T., Almgren, P., Arnold, A.M., Aspelund, T., Atwood, L.D., Balkau, B., Balmforth, A.J., Bennett, A.J., Ben-Shlomo, Y., Bergman, R.N., Bergmann, S., Biebermann, H., Blakemore, A.I., Boes, T., Bonnycastle, L.L., Bornstein, S.R., Brown, M.J., Buchanan, T.A., Busonero, F., Campbell, H., Cappuccio, F.P., Cavalcanti-Proença, C., Chen, Y.D., Chen, C.M., Chines, P.S., Clarke, R., Coin, L., Connell, J., Day, I.N., Heijer, M., Duan, J., Ebrahim, S., Elliott, P., Elosua, R., Eiriksdottir, G., Erdos, M.R., Eriksson, J.G., Facheris, M.F., Felix, S.B., Fischer-Posovszky, P., Folsom, A.R., Friedrich, N., Freimer, N.B., Fu, M., Gaget, S., Gejman, P.V., Geus, E.J., Gieger, C., Gjesing, A.P., Goel, A., Goyette, P., Grallert, H., Gräßler, J., Greenawalt, D.M., Groves, C.J., Gudnason, V., Guiducci, C., Hartikainen, A.L., Hassanali, N., Hall, A.S., Havulinna, A.S., Hayward, C., Heath, A.C., Hengstenberg, C., Hicks, A.A., Hinney, A., Hofman, A., Homuth, G., Hui, J., Igl, W., Iribarren, C., Isomaa, B., Jacobs, K.B., Jarick, I., Jewell, E., John, U., Jørgensen, T., Jousilahti, P., Jula, A., Kaakinen, M., Kajantie, E., Kaplan, L.M., Kathiresan, S., Kettunen, J., Kinnunen, L., Knowles, J.W., Kolcic, I., König, I.R., Koskinen, S., Kovacs, P., Kuusisto, J., Kraft, P., Kvaløy, K., Laitinen, J., Lantieri, O., Lanzani, C., Launer, L.J., Lecoeur, C., Lehtimäki, T., Lettre, G., Liu, J., Lokki, M.L., Lorentzon, M., Luben, R.N., Ludwig, B., Manunta, P., Marek, D., Marre, M., Martin, N.G., McArdle, W.L., McCarthy, A., McKnight, B., Meitinger, T., Melander, O., Meyre, D., Midthjell, K., Montgomery, G.W., Morken, M.A., Morris, A.P., Mulic, R., Ngwa, J.S., Nelis, M., Neville, M.J., Nyholt, D.R., O'Donnell, C.J., O'Rahilly, S., Ong, K.K., Oostra, B., Paré, G., Parker, A.N., Perola, M., Pichler, I., Pietiläinen, K.H., Platou, C.G., Polasek, O., Pouta, A., Rafelt, S., Raitakari, O., Rayner, N.W., Ridderstråle, M., Rief, W., Ruokonen, A., Robertson, N.R., Rzehak, P., Salomaa, V., Sanders, A.R., Sandhu, M.S., Sanna, S., Saramies, J., Savolainen, M.J., Scherag, S., Schipf, S., Schreiber, S., Schunkert, H., Silander, K., Sinisalo, J., Siscovick, D.S., Smit, J.H., Soranzo, N., Sovio, U., Stephens, J., Surakka, I., Swift, AJ., Tammesoo, M.L., Tardif, J.C., Teder-Laving, M., Teslovich, T.M., Thompson, J.R., Thomson, B., Tönjes, A., Tuomi, T., van Meurs, J.B., van Ommen, G.J., Vatin, V., Viikari, J., Visvikis-Siest, S., Vitart, V., Vogel, C.I., Voight, B.F., Waite, L.L., Wallaschofski, H., Walters, G.B., Widen, E., Wiegand, S., Wild, S.H., Willemsen, G., Witte, D.R., Witteman, J.C., Xu, J., Zhang, Q., Zgaga, L., Ziegler, A., Zitting, P., Beilby, J.P., Farooqi, I.S., Hebebrand, J., Huikuri, H.V., James, AL., Kähönen, M., Levinson, D.F., Macciardi, F., Nieminen, M.S., Ohlsson, C., Palmer, L.J., Ridker, P.M., Stumvoll, M., Beckmann, J.S., Boeing, H., Boerwinkle, E., Boomsma, D.I., Caulfield, M.J., Chanock, S.J., Collins, F.S., Cupples, L.A., Smith, G.D., Erdmann, J., Froguel, P., Grönberg, H., Gyllensten, U., Hall, P., Hansen, T., Harris, T.B., Hattersley, A.T., Hayes, R.B., Heinrich, J., Hu, F.B., Hveem, K., Illig, T., Jarvelin, M.R., Kaprio, J., Karpe, F., Khaw, K.T., Kiemeney, L.A., Krude, H., Laakso, M., Lawlor, D.A., Metspalu, A., Munroe, P.B., Ouwehand, W.H., Pedersen, O., Penninx, B.W., Peters, A., Pramstaller, P.P., Quertermous, T., Reinehr, T., Rissanen, A., Rudan, I., Samani, N.J., Schwarz, P.E., Shuldiner, A.R., Spector, T.D., Tuomilehto, J., Uda, M., Uitterlinden, A., Valle, T.T., Wabitsch, M., Waeber, G., Wareham, N.J., Watkins, H., Wilson, J.F., Wright, A.F., Zillikens, M.C., Chatterjee, N., McCarroll, S.A., Purcell, S., Schadt, E.E., Visscher, P.M., Assimes, T.L., Borecki, I.B., Deloukas, P., Fox, C.S., Groop, L.C., Haritunians, T., Hunter, D.J., Kaplan, R.C., Mohlke, K.L., O'Connell, J.R., Peltonen, L., Schlessinger, D., Strachan, D.P., van Duijn, C.M., Wichmann, H.E., Frayling, T.M., Thorsteinsdottir, U., Abecasis, G.R., Barroso, I., Boehnke, M., Stefansson, K., North, K.E., McCarthy, M.I., Hirschhorn, J.N., Ingelsson, E., Loos, R.J., Medical Research Council (MRC), and National Institute for Health Research

Subjects
Male, Netherlands Twin Register (NTR), Medicin och hälsovetenskap, obesity, 25-HYDROXYVITAMIN D, D INSUFFICIENCY, Epidemiology, Medizin, vitamin D, Aetiology, screening and detection [ONCOL 5], Medical and Health Sciences, Gastroenterology, Body Mass Index, chemistry.chemical_compound, 0302 clinical medicine, Risk Factors, GENETIC-VARIANTS, Medicine, 030212 general & internal medicine, Vitamin D, 2. Zero hunger, Genetics, Aged, 80 and over, Evidence-Based Medicine, Confounding, 11 Medical And Health Sciences, General Medicine, Middle Aged, 3. Good health, PREVALENCE, Europe, Phenotype, Genetic Epidemiology, Biological Markers, Female, Life Sciences & Biomedicine, Research Article, Vitamin, Adult, medicine.medical_specialty, vitamin D deficiency, genetic variants, Genetic Investigation of Anthropometric Traits-GIANT Consortium, European Continental Ancestry Group, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, body mass index, Polymorphism, Single Nucleotide, Risk Assessment, White People, COMMON OBESITY, 03 medical and health sciences, D DEFICIENCY, Medicine, General & Internal, SDG 3 - Good Health and Well-being, General & Internal Medicine, Internal medicine, Mendelian randomization, Vitamin D and neurology, INSTRUMENTAL VARIABLES, Humans, Genetic Predisposition to Disease, Obesity, GENOME-WIDE ASSOCIATION, Biology, Molecular epidemiology Aetiology, screening and detection [NCEBP 1], Aged, Science & Technology, Population Biology, business.industry, CARDIOVASCULAR-DISEASE RISK, ta3121, Mendelian Randomization Analysis, medicine.disease, Vitamin D Deficiency, BODY-MASS INDEX, chemistry, Genetic epidemiology, 3121 General medicine, internal medicine and other clinical medicine, Multivariate Analysis, North America, Genetic Polymorphism, Linear Models, business, Body mass index, Population Genetics, Biomarkers
Abstract

A mendelian randomization study based on data from multiple cohorts conducted by Karani Santhanakrishnan Vimaleswaran and colleagues re-examines the causal nature of the relationship between vitamin D levels and obesity., Background Obesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH)D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis. Methods and Findings We used information from 21 adult cohorts (up to 42,024 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH)D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects. Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n = 123,864). Each 1 kg/m2 higher BMI was associated with 1.15% lower 25(OH)D (p = 6.52×10−27). The BMI allele score was associated both with BMI (p = 6.30×10−62) and 25(OH)D (−0.06% [95% CI −0.10 to −0.02], p = 0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH)D (p≤8.07×10−57 for both scores) but not with BMI (synthesis score, p = 0.88; metabolism score, p = 0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH)D concentrations (IV ratio: −4.2 [95% CI −7.1 to −1.3], p = 0.005). No association was seen for genetically instrumented 25(OH)D with BMI, a finding that was confirmed using data from the GIANT consortium (p≥0.57 for both vitamin D scores). Conclusions On the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH)D, while any effects of lower 25(OH)D increasing BMI are likely to be small. Population level interventions to reduce BMI are expected to decrease the prevalence of vitamin D deficiency. Please see later in the article for the Editors' Summary, Editors' Summary Background Obesity—having an unhealthy amount of body fat—is increasing worldwide. In the US, for example, a third of the adult population is now obese. Obesity is defined as having a body mass index (BMI, an indicator of body fat calculated by dividing a person's weight in kilograms by their height in meters squared) of more than 30.0 kg/m2. Although there is a genetic contribution to obesity, people generally become obese by consuming food and drink that contains more energy than they need for their daily activities. Thus, obesity can be prevented by having a healthy diet and exercising regularly. Compared to people with a healthy weight, obese individuals have an increased risk of developing diabetes, heart disease and stroke, and tend to die younger. They also have a higher risk of vitamin D deficiency, another increasingly common public health concern. Vitamin D, which is essential for healthy bones as well as other functions, is made in the skin after exposure to sunlight but can also be obtained through the diet and through supplements. Why Was This Study Done? Observational studies cannot prove that obesity causes vitamin D deficiency because obese individuals may share other characteristics that reduce their circulating 25-hydroxy vitamin D [25(OH)D] levels (referred to as confounding). Moreover, observational studies cannot indicate whether the larger vitamin D storage capacity of obese individuals (vitamin D is stored in fatty tissues) lowers their 25(OH)D levels or whether 25(OH)D levels influence fat accumulation (reverse causation). If obesity causes vitamin D deficiency, monitoring and treating vitamin D deficiency might alleviate some of the adverse health effects of obesity. Conversely, if low vitamin D levels cause obesity, encouraging people to take vitamin D supplements might help to control the obesity epidemic. Here, the researchers use bi-directional “Mendelian randomization” to examine the direction and causality of the relationship between BMI and 25(OH)D. In Mendelian randomization, causality is inferred from associations between genetic variants that mimic the influence of a modifiable environmental exposure and the outcome of interest. Because gene variants do not change over time and are inherited randomly, they are not prone to confounding and are free from reverse causation. Thus, if a lower vitamin D status leads to obesity, genetic variants associated with lower 25(OH)D concentrations should be associated with higher BMI, and if obesity leads to a lower vitamin D status, then genetic variants associated with higher BMI should be associated with lower 25(OH)D concentrations. What Did the Researchers Do and Find? The researchers created a “BMI allele score” based on 12 BMI-related gene variants and two “25(OH)D allele scores,” which are based on gene variants that affect either 25(OH)D synthesis or breakdown. Using information on up to 42,024 participants from 21 studies, the researchers showed that the BMI allele score was associated with both BMI and with 25(OH)D levels among the study participants. Based on this information, they calculated that each 10% increase in BMI will lead to a 4.2% decrease in 25(OH)D concentrations. By contrast, although both 25(OH)D allele scores were strongly associated with 25(OH)D levels, neither score was associated with BMI. This lack of an association between 25(OH)D allele scores and obesity was confirmed using data from more than 100,000 individuals involved in 46 studies that has been collected by the GIANT (Genetic Investigation of Anthropometric Traits) consortium. What Do These Findings Mean? These findings suggest that a higher BMI leads to a lower vitamin D status whereas any effects of low vitamin D status on BMI are likely to be small. That is, these findings provide evidence for obesity as a causal factor in the development of vitamin D deficiency but not for vitamin D deficiency as a causal factor in the development of obesity. These findings suggest that population-level interventions to reduce obesity should lead to a reduction in the prevalence of vitamin D deficiency and highlight the importance of monitoring and treating vitamin D deficiency as a means of alleviating the adverse influences of obesity on health. Additional Information Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001383. The US Centers for Disease Control and Prevention provides information on all aspects of overweight and obesity (in English and Spanish); a data brief provides information about the vitamin D status of the US population The World Health Organization provides information on obesity (in several languages) The UK National Health Service Choices website provides detailed information about obesity and a link to a personal story about losing weight; it also provides information about vitamin D The International Obesity Taskforce provides information about the global obesity epidemic The US Department of Agriculture's ChooseMyPlate.gov website provides a personal healthy eating plan; the Weight-control Information Network is an information service provided for the general public and health professionals by the US National Institute of Diabetes and Digestive and Kidney Diseases (in English and Spanish) The US Office of Dietary Supplements provides information about vitamin D (in English and Spanish) MedlinePlus has links to further information about obesity and about vitamin D (in English and Spanish) Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages) Overview and details of the collaborative large-scale genetic association study (D-CarDia) provide information about vitamin D and the risk of cardiovascular disease, diabetes and related traits

Published
2013

13. Genome-Wide Association Analysis Identifies Variants Associated with Nonalcoholic Fatty Liver Disease That Have Distinct Effects on Metabolic Traits

Author

Benjamin Voight, Amelie Bonnefond, Mark Caulfield, Guillaume Pare, Manal Abdelmalek, Eleftheria Zeggini, Jeffrey Schwimmer, Anna Gloyn, Michael Preuss, Åsa Johansson, LAURA CRISPONI, Eco De Geus, Michael Weedon, Jeanne Clark, Joyce Van Meurs, Torben Jørgensen, Kirsi Pietiläinen, Nicole Glazer, Jaakko Kaprio, Alan Shuldiner, Braxton Mitchell, Patricia Munroe, Ozren Polasek, Elisabeth Thiering, Carla Vogel, Jennie Hui, ROBERTO ELOSUA, Amanda Bennett, Yurii Aulchenko, Michael Stumvoll, Andrew Hattersley, Alexander Doney, Peter P Pramstaller, Christian Dina, Lambertus Kiemeney, Sophie Visvikis-Siest, ANGELO SCUTERI, Udo Seedorf, Vilmundur Gudnason, Peter Kraft, Aroon Hingorani, Michael Marmot, Dale Nyholt, Mika Kivimaki, Mary Feitosa, Danielle Posthuma, Claudia Langenberg, Stavroula Kanoni, Mika Kähönen, David Hillman, Lachlan Coin, Eric Brunner, Terho Lehtimäki, Man Li, John Beilby, Peter Visscher, Anette P Gjesing, James Pankow, Ruben Hernaez, Taina Lajunen, Katja Aben, Daniel Witte, Willem Ouwehand, Eleanor Wheeler, Peter Kovacs, Debbie A Lawlor, Kevin Jacobs, Jianjun Liu, Joseph Massaro, Hana Lango Allen, Inga Prokopenko, Rafn Benediktsson, Philippe Froguel, Soumya Raychaudhuri, Cornelia Van Duijn, Annette Peters, Nita Forouhi, Chiara Lanzani, Tonu Esko, Ko Willems van Dijk, Sadaf Farooqi, John Carr, Reedik Mägi, David Melzer, Gerard Waeber, Sutapa Mukherjee, Lyle John Palmer, Francois Pattou, Claes Ohlsson, Perry Elliott, André Scherag, Inke König, Stephen O'rahilly, Thomas Meitinger, Michael Goddard, Lina Zgaga, Robert Weyant, Paul Elliott, Robert Luben, Albert Vernon Smith, MANUELA UDA, Avan Aihie Sayer, Richard Bergman, Gonneke Willemsen, Cecilia Lindgren, Olle Melander, Igor Rudan, Maris Teder-Laving, Hugh Watkins, Ulrich John, Epidemiology, Scherag, Andre (Beitragende*r), Hinney, Anke (Beitragende*r), Scherag, S. (Beitragende*r), Vogel, C. I. (Beitragende*r), Hebebrand, Johannes (Beitragende*r), Functional Genomics, Biological Psychology, Neuroscience Campus Amsterdam - integrative Analysis & Modeling, Neuroscience Campus Amsterdam - Attention & Cognition, EMGO+ - Mental Health, McCarthy, Mark I, Apollo - University of Cambridge Repository, Medical Research Council (MRC), Speliotes, Ek, YERGES ARMSTRONG, Lm, Wu, J, Hernaez, R, Kim, Lj, Palmer, Cd, Gudnason, V, Eiriksdottir, G, Garcia, Me, Launer, Lj, Nalls, Ma, Clark, Jm, Mitchell, Bd, Shuldiner, Ar, Butler, Jl, Tomas, M, Hoffmann, U, Hwang, Sj, Massaro, Jm, O'Donnell, Cj, Sahani, Dv, Salomaa, V, Schadt, Ee, Schwartz, Sm, Siscovick, D, Nash, Crn, Manunta, Paolo, Giant, Consortium, Magic, Investigator, Voight, Bf, Carr, Jj, Feitosa, Mf, Harris, Tb, Fox, C, Smith, Av, Kao, Wh, Hirschhorn, Jn, Borecki, Ib, Gold, Consortium, Hjelt Institute (-2014), Department of Public Health, Institute for Molecular Medicine Finland, Haartman Institute (-2014), Transplantation Laboratory, Genetic Epidemiology, O', Donnell, Cj, Giant, and Paolisso, Giuseppe

Subjects
Blood Glucose, Male, Netherlands Twin Register (NTR), Cancer Research, Medizin, Genome-wide association study, Hepatitis, Diabetes and Endocrinology/Obesity, Cohort Studies, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Lectins, Nonalcoholic fatty liver disease, 80 and over, Insulin, 2.1 Biological and endogenous factors, Aetiology, Tomography, Adaptor Proteins, Signal Transducing/genetics Adult Aged Aged, 80 and over Blood Glucose/analysis Case-Control Studies Chondroitin Sulfate Proteoglycans/genetics Cohort Studies Fatty Liver/*genetics/metabolism/radiography Genome-Wide Association Study Humans Insulin/blood Lectins, C-Type/genetics Lipase/genetics Male Membrane Proteins/genetics Middle Aged Mutation, Missense Nerve Tissue Proteins/genetics Polymorphism, Single Nucleotide Quantitative Trait Loci Tomography, X-Ray Computed, Genetics (clinical), Aged, 80 and over, Genetics, 0303 health sciences, education.field_of_study, Framingham Risk Score, C-Type, Liver Disease, Fatty liver, Adaptor Proteins, Single Nucleotide, Middle Aged, X-Ray Computed, 3. Good health, GOLD Consortium, 030211 gastroenterology & hepatology, Research Article, Adult, lcsh:QH426-470, Quantitative Trait Loci, Chronic Liver Disease and Cirrhosis, Mutation, Missense, genome-wide, fatty liver, metabolic, Nerve Tissue Proteins, Genetics and Genomics/Complex Traits, Biology, Polymorphism, Single Nucleotide, Gastroenterology and Hepatology/Hepatology, MAGIC Investigators, 03 medical and health sciences, Clinical Research, GIANT Consortium, medicine, Humans, Lectins, C-Type, Adiponutrin, NASH CRN, ddc:610, Polymorphism, education, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Adaptor Proteins, Signal Transducing, Aged, 030304 developmental biology, 0604 Genetics, Genetic heterogeneity, Prevention, Human Genome, Signal Transducing, Membrane Proteins, Lipase, medicine.disease, 3141 Health care science, Fatty Liver, lcsh:Genetics, Chondroitin Sulfate Proteoglycans, Case-Control Studies, Mutation, Missense, Steatosis, Steatohepatitis, Tomography, X-Ray Computed, Digestive Diseases, Neurocan, Genome-Wide Association Study, Developmental Biology
Abstract

Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (∼26%–27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ∼2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p, Author Summary NAFLD is a spectrum of disease that ranges from steatosis to steatohepatitis (nonalcoholic steatohepatitis or NASH: inflammation around the fat) to fibrosis/cirrhosis. Hepatic steatosis can be measured non-invasively using computed tomography (CT) whereas NASH/fibrosis is assessed histologically. The genetic underpinnings of NAFLD remain to be determined. Here we estimate that 26%–27% of the variation in CT measured hepatic steatosis is heritable or genetic. We identify three variants near PNPLAL3, NCAN, and PPP1R3B that associate with CT hepatic steatosis and show that variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B, associate with histologic lobular inflammation/fibrosis. Variants in or near NCAN, GCKR, and PPP1R3B associate with altered serum lipid levels, whereas those in or near LYPLAL1 and PNPLA3 do not. Variants near GCKR and PPP1R3B also affect glycemic traits. Thus, we show that NAFLD is genetically influenced and expand the number of common genetic variants that associate with this trait. Our findings suggest that development of hepatic steatosis, NASH/fibrosis, or abnormalities in metabolic traits are probably influenced by different metabolic pathways that may represent distinct therapeutic targets.

Published
2011

14. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index

Author

Fredrik Karpe, Ivonne Jarick, Julius S. Ngwa, Alan F. Wright, Robert Luben, Aaron R. Folsom, Sailaja Vedantam, Veikko Salomaa, Markku J. Savolainen, Robert Clarke, Shah Ebrahim, Thomas A. Buchanan, Mao Fu, Albert Hofman, Philippe Goyette, Camilla H. Sandholt, Fabio Macciardi, Elizabeth K. Speliotes, Barbara McKnight, Anne McCarthy, Mika Kaehoenen, Christian Gieger, Jorma S. A. Viikari, Nicholas J. Timpson, Kirsti Kvaløy, Douglas F. Levinson, Toby Johnson, Cornelia M. van Duijn, Samuli Ripatti, Andrew A. Hicks, Niina Pellikka, Charles C. White, Leena Peltonen, Reedik Maegi, John-Olov Jansson, Qunyuan Zhang, Claudia Lamina, Robert C. Kaplan, Peter M. Visscher, Laura J. Scott, Claes Ohlsson, Brian Thomson, Jubao Duan, Heikki V. Huikuri, Stephen O'Rahilly, Anette P. Gjesing, David P. Strachan, Caroline S. Fox, Sekar Kathiresan, Anna-Liisa Hartikainen, Johannes Kettunen, Maris Teder-Laving, Erik Ingelsson, Mario A. Morken, Peter Kovacs, Elisabeth Widen, Caroline Hayward, Eleanor Wheeler, Jing Hua Zhao, Vilmundur Gudnason, Panos Deloukas, Jacqueline C. M. Witteman, Gert-Jan B. van Ommen, Eric Boerwinkle, Martin Wabitsch, Christian Hengstenberg, Beverley Balkau, Thor Aspelund, Neelam Hassanali, Paul M. Ridker, Nicole L. Glazer, Joyce B. J. van Meurs, Michel Marre, Alan James, Ben A. Oostra, David Meyre, Ida Surakka, Stefan Schreiber, Nigel W. Rayner, Heribert Schunkert, Thomas Quertermous, Stefan Gustafsson, Peter Kraft, Benjamin F. Voight, Irene Pichler, Olle Melander, Ozren Polasek, Antti Jula, Alan R. Sanders, Andrew R. Wood, Yoav Ben-Shlomo, Thomas Illig, Jianjun Liu, Gerard Waeber, André G. Uitterlinden, Torben Hansen, Helene Alavere, André Scherag, Paolo Manunta, Johannes Hebebrand, Themistocles L. Assimes, Stefan R. Bornstein, Jaakko Tuomilehto, Morris Brown, Jianfeng Xu, Yii-Der Ida Chen, Nancy L. Heard-Costa, Cristen J. Willer, Henrik Greonberg, Guillaume Lettre, John R. Thompson, Inês Barroso, John R. B. Perry, Andreas Ziegler, James F. Wilson, Christopher J. O'Donnell, Maurizio F. Facheris, Robert Lawrence, Jan Smit, Lyle J. Palmer, Ulf Gyllensten, Richard B. Hayes, Shengxu Li, Barbara Ludwig, Larry D. Atwood, Valgerdur Steinthorsdottir, Sabine Schipf, Jouko Saramies, Tanja Boes, Martin Ridderstråle, Jennie Hui, Lina Zgaga, Susann Scherag, Alexandra I. F. Blakemore, Marjolein Peters, Timo T. Valle, Nelson B. Freimer, Kay-Tee Khaw, Amy J. Swift, Michael Stumvoll, Miriam F. Moffatt, Cecilia M. Lindgren, Ayellet V. Segrè, Neil Robertson, Richard N. Bergman, Francis S. Collins, Ryan P. Welch, Mari-Liis Tammesoo, Devin Absher, Tamara B. Harris, Kari E. North, Manuela Uda, Karen L. Mohlke, Inga Prokopenko, Per Hall, Gudmar Thorleifsson, Marjo-Riitta Järvelin, Guillaume Paré, Stefan Gaget, G. Bragi Walters, Michael N. Weedon, Jean-Claude Tardif, Mary F. Feitosa, Anke Toenjes, Ken K. Ong, Cécile Lecoeur, Paavo Zitting, David S. Siscovick, Chih-Mei Chen, Peter Almgren, Anneli Pouta, Philippe Froguel, Pekka Jousilahti, Jaakko Kaprio, Maria Teresa Sciarrone Alibrandi, Sophie van Wingerden, Steven A. McCarroll, Oluf Pedersen, Shaun Purcell, Veronique Vitart, Leena Kinnunen, Markus Perola, Jacques S. Beckmann, Vincent Vatin, Christopher J. Groves, Zoltán Kutalik, Lu Qi, Volker Hoesel, Seppo Koskinen, Suzanne Rafelt, Anke Hinney, Annette Peters, David Schlessinger, Eero Kajantie, Jian Yang, Nicholas G. Martin, Joshua W. Knowles, Kristian Midthjell, Olivier Lantieri, Dorret I. Boomsma, Harry Campbell, Ulrich John, Kirsi H. Pietilaeinen, George Davey Smith, Carl G. P. Platou, Sarah H. Wild, Patricia B. Munroe, Iris M. Heid, Diana Marek, Michael Boehnke, Andres Metspalu, Hana Lango Allen, Peter Rzehak, Christine Cavalcanti-Proença, M. Carola Zillikens, Åsa Johansson, Anuj Goel, Andrew T. Hattersley, Massimo Mangino, Michael E. Goddard, Tim D. Spector, Winfried Rief, Jonathan Tyrer, Lachlan J. M. Coin, Peter P. Pramstaller, Narisu Narisu, John Beilby, Jonathan Stephens, Christina Barlassina, Pamela Fischer-Posovszky, Brenda W.J.H. Penninx, Kaisa Silander, Richard H. Myers, Jouke-Jan Hottenga, Eric E. Schadt, Francesco P. Cappuccio, Martin den Heijer, Fernando Rivadeneira, Lindsay L. Waite, Wilmar Igl, Igor Rudan, Manjinder S. Sandhu, Debbie A Lawlor, Kristian Hveem, Susanna Wiegand, Mari Nelis, Thomas Reinehr, Elisabeth Thiering, Inke R. Koenig, Stephan B. Felix, Fredrik Wiklund, Ian N. M. Day, Willem H. Ouwehand, Peter Schwarz, Richard M. Watanabe, Keri L. Monda, Kari Stefansson, Gudny Eiriksdottir, H-Erich Wichmann, Jianxin Shi, Najaf Amin, Carlos Iribarren, Heiko Krude, Dale R. Nyholt, Lenore J. Launer, Stephen J. Chanock, Harald Grallert, Hugh Watkins, Juergen Graessler, Tsegaselassie Workalemahu, Jeanette Erdmann, Mattias Lorentzon, Leif Groop, Teresa Ferreira, Chiara Lanzani, Johanna Kuusisto, Johan G. Eriksson, Tõnu Esko, Torben Jørgensen, Robert J. Weyant, Michael Preuss, Lambertus A. Kiemeney, Daniel I. Chasman, Daniel R. Witte, Kevin B. Jacobs, Nicole Soranzo, John M. C. Connell, Soumya Raychaudhuri, Jian'an Luan, Joshua C. Randall, Joachim Heinrich, Anthony J. Balmforth, Eva Fisher, Elizabeth S. Jewell, Alice M. Arnold, Nele Friedrich, Olli T. Raitakari, Henri Wallaschofski, Jeffrey R. O'Connell, Terho Lehtimaeki, Marika Kaakinen, Heather M. Stringham, Bo Isomaa, I. Sadaf Farooqi, Anna L. Dixon, Anne U. Jackson, Mark I. McCarthy, Lori L. Bonnycastle, Aila Rissanen, Joel N. Hirschhorn, Nilesh J. Samani, Aimo Ruokonen, Frank B. Hu, L. Adrienne Cupples, Amanda J. Bennett, Shamika Ketkar, Ruth J. F. Loos, Nicholas J. Wareham, Tiinamaija Tuomi, Timothy M. Frayling, Ulla Sovio, Georg Homuth, Liming Liang, Heiner Boeing, Unnur Thorsteinsdottir, Ingrid B. Borecki, Danielle M. Greenawalt, Rosanda Mulić, Ivana Kolcic, Talin Haritunians, Mark J. Caulfield, Marja-Liisa Lokki, Tanya M. Teslovich, Paul Elliott, Matt Neville, Nilanjan Chatterjee, Albert V. Smith, Andrew P. Morris, Fabio Busonero, Gonçalo R. Abecasis, Jaana Laitinen, Michael R. Erdos, Candace Guiducci, Lee M. Kaplan, Aki S. Havulinna, Pablo V. Gejman, Alan R. Shuldiner, Serena Sanna, David J. Hunter, Sonja I. Berndt, Carla I. G. Vogel, Alistair S. Hall, Karol Estrada, Sven Bergmann, Thomas Meitinger, Gonneke Willemsen, Andrew C. Heath, Katja K.H. Aben, Markku Laakso, Juha Sinisalo, Tuomas O. Kilpelaenen, Mark E. Cooper, Heike Biebermann, Eco J. C. de Geus, Grant W. Montgomery, Sophie Visvikis-Siest, Thomas W. Winkler, Ju-Hyun Park, Alex N. Parker, Peter S. Chines, James Nemesh, Nabila Bouatia-Naji, Wendy L. McArdle, Roberto Elosua, Markku S. Nieminen, Psychiatry, NCA - Anxiety & Depression, EMGO - Mental health, Epidemiology, Internal Medicine, Clinical Genetics, Radiology & Nuclear Medicine, Erasmus MC other, Public Health, Biological Psychology, Neuroscience Campus Amsterdam - Anxiety & Depression, EMGO+ - Mental Health, MAGIC, Procardis Consortium, Medical Research Council (MRC), Speliotes, Ek, Willer, Cj, Berndt, Si, Monda, Kl, Thorleifsson, G, Jackson, Au, Allen, Hl, Lindgren, Cm, Luan, J, Mägi, R, Randall, Jc, Vedantam, S, Winkler, Tw, Qi, L, Workalemahu, T, Heid, Im, Steinthorsdottir, V, Stringham, Hm, Weedon, Mn, Wheeler, E, Wood, Ar, Ferreira, T, Weyant, Rj, Segrè, Av, Estrada, K, Liang, L, Nemesh, J, Park, Jh, Gustafsson, S, Kilpeläinen, To, Yang, J, BOUATIA NAJI, N, Esko, T, Feitosa, Mf, Kutalik, Z, Mangino, M, Raychaudhuri, S, Scherag, A, Smith, Av, Welch, R, Zhao, Jh, Aben, Kk, Absher, Dm, Amin, N, Dixon, Al, Fisher, E, Glazer, Nl, Goddard, Me, HEARD COSTA, Nl, Hoesel, V, Hottenga, Jj, Johansson, A, Johnson, T, Ketkar, S, Lamina, C, Li, S, Moffatt, Mf, Myers, Rh, Narisu, N, Perry, Jr, Peters, Mj, Preuss, M, Ripatti, S, Rivadeneira, F, Sandholt, C, Scott, Lj, Timpson, Nj, Tyrer, Jp, VAN WINGERDEN, S, Watanabe, Rm, White, Cc, Wiklund, F, Barlassina, C, Chasman, Di, Cooper, Mn, Jansson, Jo, Lawrence, Rw, Pellikka, N, Prokopenko, I, Shi, J, Thiering, E, Alavere, H, Alibrandi, Mt, Almgren, P, Arnold, Am, Aspelund, T, Atwood, Ld, Balkau, B, Balmforth, Aj, Bennett, Aj, BEN SHLOMO, Y, Bergman, Rn, Bergmann, S, Biebermann, H, Blakemore, Ai, Boes, T, Bonnycastle, Ll, Bornstein, Sr, Brown, Mj, Buchanan, Ta, Busonero, F, Campbell, H, Cappuccio, Fp, CAVALCANTI PROENÇA, C, Chen, Yd, Chen, Cm, Chines, P, Clarke, R, Coin, L, Connell, J, Day, In, DEN HEIJER, M, Duan, J, Ebrahim, S, Elliott, P, Elosua, R, Eiriksdottir, G, Erdos, Mr, Eriksson, Jg, Facheris, Mf, Felix, Sb, FISCHER POSOVSZKY, P, Folsom, Ar, Friedrich, N, Freimer, Nb, Fu, M, Gaget, S, Gejman, Pv, Geus, Ej, Gieger, C, Gjesing, Ap, Goel, A, Goyette, P, Grallert, H, Grässler, J, Greenawalt, Dm, Groves, Cj, Gudnason, V, Guiducci, C, Hartikainen, Al, Hassanali, N, Hall, A, Havulinna, A, Hayward, C, Heath, Ac, Hengstenberg, C, Hicks, Aa, Hinney, A, Hofman, A, Homuth, G, Hui, J, Igl, W, Iribarren, C, Isomaa, B, Jacobs, Kb, Jarick, I, Jewell, E, John, U, Jørgensen, T, Jousilahti, P, Jula, A, Kaakinen, M, Kajantie, E, Kaplan, Lm, Kathiresan, S, Kettunen, J, Kinnunen, L, Knowles, Jw, Kolcic, I, König, Ir, Koskinen, S, Kovacs, P, Kuusisto, J, Kraft, P, Kvaløy, K, Laitinen, J, Lantieri, O, Lanzani, C, Launer, Lj, Lecoeur, C, Lehtimäki, T, Lettre, G, Liu, J, Lokki, Ml, Lorentzon, M, Luben, Rn, Ludwig, B, Magic, Manunta, Paolo, Marek, D, Marre, M, Martin, Ng, Mcardle, Wl, Mccarthy, A, Mcknight, B, Meitinger, T, Melander, O, Meyre, D, Midthjell, K, Montgomery, Gw, Morken, Ma, Morris, Ap, Mulic, R, Ngwa, J, Nelis, M, Neville, Mj, Nyholt, Dr, O'Donnell, Cj, O'Rahilly, S, Ong, Kk, Oostra, B, Paré, G, Parker, An, Perola, M, Pichler, I, Pietiläinen, Kh, Platou, Cg, Polasek, O, Pouta, A, Rafelt, S, Raitakari, O, Rayner, Nw, Ridderstråle, M, Rief, W, Ruokonen, A, Robertson, Nr, Rzehak, P, Salomaa, V, Sanders, Ar, Sandhu, M, Sanna, S, Saramies, J, Savolainen, Mj, Scherag, S, Schipf, S, Schreiber, S, Schunkert, H, Silander, K, Sinisalo, J, Siscovick, D, Smit, Jh, Soranzo, N, Sovio, U, Stephens, J, Surakka, I, Swift, Aj, Tammesoo, Ml, Tardif, Jc, TEDER LAVING, M, Teslovich, Tm, Thompson, Jr, Thomson, B, Tönjes, A, Tuomi, T, VAN MEURS, Jb, VAN OMMEN, Gj, Vatin, V, Viikari, J, VISVIKIS SIEST, S, Vitart, V, Vogel, Ci, Voight, Bf, Waite, Ll, Wallaschofski, H, Walters, Gb, Widen, E, Wiegand, S, Wild, Sh, Willemsen, G, Witte, Dr, Witteman, Jc, Xu, J, Zhang, Q, Zgaga, L, Ziegler, A, Zitting, P, Beilby, Jp, Farooqi, I, Hebebrand, J, Huikuri, Hv, James, Al, Kähönen, M, Levinson, Df, Macciardi, F, Nieminen, M, Ohlsson, C, Palmer, Lj, Ridker, Pm, Stumvoll, M, Beckmann, J, Boeing, H, Boerwinkle, E, Boomsma, Di, Caulfield, Mj, Chanock, Sj, Collins, F, Cupples, La, Smith, Gd, Erdmann, J, Froguel, P, Grönberg, H, Gyllensten, U, Hall, P, Hansen, T, Harris, Tb, Hattersley, At, Hayes, Rb, Heinrich, J, Hu, Fb, Hveem, K, Illig, T, Jarvelin, Mr, Kaprio, J, Karpe, F, Khaw, Kt, Kiemeney, La, Krude, H, Laakso, M, Lawlor, Da, Metspalu, A, Munroe, Pb, Ouwehand, Wh, Pedersen, O, Penninx, Bw, Peters, A, Pramstaller, Pp, Quertermous, T, Reinehr, T, Rissanen, A, Rudan, I, Samani, Nj, Schwarz, Pe, Shuldiner, Ar, Spector, Td, Tuomilehto, J, Uda, M, Uitterlinden, A, Valle, Tt, Wabitsch, M, Waeber, G, Wareham, Nj, Watkins, H, Procardis, Consortium, Wilson, Jf, Wright, Af, Zillikens, Mc, Chatterjee, N, Mccarroll, Sa, Purcell, S, Schadt, Ee, Visscher, Pm, Assimes, Tl, Borecki, Ib, Deloukas, P, Fox, C, Groop, Lc, Haritunians, T, Hunter, Dj, Kaplan, Rc, Mohlke, Kl, O'Connell, Jr, Peltonen, L, Schlessinger, D, Strachan, Dp, VAN DUIJN, Cm, Wichmann, He, Frayling, Tm, Thorsteinsdottir, U, Abecasis, Gr, Barroso, I, Boehnke, M, Stefansson, K, North, Ke, Mccarthy, Mi, Hirschhorn, Jn, Ingelsson, E, and Loos, Rj

Subjects
Netherlands Twin Register (NTR), Medizin, Genome-wide association study, Aetiology, screening and detection [ONCOL 5], FTO gene, Body Mass Index, 0302 clinical medicine, SH2B1, GASTRIC-INHIBITORY POLYPEPTIDE, ADULT OBESITY, Glucose homeostasis, Body Size, GENETICS & HEREDITY, 2. Zero hunger, Genetics, Genetics & Heredity, RISK, 0303 health sciences, Neuronal growth regulator 1, Genetics of obesity, COMMON VARIANTS, Chromosome Mapping, 11 Medical And Health Sciences, Body Height/genetics, Body Size/genetics, Body Weight/genetics, European Continental Ancestry Group/genetics, Genetic Predisposition to Disease/genetics, Genome-Wide Association Study, Humans, Obesity/genetics, Polymorphism, Single Nucleotide, FAT MASS, Body Height/*genetics *Body Mass Index Body Size/genetics Body Weight/*genetics *Chromosome Mapping European Continental Ancestry Group/genetics Genetic Predisposition to Disease/genetics Genome-Wide Association Study Humans Obesity/genetics Polymorphism, Single Nucleotide, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, MELANOCORTIN-4 RECEPTOR GENE, Life Sciences & Biomedicine, European Continental Ancestry Group, EARLY-ONSET, 030209 endocrinology & metabolism, Locus (genetics), Biology, Article, White People, Molecular epidemiology [NCEBP 1], 03 medical and health sciences, SDG 3 - Good Health and Well-being, body mass index, genome-wide association, meta-analysis, Genetic Predisposition to Disease, Obesity, GENOME-WIDE ASSOCIATION, FTO GENE, 030304 developmental biology, Science & Technology, genome-wide association gastric-inhibitory polypeptide melanocortin-4 receptor gene glucose-homeostasis common variants adult obesity early-onset fat mass risk metaanalysis, Body Weight, 06 Biological Sciences, MAGIC, Body Height, GLUCOSE-HOMEOSTASIS, Procardis Consortium, Body mass index, Developmental Biology
Abstract

Obesity is globaLy prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined aSociations betwEn body maS index and ĝ̂1/42.8 miLion SNPs in up to 123,865 individuals with targeted foLow up of 42 SNPs in up to 125,931 aDitional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci aSociated with body maS index (P < 5-10-8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly aSociated loci may provide new insights into human body weight regulation. © 2010 Nature America, Inc. All rights reserved.

Published
2010

15. CLOCK gene variants associate with sleep duration in two independent populations

Author

Thomas Meitinger, Bertram Müller-Myhsok, Karla V. Allebrandt, Irene Pichler, Peter P. Pramstaller, Mahmut Akyol, Maris Teder-Laving, Till Roenneberg, Martha Merrow, Andreas Metspalu, and Beersma lab

Subjects
Estonia, Male, Linkage disequilibrium, Time Factors, Genotype, Circadian clock, PREFERENCE, CLOCK, CLOCK Proteins, Single-nucleotide polymorphism, Biology, CIRCADIAN CLOCK, SUSCEPTIBILITY, MOUSE, Sex Factors, Gene Frequency, Biological Clocks, ADOLESCENTS, medicine, clock genes, Humans, Bipolar disorder, Circadian rhythm, TRANSCRIPTION FACTOR, short sleepers, Biological Psychiatry, Alleles, Genetic Association Studies, Genetics, Haplotype, Chronotype, Genetic Variation, BIPOLAR DISORDER, MCTQ, medicine.disease, POLYMORPHISM, TIME, Circadian Rhythm, Phenotype, PERSPECTIVES, Haplotypes, Italy, sleep duration, Female, long sleepers, Sleep
Abstract

Background: Sleep is an active and complex behavior, yet it has two straightforward properties-timing and duration. Clock genes are associated with dysfunctional timing of sleep, mood, and obesity disorders, which are commonly associated with sleep duration.Methods: Sleep duration was assessed in Central Europe, Estonia, and South Tyrol (n approximate to 77,000) with the Munich ChronoType Questionnaire. It showed a Gaussian distribution in all investigated populations after averaging over a standard workweek and normalization according to age and gender. A follow-up, two-stage design, linkage disequilibrium-based association study was conducted with subjects from South Tyrol (discovery sample; n = 283) and with short ( 8.5 hours) sleepers from Estonia (confirmation sample; n = 1011). One hundred ninety-four single nucleotide polymorphism markers covering 19 candidate clock genes were genotyped in the discovery sample, and two of the best association signals (analyzed by a linear regression model) were investigated in the confirmation sample.Results: Single and multi-marker associations were found within a CLOCK gene intronic region (rs12649507 and rs11932595). In a meta-analysis between South Tyrol and Estonia association signals, rs12649507 (p = .0087) remained significant. Significance persisted only for the multiple-marker association signal of the rs12649507/rs11932595 haplotype GGAA with long sleep (p = .0015).Conclusions: We report an association between variants of the human CLOCK gene and sleep duration in two independent populations. This adds another putative function for CLOCK besides its possible involvement in circadian timing, depression, obesity, and personality.

Published
2009

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