Author: "Janina S Ried" / Topic: genetics - Searchworks@Jio Institute Digital Library Search Results

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1. Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation.

Author: Momoko Horikoshi, Reedik Mӓgi, Martijn van de Bunt, Ida Surakka, Antti-Pekka Sarin, Anubha Mahajan, Letizia Marullo, Gudmar Thorleifsson, Sara Hӓgg, Jouke-Jan Hottenga, Claes Ladenvall, Janina S Ried, Thomas W Winkler, Sara M Willems, Natalia Pervjakova, Tõnu Esko, Marian Beekman, Christopher P Nelson, Christina Willenborg, Steven Wiltshire, Teresa Ferreira, Juan Fernandez, Kyle J Gaulton, Valgerdur Steinthorsdottir, Anders Hamsten, Patrik K E Magnusson, Gonneke Willemsen, Yuri Milaneschi, Neil R Robertson, Christopher J Groves, Amanda J Bennett, Terho Lehtimӓki, Jorma S Viikari, Johan Rung, Valeriya Lyssenko, Markus Perola, Iris M Heid, Christian Herder, Harald Grallert, Martina Müller-Nurasyid, Michael Roden, Elina Hypponen, Aaron Isaacs, Elisabeth M van Leeuwen, Lennart C Karssen, Evelin Mihailov, Jeanine J Houwing-Duistermaat, Anton J M de Craen, Joris Deelen, Aki S Havulinna, Matthew Blades, Christian Hengstenberg, Jeanette Erdmann, Heribert Schunkert, Jaakko Kaprio, Martin D Tobin, Nilesh J Samani, Lars Lind, Veikko Salomaa, Cecilia M Lindgren, P Eline Slagboom, Andres Metspalu, Cornelia M van Duijn, Johan G Eriksson, Annette Peters, Christian Gieger, Antti Jula, Leif Groop, Olli T Raitakari, Chris Power, Brenda W J H Penninx, Eco de Geus, Johannes H Smit, Dorret I Boomsma, Nancy L Pedersen, Erik Ingelsson, Unnur Thorsteinsdottir, Kari Stefansson, Samuli Ripatti, Inga Prokopenko, Mark I McCarthy, Andrew P Morris, and ENGAGE Consortium
Subjects: Genetics, QH426-470
Abstract: Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency ≥0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated.
Published: 2015
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2. Causal and synthetic associations of variants in the SERPINA gene cluster with alpha1-antitrypsin serum levels.

Author: Gian Andri Thun, Medea Imboden, Ilaria Ferrarotti, Ashish Kumar, Ma'en Obeidat, Michele Zorzetto, Margot Haun, Ivan Curjuric, Alexessander Couto Alves, Victoria E Jackson, Eva Albrecht, Janina S Ried, Alexander Teumer, Lorna M Lopez, Jennifer E Huffman, Stefan Enroth, Yohan Bossé, Ke Hao, Wim Timens, Ulf Gyllensten, Ozren Polasek, James F Wilson, Igor Rudan, Caroline Hayward, Andrew J Sandford, Ian J Deary, Beate Koch, Eva Reischl, Holger Schulz, Jennie Hui, Alan L James, Thierry Rochat, Erich W Russi, Marjo-Riitta Jarvelin, David P Strachan, Ian P Hall, Martin D Tobin, Morten Dahl, Sune Fallgaard Nielsen, Børge G Nordestgaard, Florian Kronenberg, Maurizio Luisetti, and Nicole M Probst-Hensch
Subjects: Genetics, QH426-470
Abstract: Several infrequent genetic polymorphisms in the SERPINA1 gene are known to substantially reduce concentration of alpha1-antitrypsin (AAT) in the blood. Since low AAT serum levels fail to protect pulmonary tissue from enzymatic degradation, these polymorphisms also increase the risk for early onset chronic obstructive pulmonary disease (COPD). The role of more common SERPINA1 single nucleotide polymorphisms (SNPs) in respiratory health remains poorly understood. We present here an agnostic investigation of genetic determinants of circulating AAT levels in a general population sample by performing a genome-wide association study (GWAS) in 1392 individuals of the SAPALDIA cohort. Five common SNPs, defined by showing minor allele frequencies (MAFs) >5%, reached genome-wide significance, all located in the SERPINA gene cluster at 14q32.13. The top-ranking genotyped SNP rs4905179 was associated with an estimated effect of β = -0.068 g/L per minor allele (P = 1.20*10(-12)). But denser SERPINA1 locus genotyping in 5569 participants with subsequent stepwise conditional analysis, as well as exon-sequencing in a subsample (N = 410), suggested that AAT serum level is causally determined at this locus by rare (MAF
Published: 2013
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3. A genome-wide screen for interactions reveals a new locus on 4p15 modifying the effect of waist-to-hip ratio on total cholesterol.

Author: Ida Surakka, Aaron Isaacs, Lennart C Karssen, Pirkka-Pekka P Laurila, Rita P S Middelberg, Emmi Tikkanen, Janina S Ried, Claudia Lamina, Massimo Mangino, Wilmar Igl, Jouke-Jan Hottenga, Vasiliki Lagou, Pim van der Harst, Irene Mateo Leach, Tõnu Esko, Zoltán Kutalik, Nicholas W Wainwright, Maksim V Struchalin, Antti-Pekka Sarin, Antti J Kangas, Jorma S Viikari, Markus Perola, Taina Rantanen, Ann-Kristin Petersen, Pasi Soininen, Asa Johansson, Nicole Soranzo, Andrew C Heath, Theodore Papamarkou, Inga Prokopenko, Anke Tönjes, Florian Kronenberg, Angela Döring, Fernando Rivadeneira, Grant W Montgomery, John B Whitfield, Mika Kähönen, Terho Lehtimäki, Nelson B Freimer, Gonneke Willemsen, Eco J C de Geus, Aarno Palotie, Manj S Sandhu, Dawn M Waterworth, Andres Metspalu, Michael Stumvoll, André G Uitterlinden, Antti Jula, Gerjan Navis, Cisca Wijmenga, Bruce H R Wolffenbuttel, Marja-Riitta Taskinen, Mika Ala-Korpela, Jaakko Kaprio, Kirsten O Kyvik, Dorret I Boomsma, Nancy L Pedersen, Ulf Gyllensten, James F Wilson, Igor Rudan, Harry Campbell, Peter P Pramstaller, Tim D Spector, Jacqueline C M Witteman, Johan G Eriksson, Veikko Salomaa, Ben A Oostra, Olli T Raitakari, H-Erich Wichmann, Christian Gieger, Marjo-Riitta Järvelin, Nicholas G Martin, Albert Hofman, Mark I McCarthy, Leena Peltonen, Cornelia M van Duijn, Yurii S Aulchenko, Samuli Ripatti, and ENGAGE Consortium
Subjects: Genetics, QH426-470
Abstract: Recent genome-wide association (GWA) studies described 95 loci controlling serum lipid levels. These common variants explain ∼25% of the heritability of the phenotypes. To date, no unbiased screen for gene-environment interactions for circulating lipids has been reported. We screened for variants that modify the relationship between known epidemiological risk factors and circulating lipid levels in a meta-analysis of genome-wide association (GWA) data from 18 population-based cohorts with European ancestry (maximum N = 32,225). We collected 8 further cohorts (N = 17,102) for replication, and rs6448771 on 4p15 demonstrated genome-wide significant interaction with waist-to-hip-ratio (WHR) on total cholesterol (TC) with a combined P-value of 4.79×10(-9). There were two potential candidate genes in the region, PCDH7 and CCKAR, with differential expression levels for rs6448771 genotypes in adipose tissue. The effect of WHR on TC was strongest for individuals carrying two copies of G allele, for whom a one standard deviation (sd) difference in WHR corresponds to 0.19 sd difference in TC concentration, while for A allele homozygous the difference was 0.12 sd. Our findings may open up possibilities for targeted intervention strategies for people characterized by specific genomic profiles. However, more refined measures of both body-fat distribution and metabolic measures are needed to understand how their joint dynamics are modified by the newly found locus.
Published: 2011
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4. Discovery of sexual dimorphisms in metabolic and genetic biomarkers.

Author: Kirstin Mittelstrass, Janina S Ried, Zhonghao Yu, Jan Krumsiek, Christian Gieger, Cornelia Prehn, Werner Roemisch-Margl, Alexey Polonikov, Annette Peters, Fabian J Theis, Thomas Meitinger, Florian Kronenberg, Stephan Weidinger, Heinz Erich Wichmann, Karsten Suhre, Rui Wang-Sattler, Jerzy Adamski, and Thomas Illig
Subjects: Genetics, QH426-470
Abstract: Metabolomic profiling and the integration of whole-genome genetic association data has proven to be a powerful tool to comprehensively explore gene regulatory networks and to investigate the effects of genetic variation at the molecular level. Serum metabolite concentrations allow a direct readout of biological processes, and association of specific metabolomic signatures with complex diseases such as Alzheimer's disease and cardiovascular and metabolic disorders has been shown. There are well-known correlations between sex and the incidence, prevalence, age of onset, symptoms, and severity of a disease, as well as the reaction to drugs. However, most of the studies published so far did not consider the role of sexual dimorphism and did not analyse their data stratified by gender. This study investigated sex-specific differences of serum metabolite concentrations and their underlying genetic determination. For discovery and replication we used more than 3,300 independent individuals from KORA F3 and F4 with metabolite measurements of 131 metabolites, including amino acids, phosphatidylcholines, sphingomyelins, acylcarnitines, and C6-sugars. A linear regression approach revealed significant concentration differences between males and females for 102 out of 131 metabolites (p-values
Published: 2011
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5. Genome-wide association study identifies two novel regions at 11p15.5-p13 and 1p31 with major impact on acute-phase serum amyloid A.

Author: Carola Marzi, Eva Albrecht, Pirro G Hysi, Vasiliki Lagou, Melanie Waldenberger, Anke Tönjes, Inga Prokopenko, Katharina Heim, Hannah Blackburn, Janina S Ried, Marcus E Kleber, Massimo Mangino, Barbara Thorand, Annette Peters, Christopher J Hammond, Harald Grallert, Bernhard O Boehm, Peter Kovacs, Ludwig Geistlinger, Holger Prokisch, Bernhard R Winkelmann, Tim D Spector, H-Erich Wichmann, Michael Stumvoll, Nicole Soranzo, Winfried März, Wolfgang Koenig, Thomas Illig, and Christian Gieger
Subjects: Genetics, QH426-470
Abstract: Elevated levels of acute-phase serum amyloid A (A-SAA) cause amyloidosis and are a risk factor for atherosclerosis and its clinical complications, type 2 diabetes, as well as various malignancies. To investigate the genetic basis of A-SAA levels, we conducted the first genome-wide association study on baseline A-SAA concentrations in three population-based studies (KORA, TwinsUK, Sorbs) and one prospective case cohort study (LURIC), including a total of 4,212 participants of European descent, and identified two novel genetic susceptibility regions at 11p15.5-p13 and 1p31. The region at 11p15.5-p13 (rs4150642; p = 3.20×10(-111)) contains serum amyloid A1 (SAA1) and the adjacent general transcription factor 2 H1 (GTF2H1), Hermansky-Pudlak Syndrome 5 (HPS5), lactate dehydrogenase A (LDHA), and lactate dehydrogenase C (LDHC). This region explains 10.84% of the total variation of A-SAA levels in our data, which makes up 18.37% of the total estimated heritability. The second region encloses the leptin receptor (LEPR) gene at 1p31 (rs12753193; p = 1.22×10(-11)) and has been found to be associated with CRP and fibrinogen in previous studies. Our findings demonstrate a key role of the 11p15.5-p13 region in the regulation of baseline A-SAA levels and provide confirmative evidence of the importance of the 1p31 region for inflammatory processes and the close interplay between A-SAA, leptin, and other acute-phase proteins.
Published: 2010
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6. Genome-wide association studies of serum magnesium, potassium, and sodium concentrations identify six Loci influencing serum magnesium levels.

Author: Tamra E Meyer, Germaine C Verwoert, Shih-Jen Hwang, Nicole L Glazer, Albert V Smith, Frank J A van Rooij, Georg B Ehret, Eric Boerwinkle, Janine F Felix, Tennille S Leak, Tamara B Harris, Qiong Yang, Abbas Dehghan, Thor Aspelund, Ronit Katz, Georg Homuth, Thomas Kocher, Rainer Rettig, Janina S Ried, Christian Gieger, Hanna Prucha, Arne Pfeufer, Thomas Meitinger, Josef Coresh, Albert Hofman, Mark J Sarnak, Yii-Der Ida Chen, André G Uitterlinden, Aravinda Chakravarti, Bruce M Psaty, Cornelia M van Duijn, W H Linda Kao, Jacqueline C M Witteman, Vilmundur Gudnason, David S Siscovick, Caroline S Fox, Anna Köttgen, Genetic Factors for Osteoporosis Consortium, and Meta Analysis of Glucose and Insulin Related Traits Consortium
Subjects: Genetics, QH426-470
Abstract: Magnesium, potassium, and sodium, cations commonly measured in serum, are involved in many physiological processes including energy metabolism, nerve and muscle function, signal transduction, and fluid and blood pressure regulation. To evaluate the contribution of common genetic variation to normal physiologic variation in serum concentrations of these cations, we conducted genome-wide association studies of serum magnesium, potassium, and sodium concentrations using approximately 2.5 million genotyped and imputed common single nucleotide polymorphisms (SNPs) in 15,366 participants of European descent from the international CHARGE Consortium. Study-specific results were combined using fixed-effects inverse-variance weighted meta-analysis. SNPs demonstrating genome-wide significant (p
Published: 2010
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7. Genetic Risk Score for Intracranial Aneurysms: Prediction of Subarachnoid Hemorrhage and Role in Clinical Heterogeneity

Author: Mark K. Bakker, Jos P. Kanning, Gad Abraham, Amy E. Martinsen, Bendik S. Winsvold, John-Anker Zwart, Romain Bourcier, Tomonobu Sawada, Masaru Koido, Yoichiro Kamatani, Sandrine Morel, Philippe Amouyel, Stéphanie Debette, Philippe Bijlenga, Takiy Berrandou, Santhi K. Ganesh, Nabila Bouatia-Naji, Gregory Jones, Matthew Bown, Gabriel J.E. Rinkel, Jan H. Veldink, Ynte M. Ruigrok, Anne Hege Aamodt, Anne Heidi Skogholt, Ben M Brumpton, Cristen J Willer, Else C Sandset, Espen S Kristoffersen, Hanne Ellekjær, Ingrid Heuch, Jonas B Nielsen, Knut Hagen, Kristian Hveem, Lars G Fritsche, Laurent F Thomas, Linda M Pedersen, Maiken E Gabrielsen, Oddgeir L Holmen, Sigrid Børte, Wei Zhou, Shérine Abboud, Massimo Pandolfo, Vincent Thijs, Didier Leys, Marie Bodenant, Fabien Louillet, Emmanuel Touzé, Jean-Louis Mas, Yves Samson, Sara Leder, Anne Léger, Sandrine Deltour, Sophie Crozier, Isabelle Méresse, Sandrine Canaple, Olivier Godefroy, Maurice Giroud, Yannick Béjot, Pierre Decavel, Elizabeth Medeiros, Paola Montiel, Thierry Moulin, Fabrice Vuillier, Jean Dallongeville, Antti J Metso, Tiina Metso, Turgut Tatlisumak, Caspar Grond-Ginsbach, Christoph Lichy, Manja Kloss, Inge Werner, Marie-Luise Arnold, Michael Dos Santos, Armin Grau, Martin Dichgans, Constanze Thomas-Feles, Ralf Weber, Tobias Brandt, Alessandro Pezzini, Valeria De Giuli, Filomena Caria, Loris Poli, Alessandro Padovani, Anna Bersano, Silvia Lanfranconi, Simone Beretta, Carlo Ferrarese, Giacomo Giacolone, Stefano Paolucci, Philippe Lyrer, Stefan Engelter, Felix Fluri, Florian Hatz, Dominique Gisler, Leo Bonati, Henrik Gensicke, Margareth Amort, Hugh Markus, Jennifer Majersik, Bradford Worrall, Andrew Southerland, John Cole, Steven Kittner, Evangelos Evangelou, Helen R Warren, He Gao, Georgios Ntritsos, Niki Dimou, Tonu Esko, Reedik Mägi, Lili Milani, Peter Almgren, Thibaud Boutin, Jun Ding, Franco Giulianini, Elizabeth G Holliday, Anne U Jackson, Ruifang Li-Gao, Wei-Yu Lin, Jian’an Luan, Massimo Mangino, Christopher Oldmeadow, Bram Peter Prins, Yong Qian, Muralidharan Sargurupremraj, Nabi Shah, Praveen Surendran, Sébastien Thériault, Niek Verweij, Sara M Willems, Jing-Hua Zhao, John Connell, Renée de Mutsert, Alex SF Doney, Martin Farrall, Cristina Menni, Andrew D Morris, Raymond Noordam, Guillaume Paré, Neil R Poulter, Denis C Shields, Alice Stanton, Simon Thom, Gonçalo Abecasis, Najaf Amin, Dan E Arking, Kristin L Ayers, Caterina M Barbieri, Chiara Batini, Joshua C Bis, Tineka Blake, Murielle Bochud, Michael Boehnke, Eric Boerwinkle, Dorret I Boomsma, Erwin P Bottinger, Peter S Braund, Marco Brumat, Archie Campbell, Harry Campbell, Aravinda Chakravarti, John C Chambers, Ganesh Chauhan, Marina Ciullo, Massimiliano Cocca, Francis Collins, Heather J Cordell, Gail Davies, Martin H de Borst, Eco J de Geus, Ian J Deary, Joris Deelen, Fabiola Del Greco M, Cumhur Yusuf Demirkale, Marcus Dörr, Georg B Ehret, Roberto Elosua, Stefan Enroth, A Mesut Erzurumluoglu, Teresa Ferreira, Mattias Frånberg, Oscar H Franco, Ilaria Gandin, Paolo Gasparini, Vilmantas Giedraitis, Christian Gieger, Giorgia Girotto, Anuj Goel, Alan J Gow, Vilmundur Gudnason, Xiuqing Guo, Ulf Gyllensten, Anders Hamsten, Tamara B Harris, Sarah E Harris, Catharina A Hartman, Aki S Havulinna, Andrew A Hicks, Edith Hofer, Albert Hofman, Jouke-Jan Hottenga, Jennifer E Huffman, Shih-Jen Hwang, Erik Ingelsson, Alan James, Rick Jansen, Marjo-Riitta Jarvelin, Roby Joehanes, Åsa Johansson, Andrew D Johnson, Peter K Joshi, Pekka Jousilahti, J Wouter Jukema, Antti Jula, Mika Kähönen, Sekar Kathiresan, Bernard D Keavney, Kay-Tee Khaw, Paul Knekt, Joanne Knight, Ivana Kolcic, Jaspal S Kooner, Seppo Koskinen, Kati Kristiansson, Zoltan Kutalik, Maris Laan, Marty Larson, Lenore J Launer, Benjamin Lehne, Terho Lehtimäki, David CM Liewald, Li Lin, Lars Lind, Cecilia M Lindgren, YongMei Liu, Ruth JF Loos, Lorna M Lopez, Yingchang Lu, Leo-Pekka Lyytikäinen, Anubha Mahajan, Chrysovalanto Mamasoula, Jaume Marrugat, Jonathan Marten, Yuri Milaneschi, Anna Morgan, Andrew P Morris, Alanna C Morrison, Peter J Munson, Mike A Nalls, Priyanka Nandakumar, Christopher P Nelson, Teemu Niiranen, Ilja M Nolte, Teresa Nutile, Albertine J Oldehinkel, Ben A Oostra, Paul F O’Reilly, Elin Org, Sandosh Padmanabhan, Walter Palmas, Aarno Palotie, Alison Pattie, Brenda WJH Penninx, Markus Perola, Annette Peters, Ozren Polasek, Peter P Pramstaller, Quang Tri Nguyen, Olli T Raitakari, Rainer Rettig, Kenneth Rice, Paul M Ridker, Janina S Ried, Harriëtte Riese, Samuli Ripatti, Antonietta Robino, Lynda M Rose, Jerome I Rotter, Igor Rudan, Daniela Ruggiero, Yasaman Saba, Cinzia F Sala, Veikko Salomaa, Nilesh J Samani, Antti-Pekka Sarin, Reinhold Schmidt, Helena Schmidt, Nick Shrine, David Siscovick, Albert V Smith, Harold Snieder, Siim Sõber, Rossella Sorice, John M Starr, David J Stott, David P Strachan, Rona J Strawbridge, Johan Sundström, Morris A Swertz, Kent D Taylor, Alexander Teumer, Martin D Tobin, Maciej Tomaszewski, Daniela Toniolo, Michela Traglia, Stella Trompet, Jaakko Tuomilehto, Christophe Tzourio, André G Uitterlinden, Ahmad Vaez, Peter J van der Most, Cornelia M van Duijn, Germaine C Verwoert, Veronique Vitart, Uwe Völker, Peter Vollenweider, Dragana Vuckovic, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, James F Wilson, Alan F Wright, Jie Yao, Tatijana Zemunik, Weihua Zhang, John R Attia, Adam S Butterworth, Daniel I Chasman, David Conen, Francesco Cucca, John Danesh, Caroline Hayward, Joanna MM Howson, Markku Laakso, Edward G Lakatta, Claudia Langenberg, Olle Melander, Dennis O Mook-Kanamori, Colin NA Palmer, Lorenz Risch, Robert A Scott, Rodney J Scott, Peter Sever, Tim D Spector, Pim van der Harst, Nicholas J Wareham, Eleftheria Zeggini, Daniel Levy, Patricia B Munroe, Christopher Newton-Cheh, Morris J Brown, Andres Metspalu, Bruce M. Psaty, Louise V Wain, Paul Elliott, Mark J Caulfield, Padhraig Gormley, Verneri Anttila, Priit Palta, Tune H Pers, Kai-How Farh, Ester Cuenca-Leon, Mikko Muona, Nicholas A Furlotte, Tobias Kurth, Andres Ingason, George McMahon, Lannie Ligthart, Gisela M Terwindt, Mikko Kallela, Tobias M Freilinger, Caroline Ran, Scott G Gordon, Anine H Stam, Stacy Steinberg, Guntram Borck, Markku Koiranen, Lydia Quaye, Hieab H H Adams, Juho Wedenoja, David A Hinds, Julie E Buring, Markus Schürks, Maria Gudlaug Hrafnsdottir, Hreinn Stefansson, Susan M Ring, Brenda W J H Penninx, Markus Färkkilä, Ville Artto, Mari Kaunisto, Salli Vepsäläinen, Rainer Malik, Andrew C Heath, Pamela A F Madden, Nicholas G Martin, Grant W Montgomery, Mitja I Kurki, Mart Kals, Kalle Pärn, Eija Hämäläinen, Hailiang Huang, Andrea E Byrnes, Lude Franke, Jie Huang, Evie Stergiakouli, Phil H Lee, Cynthia Sandor, Caleb Webber, Zameel Cader, Bertram Muller-Myhsok, Stefan Schreiber, Thomas Meitinger, Johan G Eriksson, Kauko Heikkilä, Elizabeth Loehrer, Andre G Uitterlinden, Lynn Cherkas, Audun Stubhaug, Christopher S Nielsen, Minna Männikkö, Evelin Mihailov, Hartmut Göbel, Ann-Louise Esserlind, Anne Francke Christensen, Thomas Folkmann Hansen, Thomas Werge, Jaakko Kaprio, Arpo J Aromaa, Olli Raitakari, M Arfan Ikram, Tim Spector, Marjo-Riitta Järvelin, Christian Kubisch, Michel D Ferrari, Andrea C Belin, Maija Wessman, Arn M J M van den Maagdenberg, George Davey Smith, Kari Stefansson, Nicholas Eriksson, Mark J Daly, Benjamin M Neale, Jes Olesen, Dale R Nyholt, Masato Akiyama, Varinder S. Alg, Joseph P. Broderick, Ben M. Brumpton, Jérôme Dauvillier, Hubert Desal, Christian Dina, Christoph M. Friedrich, Emília I. Gaál-Paavola, Jean-Christophe Gentric, Sven Hirsch, Isabel C. Hostettler, Henry Houlden, Juha E. Jääskeläinen, Marianne Bakke Johnsen, Liming Li, Kuang Lin, Antti Lindgren, Olivier Martin, Koichi Matsuda, Iona Y. Millwood, Olivier Naggara, Mika Niemelä, Joanna Pera, Richard Redon, Guy A. Rouleau, Marie Søfteland Sandvei, Sabine Schilling, Eimad Shotar, Agnieszka Slowik, Chikashi Terao, W. M. Monique Verschuren, Robin G. Walters, David J. Werring, Cristen J. Willer, Daniel Woo, Bradford B. Worrall, Sirui Zhou, Biological Psychology, Amsterdam Reproduction & Development, APH - Mental Health, APH - Methodology, AMS - Sports, AMS - Ageing & Vitality, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Systems Ecology, Sociology and Social Gerontology, Bakker, Mark K., Kanning, Jos P., Abraham, Gad, Martinsen, Amy E., Winsvold, Bendik S., Zwart, John-Anker, Bourcier, Romain, Sawada, Tomonobu, Koido, Masaru, Kamatani, Yoichiro, Morel, Sandrine, Amouyel, Philippe, Debette, Stéphanie, Bijlenga, Philippe, Berrandou, Takiy, Ganesh, Santhi K., Bouatia-Naji, Nabila, Jones, Gregory, Bown, Matthew, Rinkel, Gabriel J. E., Veldink, Jan H., Ruigrok, Ynte M., Girotto, G., All-In Stroke, Hunt, Group, Cadisp, Consortium for Blood Pressure, International, Headache Genetics Consortium, International, Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group, International, Utrecht University [Utrecht], Baker Heart and Diabetes Institute (AUSTRALIA), University of Melbourne, University of Oslo (UiO), Norwegian University of Science and Technology (NTNU), Oslo University Hospital [Oslo], Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), The University of Tokyo (UTokyo), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Hôpital Universitaire de Genève = University Hospitals of Geneva (HUG), Université de Genève = University of Geneva (UNIGE), Excellence Laboratory LabEx DISTALZ, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Michigan Medical School [Ann Arbor], University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, University of Otago [Dunedin, Nouvelle-Zélande], University of Leicester, Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), CHU Amiens-Picardie, HUNT All-In Stroke, CADISP group, International Consortium for Blood Pressure, International Headache Genetics Consortium, International Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group: Anne Hege Aamodt, Anne Heidi Skogholt, Ben M Brumpton, Cristen J Willer, Else C Sandset, Espen S Kristoffersen, Hanne Ellekjær, Ingrid Heuch, Jonas B Nielsen, Knut Hagen, Kristian Hveem, Lars G Fritsche, Laurent F Thomas, Linda M Pedersen, Maiken E Gabrielsen, Oddgeir L Holmen, Sigrid Børte, Wei Zhou, Shérine Abboud, Massimo Pandolfo, Vincent Thijs, Didier Leys, Marie Bodenant, Fabien Louillet, Emmanuel Touzé, Jean-Louis Mas, Yves Samson, Sara Leder, Anne Léger, Sandrine Deltour, Sophie Crozier, Isabelle Méresse, Sandrine Canaple, Olivier Godefroy, Maurice Giroud, Yannick Béjot, Pierre Decavel, Elizabeth Medeiros, Paola Montiel, Thierry Moulin, Fabrice Vuillier, Jean Dallongeville, Antti J Metso, Tiina Metso, Turgut Tatlisumak, Caspar Grond-Ginsbach, Christoph Lichy, Manja Kloss, Inge Werner, Marie-Luise Arnold, Michael Dos Santos, Armin Grau, Martin Dichgans, Constanze Thomas-Feles, Ralf Weber, Tobias Brandt, Alessandro Pezzini, Valeria De Giuli, Filomena Caria, Loris Poli, Alessandro Padovani, Anna Bersano, Silvia Lanfranconi, Simone Beretta, Carlo Ferrarese, Giacomo Giacolone, Stefano Paolucci, Philippe Lyrer, Stefan Engelter, Felix Fluri, Florian Hatz, Dominique Gisler, Leo Bonati, Henrik Gensicke, Margareth Amort, Hugh Markus, Jennifer Majersik, Bradford Worrall, Andrew Southerland, John Cole, Steven Kittner, Evangelos Evangelou, Helen R Warren, He Gao, Georgios Ntritsos, Niki Dimou, Tonu Esko, Reedik Mägi, Lili Milani, Peter Almgren, Thibaud Boutin, Jun Ding, Franco Giulianini, Elizabeth G Holliday, Anne U Jackson, Ruifang Li-Gao, Wei-Yu Lin, Jian'an Luan, Massimo Mangino, Christopher Oldmeadow, Bram Peter Prins, Yong Qian, Muralidharan Sargurupremraj, Nabi Shah, Praveen Surendran, Sébastien Thériault, Niek Verweij, Sara M Willems, Jing-Hua Zhao, John Connell, Renée de Mutsert, Alex Sf Doney, Martin Farrall, Cristina Menni, Andrew D Morris, Raymond Noordam, Guillaume Paré, Neil R Poulter, Denis C Shields, Alice Stanton, Simon Thom, Gonçalo Abecasis, Najaf Amin, Dan E Arking, Kristin L Ayers, Caterina M Barbieri, Chiara Batini, Joshua C Bis, Tineka Blake, Murielle Bochud, Michael Boehnke, Eric Boerwinkle, Dorret I Boomsma, Erwin P Bottinger, Peter S Braund, Marco Brumat, Archie Campbell, Harry Campbell, Aravinda Chakravarti, John C Chambers, Ganesh Chauhan, Marina Ciullo, Massimiliano Cocca, Francis Collins, Heather J Cordell, Gail Davies, Martin H de Borst, Eco J de Geus, Ian J Deary, Joris Deelen, Fabiola Del Greco M, Cumhur Yusuf Demirkale, Marcus Dörr, Georg B Ehret, Roberto Elosua, Stefan Enroth, A Mesut Erzurumluoglu, Teresa Ferreira, Mattias Frånberg, Oscar H Franco, Ilaria Gandin, Paolo Gasparini, Vilmantas Giedraitis, Christian Gieger, Giorgia Girotto, Anuj Goel, Alan J Gow, Vilmundur Gudnason, Xiuqing Guo, Ulf Gyllensten, Anders Hamsten, Tamara B Harris, Sarah E Harris, Catharina A Hartman, Aki S Havulinna, Andrew A Hicks, Edith Hofer, Albert Hofman, Jouke-Jan Hottenga, Jennifer E Huffman, Shih-Jen Hwang, Erik Ingelsson, Alan James, Rick Jansen, Marjo-Riitta Jarvelin, Roby Joehanes, Åsa Johansson, Andrew D Johnson, Peter K Joshi, Pekka Jousilahti, J Wouter Jukema, Antti Jula, Mika Kähönen, Sekar Kathiresan, Bernard D Keavney, Kay-Tee Khaw, Paul Knekt, Joanne Knight, Ivana Kolcic, Jaspal S Kooner, Seppo Koskinen, Kati Kristiansson, Zoltan Kutalik, Maris Laan, Marty Larson, Lenore J Launer, Benjamin Lehne, Terho Lehtimäki, David Cm Liewald, Li Lin, Lars Lind, Cecilia M Lindgren, YongMei Liu, Ruth Jf Loos, Lorna M Lopez, Yingchang Lu, Leo-Pekka Lyytikäinen, Anubha Mahajan, Chrysovalanto Mamasoula, Jaume Marrugat, Jonathan Marten, Yuri Milaneschi, Anna Morgan, Andrew P Morris, Alanna C Morrison, Peter J Munson, Mike A Nalls, Priyanka Nandakumar, Christopher P Nelson, Teemu Niiranen, Ilja M Nolte, Teresa Nutile, Albertine J Oldehinkel, Ben A Oostra, Paul F O'Reilly, Elin Org, Sandosh Padmanabhan, Walter Palmas, Aarno Palotie, Alison Pattie, Brenda Wjh Penninx, Markus Perola, Annette Peters, Ozren Polasek, Peter P Pramstaller, Quang Tri Nguyen, Olli T Raitakari, Rainer Rettig, Kenneth Rice, Paul M Ridker, Janina S Ried, Harriëtte Riese, Samuli Ripatti, Antonietta Robino, Lynda M Rose, Jerome I Rotter, Igor Rudan, Daniela Ruggiero, Yasaman Saba, Cinzia F Sala, Veikko Salomaa, Nilesh J Samani, Antti-Pekka Sarin, Reinhold Schmidt, Helena Schmidt, Nick Shrine, David Siscovick, Albert V Smith, Harold Snieder, Siim Sõber, Rossella Sorice, John M Starr, David J Stott, David P Strachan, Rona J Strawbridge, Johan Sundström, Morris A Swertz, Kent D Taylor, Alexander Teumer, Martin D Tobin, Maciej Tomaszewski, Daniela Toniolo, Michela Traglia, Stella Trompet, Jaakko Tuomilehto, Christophe Tzourio, André G Uitterlinden, Ahmad Vaez, Peter J van der Most, Cornelia M van Duijn, Germaine C Verwoert, Veronique Vitart, Uwe Völker, Peter Vollenweider, Dragana Vuckovic, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, James F Wilson, Alan F Wright, Jie Yao, Tatijana Zemunik, Weihua Zhang, John R Attia, Adam S Butterworth, Daniel I Chasman, David Conen, Francesco Cucca, John Danesh, Caroline Hayward, Joanna Mm Howson, Markku Laakso, Edward G Lakatta, Claudia Langenberg, Olle Melander, Dennis O Mook-Kanamori, Colin Na Palmer, Lorenz Risch, Robert A Scott, Rodney J Scott, Peter Sever, Tim D Spector, Pim van der Harst, Nicholas J Wareham, Eleftheria Zeggini, Daniel Levy, Patricia B Munroe, Christopher Newton-Cheh, Morris J Brown, Andres Metspalu, Bruce M Psaty, Louise V Wain, Paul Elliott, Mark J Caulfield, Padhraig Gormley, Verneri Anttila, Priit Palta, Tonu Esko, Tune H Pers, Kai-How Farh, Ester Cuenca-Leon, Mikko Muona, Nicholas A Furlotte, Tobias Kurth, Andres Ingason, George McMahon, Lannie Ligthart, Gisela M Terwindt, Mikko Kallela, Tobias M Freilinger, Caroline Ran, Scott G Gordon, Anine H Stam, Stacy Steinberg, Guntram Borck, Markku Koiranen, Lydia Quaye, Hieab H H Adams, Terho Lehtimäki, Antti-Pekka Sarin, Juho Wedenoja, David A Hinds, Julie E Buring, Markus Schürks, Paul M Ridker, Maria Gudlaug Hrafnsdottir, Hreinn Stefansson, Susan M Ring, Jouke-Jan Hottenga, Brenda W J H Penninx, Markus Färkkilä, Ville Artto, Mari Kaunisto, Salli Vepsäläinen, Rainer Malik, Andrew C Heath, Pamela A F Madden, Nicholas G Martin, Grant W Montgomery, Mitja I Kurki, Mart Kals, Reedik Mägi, Kalle Pärn, Eija Hämäläinen, Hailiang Huang, Andrea E Byrnes, Lude Franke, Jie Huang, Evie Stergiakouli, Phil H Lee, Cynthia Sandor, Caleb Webber, Zameel Cader, Bertram Muller-Myhsok, Stefan Schreiber, Thomas Meitinger, Johan G Eriksson, Veikko Salomaa, Kauko Heikkilä, Elizabeth Loehrer, Andre G Uitterlinden, Albert Hofman, Cornelia M van Duijn, Lynn Cherkas, Linda M Pedersen, Audun Stubhaug, Christopher S Nielsen, Minna Männikkö, Evelin Mihailov, Lili Milani, Hartmut Göbel, Ann-Louise Esserlind, Anne Francke Christensen, Thomas Folkmann Hansen, Thomas Werge, Jaakko Kaprio, Arpo J Aromaa, Olli Raitakari, M Arfan Ikram, Tim Spector, Marjo-Riitta Järvelin, Andres Metspalu, Christian Kubisch, David P Strachan, Michel D Ferrari, Andrea C Belin, Martin Dichgans, Maija Wessman, Arn M J M van den Maagdenberg, Dorret I Boomsma, George Davey Smith, Kari Stefansson, Nicholas Eriksson, Mark J Daly, Benjamin M Neale, Jes Olesen, Daniel I Chasman, Dale R Nyholt, Aarno Palotie, Masato Akiyama, Varinder S Alg, Sigrid Børte, Joseph P Broderick, Ben M Brumpton, Jérôme Dauvillier, Hubert Desal, Christian Dina, Christoph M Friedrich, Emília I Gaál-Paavola, Jean-Christophe Gentric, Sven Hirsch, Isabel C Hostettler, Henry Houlden, Kristian Hveem, Juha E Jääskeläinen, Marianne Bakke Johnsen, Liming Li, Kuang Lin, Antti Lindgren, Olivier Martin, Koichi Matsuda, Iona Y Millwood, Olivier Naggara, Mika Niemelä, Joanna Pera, Richard Redon, Guy A Rouleau, Marie Søfteland Sandvei, Sabine Schilling, Eimad Shotar, Agnieszka Slowik, Chikashi Terao, W M Monique Verschuren, Robin G Walters, David J Werring, Cristen J Willer, Daniel Woo, Bradford B Worrall, Sirui Zhou, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and Admin, Oskar
Subjects: Advanced and Specialized Nursing, Incidence, risk assessment, Smoking/epidemiology, intracranial aneurysm, genetic heterogeneity, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Risk Factors, Intracranial Aneurysm/epidemiology, Humans, Subarachnoid Hemorrhage/epidemiology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, genetics, Neurology (clinical), aneurysmal subarachnoid hemorrhage, genetic, Cardiology and Cardiovascular Medicine
Abstract: Background: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. Methods: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. Results: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20–1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01–1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59–0.67) to 0.65 (95% CI, 0.62–0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=−4.82×10 −3 per year [95% CI, −6.49×10 −3 to −3.14×10 −3 ]; P =1.82×10 −8 ), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86–0.98]; P =0.0041). Conclusions: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.
Published: 2023

8. A genome-wide association meta-analysis on lipoprotein (a) concentrations adjusted for apolipoprotein (a) isoforms[S]

Author: Salome Mack, Stefan Coassin, Rico Rueedi, Noha A. Yousri, Ilkka Seppälä, Christian Gieger, Sebastian Schönherr, Lukas Forer, Gertraud Erhart, Pedro Marques-Vidal, Janina S. Ried, Gerard Waeber, Sven Bergmann, Doreen Dähnhardt, Andrea Stöckl, Olli T. Raitakari, Mika Kähönen, Annette Peters, Thomas Meitinger, Konstantin Strauch, Ludmilla Kedenko, Bernhard Paulweber, Terho Lehtimäki, Steven C. Hunt, Peter Vollenweider, Claudia Lamina, and Florian Kronenberg
Subjects: genetics, epidemiology, coronary artery disease, Biochemistry, QD415-436
Abstract: High lipoprotein (a) [Lp(a)] concentrations are an independent risk factor for cardiovascular outcomes. Concentrations are strongly influenced by apo(a) kringle IV repeat isoforms. We aimed to identify genetic loci associated with Lp(a) concentrations using data from five genome-wide association studies (n = 13,781). We identified 48 independent SNPs in the LPA and 1 SNP in the APOE gene region to be significantly associated with Lp(a) concentrations. We also adjusted for apo(a) isoforms to identify loci affecting Lp(a) levels independently from them, which resulted in 31 SNPs (30 in the LPA, 1 in the APOE gene region). Seven SNPs showed a genome-wide significant association with coronary artery disease (CAD) risk. A rare SNP (rs186696265; MAF ∼1%) showed the highest effect on Lp(a) and was also associated with increased risk of CAD (odds ratio = 1.73, P = 3.35 × 10−30). Median Lp(a) values increased from 2.1 to 91.1 mg/dl with increasing number of Lp(a)-increasing alleles. We found the APOE2-determining allele of rs7412 to be significantly associated with Lp(a) concentrations (P = 3.47 × 10−10). Each APOE2 allele decreased Lp(a) by 3.34 mg/dl corresponding to ∼15% of the populationŉs mean values. Performing a gene-based test of association, including suspected Lp(a) receptors and regulators, resulted in one significant association of the TLR2 gene with Lp(a) (P = 3.4 × 10−4). In summary, we identified a large number of independent SNPs in the LPA gene region, as well as the APOE2 allele, to be significantly associated with Lp(a) concentrations.
Published: 2017
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9. Multilayer OMICS characterization of APOE‐modulated isogenic hiPSCs elucidates cell‐type–specific mechanisms modified by APOE: A study of the IMI ADAPTED Consortium

Author: Peter Reinhardt, Alfredo Cabrera Socorro, Eric G. Mohler, Margot H.M. Bakker, Marco Rocha Curado, Francesco V. Rao, Janina S. Ried, Laura Madrid, Armel Nicolas, Lamiaa Bahnassawy, Clara Grezella, Gayathri Ramaswamy, María Eugenia Sáez, and Heyne Lee
Subjects: Genetics, Apolipoprotein E, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Systems biology, Cell type specific, Neurology (clinical), Geriatrics and Gerontology, Biology, Omics
Published: 2020

10. Characterization of transcriptional and proteomics changes in brain cells derived from isogenic hiPSCs reveals cell type–and genotype‐specific mechanisms modified by APOE

Author: Janina S. Ried, Heyne Lee, Marco Rocha Curado, Clara Grezella, Armel Nicolas, Gayathri Ramaswamy, María Eugenia Sáez, Lamiaa Bahnassawy, Laura Madrid, Eric G. Mohler, Francesco V. Rao, Peter Reinhardt, Alfredo Cabrera Socorro, and Margot H.M. Bakker
Subjects: Genetics, Apolipoprotein E, Cell type, Apolipoprotein B, biology, Epidemiology, Health Policy, Disease, Proteomics, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Genotype, biology.protein, Neurology (clinical), Geriatrics and Gerontology
Published: 2020

11. Proteomic, metabolomic, and transcriptomic examination of APOE transgenic mice

Author: Armel Nicolas, Francesco V. Rao, Thomas Hankemeier, Marco Rocha Curado, Lamiaa Bahnassawy, Janina S. Ried, Gayathri Ramaswamy, Isabelle Kohler, Eric G. Mohler, María Eugenia Sáez, Margot H.M. Bakker, and Peter Reinhardt
Subjects: Genetics, Apolipoprotein E, Genetically modified mouse, Epidemiology, Health Policy, Systems biology, Biology, Omics, Transcriptome, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Metabolomics, Developmental Neuroscience, Neurology (clinical), Geriatrics and Gerontology
Published: 2020

12. APOE and sex‐stratified genome‐wide meta‐analyses of Alzheimer’s disease

Author: Agustín Ruiz, Janina S. Ried, Sonia Moreno-Grau, María Eugenia Sáez, Laura Madrid, Alfredo Ramirez, and Antonio González-Pérez
Subjects: Genetics, Apolipoprotein E, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Disease, Geriatrics and Gerontology, Biology, Genome
Published: 2020

13. Reproducibility of Molecular Phenotypes after Long-Term Differentiation to Human iPSC-Derived Neurons: A Multi-Site Omics Study

Author: George Nicholson, Lyle Armstrong, Caroline Muschet, Adam E. Handel, Wendy E. Heywood, Eshita Sharma, Pieter J. Peeters, Philip W. Brownjohn, Frank Wessely, Georg C. Terstappen, Carlo Cusulin, Majlinda Lako, Katharina Janssen, Viktor Lakics, Satyan Chintawar, Kevin Mills, Jerzy Adamski, Thomas Barta, Anna Baud, Caleb Webber, Viola Volpato, Moustafa Attar, Roberta De Filippis, Janina S. Ried, Frederick J. Livesey, Peter Reinhardt, Martin Graf, Cynthia Sandor, Jérôme Nicod, Rory Bowden, M. Zameel Cader, Sarah E. Newey, Ines Royaux, Emma S. Whiteley, Aanna Artati, Victoria Stubbs, Paul Gissen, James Smith, An Verheyen, Christoph Patsch, Klaus Christensen, Colin J. Akerman, Smith, James [0000-0001-9131-5849], Brownjohn, Phil [0000-0002-4707-3077], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Proteomics, induced pluripotent stem cell, Genotype, Cellular differentiation, molecular profiling, Induced Pluripotent Stem Cells, Computational biology, Biology, single-cell sequencing, Biochemistry, Article, Cell Line, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Genetics, cross-site experimental variation, Humans, Induced pluripotent stem cell, lcsh:QH301-705.5, reproducibility, Regulation of gene expression, Neurons, lcsh:R5-920, Reproducibility, Cortical Neurons, Cross-site Experimental Variation, Gene Expression Profile, Induced Pluripotent Stem Cell, Molecular Profiling, Proteomic Profiles, Public-private Partnership, Single-cell Sequencing, Stembancc, cortical neurons, Reproducibility of Results, Cell Differentiation, Cell Biology, proteomic profiles, Phenotype, 3. Good health, public-private partnership, 030104 developmental biology, lcsh:Biology (General), Single cell sequencing, Gene Expression Regulation, gene expression profile, lcsh:Medicine (General), Factor Analysis, Statistical, 030217 neurology & neurosurgery, Developmental Biology, stembancc
Abstract: Summary Reproducibility in molecular and cellular studies is fundamental to scientific discovery. To establish the reproducibility of a well-defined long-term neuronal differentiation protocol, we repeated the cellular and molecular comparison of the same two iPSC lines across five distinct laboratories. Despite uncovering acceptable variability within individual laboratories, we detect poor cross-site reproducibility of the differential gene expression signature between these two lines. Factor analysis identifies the laboratory as the largest source of variation along with several variation-inflating confounders such as passaging effects and progenitor storage. Single-cell transcriptomics shows substantial cellular heterogeneity underlying inter-laboratory variability and being responsible for biases in differential gene expression inference. Factor analysis-based normalization of the combined dataset can remove the nuisance technical effects, enabling the execution of robust hypothesis-generating studies. Our study shows that multi-center collaborations can expose systematic biases and identify critical factors to be standardized when publishing novel protocols, contributing to increased cross-site reproducibility., Highlights • Cross-site reproducibility in iPSC-based molecular experiments is poor • Factor analysis-based normalization can be used to analyze nuisance variation • External validation of iPSC experimental molecular data is critical for reproducibility • Collaborative studies are needed to reveal systematic biases to improve reproducibility, In this article, Lakics and colleagues show that, while individual laboratories are able to identify consistent molecular and seemingly statistically robust differences between iPSC neuronal models, cross-site reproducibility is poor. Their findings support multi-center collaborations to expose systematic biases and identify critical factors to be standardized to improve reproducibility in iPSC-based molecular experiments.
Published: 2018

14. The genetic architecture of type 2 diabetes

Author: Clement Ma, Liisa Hakaste, Claes Ladenvall, Massimo Mangino, Lars Lind, Aaron G. Day-Williams, Ryan Poplin, Thomas Schwarzmayr, Annette Peters, Thomas Meitinger, Satish Kumar, Kyong Soo Park, Ching-Yu Cheng, Farook Thameem, Kyle J. Gaulton, Olov Rolandsson, Yossi Farjoun, Neil Robertson, Mauricio O. Carneiro, Mark A. DePristo, Pierre Fontanillas, Ruth J. F. Loos, Heather M. Highland, Vilmantas Giedraitis, Gemma Buck, Fredrik Karpe, Mohammad Kamran Ikram, Alex S. F. Doney, Hae Kyung Im, Eric S. Lander, Johanna Kuusisto, Dorothée Thuillier, Denis Rybin, Jacquelyn Murphy, Benjamin M. Neale, Martina Müller-Nurasyid, Eric R. Gamazon, Johanne Marie Justesen, Tin Aung, Vincent K. L. Lam, John Danesh, Donna M. Lehman, Goo Jun, Marit E. Jørgensen, Christian Herder, Edmund Chan, Pamela J. Hicks, Todd Green, Claudia Langenberg, Yoon Shin Cho, James G. Wilson, Daniel E. Hale, Rector Arya, Giriraj R. Chandak, Juan Fernandez Tajes, Jaakko Tuomilehto, Christopher P. Jenkinson, Anders Rosengren, Torsten Lauritzen, Michael Griswold, Karen L. Mohlke, Amy J. Swift, Alena Stančáková, Christian Fuchsberger, Iksoo Huh, Nikhil Tandon, João Fadista, Christa Meisinger, Gonçalo R. Abecasis, Pål R. Njølstad, Dwaipayan Bharadwaj, Richard M. Watanabe, Shaun Purcell, Veikko Salomaa, Tim D. Spector, Paul W. Franks, Adam E. Locke, Sharon P. Fowler, Panos Deloukas, Reedik Mägi, Solomon K. Musani, Kee Seng Chia, Barbara Thorand, Soo Heon Kwak, Annemari Käräjämäki, Evelin Mihailov, John Blangero, Thomas Wieland, Christian Gieger, E. Shyong Tai, Jianjun Liu, James B. Meigs, Teemu Kuulasmaa, Martin Hrabé de Angelis, Francis S. Collins, Tim M. Strom, Tibor V. Varga, Juyoung Lee, Mark I. McCarthy, Domenico Palli, Jong-Young Lee, Benjamin Glaser, Tasha E. Fingerlin, Stephen O'Rahilly, Andrew T. Hattersley, Gil Atzmon, Manuel A. Rivas, Noël P. Burtt, Ivan Brandslund, Young-Jin Kim, Dorairaj Prabhakaran, Xu Wang, Taylor J. Maxwell, Valeriya Lyssenko, Frank B. Hu, Adolfo Correa, Khalid Shakir, Kathleen A. Jablonski, Yingchang Lu, Wei-Yen Lim, Min Jin Go, William R. Scott, Hanna E. Abboud, Leena Kinnunen, Inês Barroso, Gabriela L. Surdulescu, Peng Chen, Robert Sladek, Marju Orho-Melander, Xueling Sim, Robert A. Scott, Joanna M. M. Howson, Markku Laakso, David Altshuler, Vidya S. Farook, Harald Grallert, Janina S. Ried, Vineeta Agarwala, Philippe Froguel, Nicholas J. Wareham, Tiinamaija Tuomi, Joon Yoon, Heikki A. Koistinen, Toni I. Pollin, Heiner Boeing, Marie Loh, Nicola L. Beer, Joanne E. Curran, Lars Lannfelt, Dorota Pasko, Taesung Park, David Buck, Nir Barzilai, Stephen C. J. Parker, Michael Roden, Bok-Ghee Han, David Aguilar, Timothy Fennell, Sian-Tsung Tan, Gregory P. Wilson, Momoko Horikoshi, Cramer Christensen, Craig L. Hanis, Gilean McVean, Benjamin F. Voight, Wolfgang Rathmann, Jared Maguire, Ashok Kumar, Donald W. Bowden, Michael L. Stitzel, Yongkang Kim, Christine Blancher, Jason Carey, Min-Seok Kwon, Nicholette D. Palmer, Oluf Pedersen, Niels Grarup, Peter S. Chines, Cornelia Huth, James Scott, Torben Hansen, Konstantin Strauch, Erwin P. Bottinger, Andrew D. Morris, Anette P. Gjesing, Erik Ingelsson, Colin N. A. Palmer, Claudia H. T. Tam, Stacey Gabriel, Pablo Cingolani, Beverley Balkau, Michael Boehnke, Peter M. Nilsson, Wing-Yee So, Andrew R. Wood, Lili Milani, Ravindranath Duggirala, Qibin Qi, Mark Walker, Weiping Jia, Mark Seielstad, Narisu Narisu, Tien Yin Wong, Martijn van de Bunt, Anubha Mahajan, Davis J. McCarthy, Ann-Christine Syvänen, Jennifer Kriebel, N. William Rayner, Han Chen, Jinyan Huang, Chiea Chuen Khor, Richard N. Bergman, Shah Ebrahim, Dylan Hodgkiss, Weihua Zhang, Manjinder S. Sandhu, Richard D. Pearson, Juliana C.N. Chan, Rainer Rauramaa, Ralph A. DeFronzo, Andrew Farmer, Yoshihiko Nagai, Allan Linneberg, Herman A. Taylor, Jose C. Florez, Jaspal S. Kooner, Lori L. Bonnycastle, Jeroen R. Huyghe, Leif Groop, Joseph Trakalo, Sobha Puppala, Bong-Jo Kim, Kathleen Stirrups, Kerrin S. Small, Cecilia M. Lindgren, Jennifer E. Below, Heung Man Lee, Inga Prokopenko, Liming Liang, Timothy M. Frayling, Uzma Afzal, Mark J. Daly, Yik Ying Teo, Andrew P. Morris, Phoenix Kwan, Yvonne T. van der Schouw, Cheng Hu, Katharine R. Owen, Alisa K. Manning, Christopher J. Groves, Josée Dupuis, Ryan P. Welch, Loukas Moutsianas, Joshua D. Smith, Tanya M. Teslovich, Robert C. Onofrio, Maggie C.Y. Ng, Peter Donnelly, Tõnu Esko, Matt Neville, Bo Isomaa, Anne U. Jackson, Jette Bork-Jensen, Barry I. Freedman, Yi Chen, Danish Saleheen, Lu Qi, Laura J. Scott, Jasmina Kravic, Paul Elliott, Mette Hollensted, Carmen Navarro, Selyeong Lee, Benjamin Lehne, Thomas Illig, Nancy J. Cox, Jonathan C. Levy, George B. Grant, John C. Chambers, Adam S. Butterworth, Ronald C.W. Ma, Teresa Ferreira, John R. B. Perry, Eleftheria Zeggini, Hyun Min Kang, Loic Yengo, Eric Banks, Jae-Hoon Lee, Anna L. Gloyn, Christopher Hartl, Wei Zhao, Andres Metspalu, Keng-Han Lin, Graeme I. Bell, Jason Flannick, Torben Jørgensen, Thomas W. Blackwell, Heather M. Stringham, Olle Melander, Omri Gottesman, Other departments, British Heart Foundation, Wellcome Trust, Medical Research Council (MRC), Massachusetts Institute of Technology. Department of Biology, Altshuler, David M, Internal Medicine, Perry, John [0000-0001-6483-3771], Butterworth, Adam [0000-0002-6915-9015], Howson, Joanna [0000-0001-7618-0050], Danesh, John [0000-0003-1158-6791], Johnson, Kathleen [0000-0002-6823-3252], O'Rahilly, Stephen [0000-0003-2199-4449], Langenberg, Claudia [0000-0002-5017-7344], Sandhu, Manjinder [0000-0002-2725-142X], Barroso, Ines [0000-0001-5800-4520], Wareham, Nicholas [0000-0003-1422-2993], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, PROTEIN INTERACTION NETWORKS, SUSCEPTIBILITY LOCI, Genotyping Techniques, General Science & Technology, DNA Mutational Analysis, SEQUENCING ASSOCIATION, 030209 endocrinology & metabolism, Genome-wide association study, Biology, Research Support, N.I.H, 03 medical and health sciences, 0302 clinical medicine, Research Support, N.I.H., Extramural, SDG 3 - Good Health and Well-being, MD Multidisciplinary, Genetic predisposition, Journal Article, Humans, Exome, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Non-U.S. Gov't, Exome sequencing, Alleles, Genetic association, Genetics, RISK, Multidisciplinary, HERITABILITY, Research Support, Non-U.S. Gov't, COMPLEX TRAITS, Extramural, Genetic Variation, Genetic architecture, HUMAN-DISEASE, Europe, 030104 developmental biology, Diabetes Mellitus, Type 2, RARE VARIANTS, Sample Size, LOW-FREQUENCY, Imputation (genetics), Common disease-common variant, Genome-Wide Association Study
Abstract: The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.
Published: 2016

15. Harmonising and linking biomedical and clinical data across disparate data archives to enable integrative cross-biobank research

Author: Tõnu Esko, Ola Spjuth, Huei-Yi Shen, Eco J. C. de Geus, Mats-Ake Persson, Andres Metspalu, Jon Heggland, Leif Groop, Sandra Ose, Isabel Fortier, Johan Rung, Claes Ladenvall, Dorret I. Boomsma, Cornelia M. van Duijn, Samuli Ripatti, Linda Zaharenko, Arnulf Langhammer, Jouke-Jan Hottenga, Annette Peters, Janis Klovins, Christian Gieger, Jennifer R. Harris, Joern Dietrich, Kristian Hveem, Inga Prokopenko, Juni Palmgren, Melanie Waldenberger, Mark I. McCarthy, Jani Heikkinen, Nancy L. Pedersen, Janina S. Ried, Janna Hastings, Jan-Eric Litton, Juha Karvanen, Gonneke Willemsen, Maria Krestyaninova, Epidemiology, Biological Psychology, and Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), Databases, Factual, Computer science, Information Storage and Retrieval, Sample (statistics), Ontology (information science), Endocrinology and Diabetes, Bioinformatics, computer.software_genre, data archives, Article, 03 medical and health sciences, SDG 17 - Partnerships for the Goals, SDG 3 - Good Health and Well-being, Genetics, Use case, biomedical data, Genetics (clinical), Biological Specimen Banks, Genetics & Heredity, 0604 Genetics, Bioinformatics (Computational Biology), ta112, ta1184, Data science, Biobank, 3. Good health, cross-biotank research, 030104 developmental biology, Project planning, Exchange of information, Disparate system, Privacy, Bioinformatik (beräkningsbiologi), clinical data, computer, Data integration
Abstract: A wealth of biospecimen samples are stored in modern globally distributed biobanks. Biomedical researchers worldwide need to be able to combine the available resources to improve the power of large-scale studies. A prerequisite for this effort is to be able to search and access phenotypic, clinical and other information about samples that are currently stored at biobanks in an integrated manner. However, privacy issues together with heterogeneous information systems and the lack of agreed-upon vocabularies have made specimen searching across multiple biobanks extremely challenging. We describe three case studies where we have linked samples and sample descriptions in order to facilitate global searching of available samples for research. The use cases include the ENGAGE (European Network for Genetic and Genomic Epidemiology) consortium comprising at least 39 cohorts, the SUMMIT (surrogate markers for micro- and macro-vascular hard endpoints for innovative diabetes tools) consortium and a pilot for data integration between a Swedish clinical health registry and a biobank. We used the Sample avAILability (SAIL) method for data linking: first, created harmonised variables and then annotated and made searchable information on the number of specimens available in individual biobanks for various phenotypic categories. By operating on this categorised availability data we sidestep many obstacles related to privacy that arise when handling real values and show that harmonised and annotated records about data availability across disparate biomedical archives provide a key methodological advance in pre-analysis exchange of information between biobanks, that is, during the project planning phase. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published: 2016

16. Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits

Author: Olle Melander, Niek Verweij, Uwe Völker, Morris A. Swertz, Seppo Koskinen, David Conen, Lars Lind, Rossella Sorice, Philippe Amouyel, Andres Metspalu, David J. Stott, Marty Larson, Francis S. Collins, Ozren Polasek, Paul F. O'Reilly, Albertine J. Oldehinkel, Evangelos Evangelou, Pekka Jousilahti, Michela Traglia, Tineka Blake, John Attia, Bruce M. Psaty, Massimo Mangino, Alison Pattie, Marco Brumat, Dorret I. Boomsma, Harry Campbell, Daniel I. Chasman, Tõnu Esko, Wei-Yu Lin, Rodney J. Scott, Marjo-Riitta Järvelin, Guillaume Paré, Adriana M. Hung, Marina Evangelou, Quang Tri Nguyen, Markus Perola, Kenneth Rice, Yong Qian, Antonietta Robino, Anne U. Jackson, Ian J. Deary, Mika Kähönen, Cristina Menni, Veronique Vitart, Igor Rudan, Ganesh Chauhan, Aravinda Chakravarti, Jennifer E. Huffman, John M. Starr, Anubha Mahajan, Christopher Newton-Cheh, Peter Almgren, Yuri Milaneschi, Jacklyn N. Hellwege, Roby Joehanes, Christopher P. Nelson, Eleftheria Zeggini, Elizabeth G. Holliday, Peter J. van der Most, Annette Peters, Paul M. Ridker, Michael Boehnke, Joris Deelen, Brenda W.J.H. Penninx, Neil Poulter, Renée de Mutsert, Rick Jansen, Fu Liang Ng, Anne-Claire Vergnaud, Ilja M. Nolte, Meixia Ren, Gail Davies, John M. C. Connell, Jian'an Luan, Todd L. Edwards, Benjamin Lehne, K. Witkowska, Lili Milani, Stéphanie Debette, Georgios Ntritsos, Claudia P. Cabrera, Paolo Gasparini, Jouke-Jan Hottenga, Antti-Pekka Sarin, Kelly Cho, Robert A. Scott, Veikko Salomaa, Niki Dimou, David C. Liewald, Pim van der Harst, Teemu J. Niiranen, Denis C. Shields, Leo-Pekka Lyytikäinen, Andrew P. Morris, Murielle Bochud, Helena Schmidt, Bernard Keavney, Christopher Oldmeadow, Ioanna Tzoulaki, Jaakko Tuomilehto, Louise V. Wain, Reedik Mägi, Christian Gieger, Caterina Barbieri, Aki S. Havulinna, Fabiola Del Greco M, Dragana Vuckovic, Alan F. Wright, J. Wouter Jukema, Reinhold Schmidt, Marcus Dörr, Franco Giulianini, Evan Tzanis, Erwin P. Bottinger, David Mosen-Ansorena, Ruth J. F. Loos, A. Mesut Erzurumluoglu, Teresa Nutile, Alice Stanton, Jun Ding, Yingchang Lu, Roberto Elosua, Walter Palmas, James F. Wilson, Edith Hofer, Giorgia Girotto, Bram P. Prins, Anna Morgan, Anuj Goel, Edward G. Lakatta, Alex S. F. Doney, Najaf Amin, Lenore J. Launer, Siim Sõber, Nicholas J. Wareham, Adam S. Butterworth, Ilaria Gandin, Xiuqing Guo, Kent D. Taylor, Andrew D. Morris, Paul Knekt, Cinzia Sala, Peter P. Pramstaller, Joshua C. Bis, Archie Campbell, Raha Pazoki, Hugh Watkins, Csaba P. Kovesdy, Yan V. Sun, Lynda M. Rose, Jaspal S. Kooner, Maciej Tomaszewski, Massimiliano Cocca, Claudia Langenberg, Gonneke Willemsen, Eco J. C. de Geus, Peter W.F. Wilson, Ahmad Vaez, Albert Hofman, Kristin L. Ayers, Sara M. Willems, Germaine C. Verwoert, Christophe Tzourio, Martin Farrall, Albert V. Smith, Joanna M. M. Howson, Daniela Toniolo, Digna R. Velez Edwards, Antti Jula, Stefan Enroth, Ruifang Li-Gao, Nabi Shah, Weihua Zhang, Paul Elliott, Dennis O. Mook-Kanamori, Tatijana Zemunik, Shih-Jen Hwang, Helen R. Warren, Peter J. Munson, He Gao, Ivana Kolcic, Peter S. Braund, Tamara B. Harris, Raymond Noordam, Stella Trompet, Markku Laakso, Peter K. Joshi, Zoltán Kutalik, Sébastien Thériault, Åsa Johansson, Rainer Rettig, Sarah H. Wild, Patricia B. Munroe, John Danesh, Anders Hamsten, Mark J. Caulfield, Gonçalo R. Abecasis, Praveen Surendran, Peter S. Sever, David S. Siscovick, Terho Lehtimäki, Priyanka Nandakumar, Aarno Palotie, Muralidharan Sargurupremraj, Chiara Batini, Nick Shrine, Harold Snieder, Cumhur Y Demirkale, Teresa Ferreira, André G. Uitterlinden, Sekar Kathiresan, Mattias Frånberg, Lorna M. Lopez, J. Michael Gaziano, Cornelia M. van Duijn, Maris Laan, Samuli Ripatti, John C. Chambers, Martin H. de Borst, Johan Sundström, Alan J. Gow, Caroline Hayward, Oscar H. Franco, Yongmei Liu, Sandosh Padmanabhan, Ibrahim Karaman, Georg Ehret, Cecilia M. Lindgren, Mike A. Nalls, Chrysovalanto Mamasoula, Daniela Ruggiero, Erik Ingelsson, Colin N. A. Palmer, Alan James, Elin Org, Kati Kristiansson, Alexander Teumer, Ulf Gyllensten, Joanne Knight, Vilmantas Giedraitis, Jerome I. Rotter, Yasaman Saba, Daniel Levy, Li Lin, Janina S. Ried, Michael R. Barnes, Harriëtte Riese, Andrew D. Johnson, David P. Strachan, Martin D. Tobin, Lorenz Risch, Rona J. Strawbridge, Jing Hua Zhao, Vilmundur Gudnason, Borbala Mifsud, Eric Boerwinkle, Catharina A. Hartman, Ben A. Oostra, Dan E. Arking, Andrew A. Hicks, Peter Vollenweider, Thibaud Boutin, Philip S. Tsao, Jie Yao, Ayush Giri, Marina Ciullo, Morris J. Brown, Alanna C. Morrison, Kay-Tee Khaw, Francesco Cucca, Jonathan Marten, Olli T. Raitakari, Christopher J. O'Donnell, Jaume Marrugat, Tim D. Spector, Heather J. Cordell, Nilesh J. Samani, Simon Thom, Sarah E. Harris, UNIVERSITY OF OULU, Commission of the European Communities, Home Office, Action on Hearing Loss, Imperial College Healthcare NHS Trust- BRC Funding, National Institute for Health Research, British Heart Foundation, Medical Research Council (MRC), UK DRI Ltd, Epidemiology, Internal Medicine, Lee Kong Chian School of Medicine (LKCMedicine), Biological Psychology, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Ehret, Georg Benedikt, Lin, Li, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Evangelou, Evangelo, Warren, Helen R, Mosen-Ansorena, David, Mifsud, Borbala, Pazoki, Raha, Gao, He, Ntritsos, Georgio, Dimou, Niki, Cabrera, Claudia P, Karaman, Ibrahim, Ng, Fu Liang, Evangelou, Marina, Witkowska, Katarzyna, Tzanis, Evan, Hellwege, Jacklyn N, Giri, Ayush, Velez Edwards, Digna R, Sun, Yan V, Cho, Kelly, Gaziano, J Michael, Wilson, Peter W F, Tsao, Philip S, Kovesdy, Csaba P, Esko, Tonu, Mägi, Reedik, Milani, Lili, Almgren, Peter, Boutin, Thibaud, Debette, Stéphanie, Ding, Jun, Giulianini, Franco, Holliday, Elizabeth G, Jackson, Anne U, Li-Gao, Ruifang, Lin, Wei-Yu, Luan, Jian'An, Mangino, Massimo, Oldmeadow, Christopher, Prins, Bram Peter, Qian, Yong, Sargurupremraj, Muralidharan, Shah, Nabi, Surendran, Praveen, Thériault, Sébastien, Verweij, Niek, Willems, Sara M, Zhao, Jing-Hua, Amouyel, Philippe, Connell, John, de Mutsert, Renée, Doney, Alex S F, Farrall, Martin, Menni, Cristina, Morris, Andrew D, Noordam, Raymond, Paré, Guillaume, Poulter, Neil R, Shields, Denis C, Stanton, Alice, Thom, Simon, Abecasis, Gonçalo, Amin, Najaf, Arking, Dan E, Ayers, Kristin L, Barbieri, Caterina M, Batini, Chiara, Bis, Joshua C, Blake, Tineka, Bochud, Murielle, Boehnke, Michael, Boerwinkle, Eric, Boomsma, Dorret I, Bottinger, Erwin P, Braund, Peter S, Brumat, Marco, Campbell, Archie, Campbell, Harry, Chakravarti, Aravinda, Chambers, John C, Chauhan, Ganesh, Ciullo, Marina, Cocca, Massimiliano, Collins, Franci, Cordell, Heather J, Davies, Gail, Borst, Martin H de, Geus, Eco J de, Deary, Ian J, Deelen, Jori, Del Greco M, Fabiola, Demirkale, Cumhur Yusuf, Dörr, Marcu, Ehret, Georg B, Elosua, Roberto, Enroth, Stefan, Erzurumluoglu, A Mesut, Ferreira, Teresa, Frånberg, Mattia, Franco, Oscar H, Gandin, Ilaria, Gasparini, Paolo, Giedraitis, Vilmanta, Gieger, Christian, Girotto, Giorgia, Goel, Anuj, Gow, Alan J, Gudnason, Vilmundur, Guo, Xiuqing, Gyllensten, Ulf, Hamsten, Ander, Harris, Tamara B, Harris, Sarah E, Hartman, Catharina A, Havulinna, Aki S, Hicks, Andrew A, Hofer, Edith, Hofman, Albert, Hottenga, Jouke-Jan, Huffman, Jennifer E, Hwang, Shih-Jen, Ingelsson, Erik, James, Alan, Jansen, Rick, Jarvelin, Marjo-Riitta, Joehanes, Roby, Johansson, Åsa, Johnson, Andrew D, Joshi, Peter K, Jousilahti, Pekka, Jukema, J Wouter, Jula, Antti, Kähönen, Mika, Kathiresan, Sekar, Keavney, Bernard D, Khaw, Kay-Tee, Knekt, Paul, Knight, Joanne, Kolcic, Ivana, Kooner, Jaspal S, Koskinen, Seppo, Kristiansson, Kati, Kutalik, Zoltan, Laan, Mari, Larson, Marty, Launer, Lenore J, Lehne, Benjamin, Lehtimäki, Terho, Liewald, David C M, Lind, Lar, Lindgren, Cecilia M, Liu, Yongmei, Loos, Ruth J F, Lopez, Lorna M, Lu, Yingchang, Lyytikäinen, Leo-Pekka, Mahajan, Anubha, Mamasoula, Chrysovalanto, Marrugat, Jaume, Marten, Jonathan, Milaneschi, Yuri, Morgan, Anna, Morris, Andrew P, Morrison, Alanna C, Munson, Peter J, Nalls, Mike A, Nandakumar, Priyanka, Nelson, Christopher P, Niiranen, Teemu, Nolte, Ilja M, Nutile, Teresa, Oldehinkel, Albertine J, Oostra, Ben A, O'Reilly, Paul F, Org, Elin, Padmanabhan, Sandosh, Palmas, Walter, Palotie, Aarno, Pattie, Alison, Penninx, Brenda W J H, Perola, Marku, Peters, Annette, Polasek, Ozren, Pramstaller, Peter P, Nguyen, Quang Tri, Raitakari, Olli T, Ren, Meixia, Rettig, Rainer, Rice, Kenneth, Ridker, Paul M, Ried, Janina S, Riese, Harriëtte, Ripatti, Samuli, Robino, Antonietta, Rose, Lynda M, Rotter, Jerome I, Rudan, Igor, Ruggiero, Daniela, Saba, Yasaman, Sala, Cinzia F, Salomaa, Veikko, Samani, Nilesh J, Sarin, Antti-Pekka, Schmidt, Reinhold, Schmidt, Helena, Shrine, Nick, Siscovick, David, Smith, Albert V, Snieder, Harold, Sõber, Siim, Sorice, Rossella, Starr, John M, Stott, David J, Strachan, David P, Strawbridge, Rona J, Sundström, Johan, Swertz, Morris A, Taylor, Kent D, Teumer, Alexander, Tobin, Martin D, Tomaszewski, Maciej, Toniolo, Daniela, Traglia, Michela, Trompet, Stella, Tuomilehto, Jaakko, Tzourio, Christophe, Uitterlinden, André G, Vaez, Ahmad, van der Most, Peter J, van Duijn, Cornelia M, Vergnaud, Anne-Claire, Verwoert, Germaine C, Vitart, Veronique, Völker, Uwe, Vollenweider, Peter, Vuckovic, Dragana, Watkins, Hugh, Wild, Sarah H, Willemsen, Gonneke, Wilson, James F, Wright, Alan F, Yao, Jie, Zemunik, Tatijana, Zhang, Weihua, Attia, John R, Butterworth, Adam S, Chasman, Daniel I, Conen, David, Cucca, Francesco, Danesh, John, Hayward, Caroline, Howson, Joanna M M, Laakso, Markku, Lakatta, Edward G, Langenberg, Claudia, Melander, Olle, Mook-Kanamori, Dennis O, Palmer, Colin N A, Risch, Lorenz, Scott, Robert A, Scott, Rodney J, Sever, Peter, Spector, Tim D, van der Harst, Pim, Wareham, Nicholas J, Zeggini, Eleftheria, Levy, Daniel, Munroe, Patricia B, Newton-Cheh, Christopher, Brown, Morris J, Metspalu, Andre, Hung, Adriana M, O'Donnell, Christopher J, Edwards, Todd L, Psaty, Bruce M, Tzoulaki, Ioanna, Barnes, Michael R, Wain, Louise V, Elliott, Paul, Caulfield, Mark J, Groningen Kidney Center (GKC), Lifestyle Medicine (LM), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Cardiovascular Centre (CVC), Groningen Institute for Organ Transplantation (GIOT), VU University medical center, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, APH - Digital Health, Institute for Molecular Medicine Finland, Centre of Excellence in Complex Disease Genetics, Research Programme of Molecular Medicine, Research Programs Unit, Aarno Palotie / Principal Investigator, University of Helsinki, Clinicum, Samuli Olli Ripatti / Principal Investigator, Biostatistics Helsinki, Department of Public Health, Complex Disease Genetics, and Genomics of Neurological and Neuropsychiatric Disorders
Subjects: Male, 0301 basic medicine, Netherlands Twin Register (NTR), Population/methods, Genome Informatics, Blood Pressure, Genome-wide association study, GENOME-WIDE ASSOCIATION, CARDIOVASCULAR-DISEASE RISK, UK BIOBANK, HYPERTENSION, VARIANTS, METAANALYSIS, COMMON, HEALTH, RARE, HYPERALDOSTERONISM, Disease, Bioinformatics, Cardiovascular Diseases/epidemiology/genetics, Risk Factors, 80 and over, GWAS, Cells, Cultured, 11 Medical and Health Sciences, ddc:616, Genetics & Heredity, Aged, 80 and over, Cultured, medicine.diagnostic_test, CARDIOVASCULAR RISK, Genetic analysis, Million Veteran Program, Genetics, Population/methods, Single Nucleotide, Middle Aged, PREVALENCE, 3. Good health, Pulse pressure, VINTAGE, Cardiovascular Diseases, Blood pressure, Medical genetics, Female, Medical Genetics, Life Sciences & Biomedicine, Genetic Testing/methods, Adult, medicine.medical_specialty, Blood Pressure/genetics, Cells, Quantitative Trait Loci, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Human Umbilical Vein Endothelial Cells, Genetics, medicine, Humans, Medicine [Science], Genetic Predisposition to Disease, Genetic Testing, Polymorphism, HEALTHY, Life Style, Medicinsk genetik, Aged, Genetic testing, Genetic association, Science & Technology, Cardiovascular Diseases/epidemiology, 06 Biological Sciences, Genetic architecture, Genetics, Population, 030104 developmental biology, Genetic Loci, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 3111 Biomedicine, Hypertension/genetics, Genome-Wide Association Study, Developmental Biology
Abstract: High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future. NMRC (Natl Medical Research Council, S’pore) MOH (Min. of Health, S’pore)
Published: 2018

17. Gender-specific pathway differences in the human serum metabolome

Author: Christian Gieger, Fabian J. Theis, Matthias Nauck, Thomas Illig, Jan Krumsiek, Florian Kronenberg, Jerzy Adamski, Kieu Trinh Do, Nele Friedrich, Annette Peters, Dennis O. Mook-Kanamori, Ferdinand Stückler, Karsten Suhre, Kirstin Mittelstrass, Maik Pietzner, Harald Grallert, Janina S. Ried, and Gabi Kastenmüller
Subjects: Genetics, Epidemiology, Endocrinology, Diabetes and Metabolism, Metabolite, Systems biology, Clinical Biochemistry, Metabolic network, Metabolic networks, Oxidative phosphorylation, Biology, Biochemistry, Molecular medicine, 3. Good health, chemistry.chemical_compound, Metabolomics, chemistry, Gender Differences, Metabolic Networks, Systems Biology, Metabolome, Gender differences, Original Article, Purine metabolism
Abstract: The susceptibility for various diseases as well as the response to treatments differ considerably between men and women. As a basis for a gender-specific personalized healthcare, an extensive characterization of the molecular differences between the two genders is required. In the present study, we conducted a large-scale metabolomics analysis of 507 metabolic markers measured in serum of 1756 participants from the German KORA F4 study (903 females and 853 males). One-third of the metabolites show significant differences between males and females. A pathway analysis revealed strong differences in steroid metabolism, fatty acids and further lipids, a large fraction of amino acids, oxidative phosphorylation, purine metabolism and gamma-glutamyl dipeptides. We then extended this analysis by a network-based clustering approach. Metabolite interactions were estimated using Gaussian graphical models to get an unbiased, fully data-driven metabolic network representation. This approach is not limited to possibly arbitrary pathway boundaries and can even include poorly or uncharacterized metabolites. The network analysis revealed several strongly gender-regulated submodules across different pathways. Finally, a gender-stratified genome-wide association study was performed to determine whether the observed gender differences are caused by dimorphisms in the effects of genetic polymorphisms on the metabolome. With only a single genome-wide significant hit, our results suggest that this scenario is not the case. In summary, we report an extensive characterization and interpretation of gender-specific differences of the human serum metabolome, providing a broad basis for future analyses. Electronic supplementary material The online version of this article (doi:10.1007/s11306-015-0829-0) contains supplementary material, which is available to authorized users.
Published: 2015

18. Nonadditive Effects of Genes in Human Metabolomics

Author: Christian Gieger, Tim D. Spector, Yakov A. Tsepilov, Cornelia Prehn, Nicole Soranzo, Yurii S. Aulchenko, Rui Wang-Sattler, Janina S. Ried, Jerzy Adamski, Gabi Kastenmüller, So-Youn Shin, and Konstantin Strauch
Subjects: Genetics, education.field_of_study, Kora, Genome-wide Association Studies, Genotypic Model, Metabolomics, Non-additive Models, Metabolite, Population, Inheritance Patterns, Genome-wide association study, Investigations, Biology, Polymorphism, Single Nucleotide, chemistry.chemical_compound, chemistry, Genetic Loci, Genetic model, Metabolome, Humans, SNP, education, Genome-Wide Association Study, Genetic association
Abstract: Genome-wide association studies (GWAS) are widely applied to analyze the genetic effects on phenotypes. With the availability of high-throughput technologies for metabolite measurements, GWAS successfully identified loci that affect metabolite concentrations and underlying pathways. In most GWAS, the effect of each SNP on the phenotype is assumed to be additive. Other genetic models such as recessive, dominant, or overdominant were considered only by very few studies. In contrast to this, there are theories that emphasize the relevance of nonadditive effects as a consequence of physiologic mechanisms. This might be especially important for metabolites because these intermediate phenotypes are closer to the underlying pathways than other traits or diseases. In this study we analyzed systematically nonadditive effects on a large panel of serum metabolites and all possible ratios (22,801 total) in a population-based study [Cooperative Health Research in the Region of Augsburg (KORA) F4, N = 1,785]. We applied four different 1-degree-of-freedom (1-df) tests corresponding to an additive, dominant, recessive, and overdominant trait model as well as a genotypic model with two degree-of-freedom (2-df) that allows a more general consideration of genetic effects. Twenty-three loci were found to be genome-wide significantly associated (Bonferroni corrected P ≤ 2.19 × 10−12) with at least one metabolite or ratio. For five of them, we show the evidence of nonadditive effects. We replicated 17 loci, including 3 loci with nonadditive effects, in an independent study (TwinsUK, N = 846). In conclusion, we found that most genetic effects on metabolite concentrations and ratios were indeed additive, which verifies the practice of using the additive model for analyzing SNP effects on metabolites.
Published: 2015

19. Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets from Blood and the Kidney

Author: Peter Vollenweider, Christophe Tzourio, Stefan Enroth, Cinzia Sala, Mark J. Caulfield, Murielle Bochud, Peter P. Pramstaller, Ozren Polasek, Paul Elliott, Dennis O. Mook-Kanamori, Daniel I. Chasman, Christian Gieger, Harriëtte Riese, Rodney J. Scott, Cristina Menni, Anubha Mahajan, Elizabeth G. Holliday, Ilja M. Nolte, Priyanka Nandakumar, Tatijana Zemunik, Dragana Vuckovic, Tõnu Esko, Franco Giulianini, Michael Boehnke, Antonietta Robino, Anne U. Jackson, Roby Joehanes, Alanna C. Morrison, Kay-Tee Khaw, Alison Pattie, Peter J. van der Most, Mika Kähönen, Rick Jansen, Andrew D. Johnson, John M. Starr, Marcus Dörr, Anders Hamsten, Kenneth Rice, Alice Stanton, James F. Wilson, Nabi Shah, Weihua Zhang, Andrew A. Hicks, Jeffrey Damman, Jing Hua Zhao, Aarno Palotie, Veronique Vitart, Alan J. Gow, Caroline Hayward, Alan James, Ben A. Oostra, Janina S. Ried, John Beilby, David P. Strachan, Martin D. Tobin, Eco J. C. de Geus, Vilmundur Gudnason, Bruce M. Psaty, Zoltán Kutalik, Neil Poulter, Paul M. Ridker, Johan Sundström, Cornelia M. van Duijn, Eleftheria Zeggini, Christopher Oldmeadow, Borbala Mifsud, Giorgia Girotto, Aravinda Chakravarti, Jonathan Marten, Alexander Teumer, Joanne Knight, Robert A. Scott, Vilmantas Giedraitis, Paul F. O'Reilly, Marco Brumat, Brenda W.J.H. Penninx, Peter J. Munson, Olli T. Raitakari, Leo-Pekka Lyytikäinen, He Gao, Massimo Mangino, Benjamin Lehne, J. Wouter Jukema, Paul Knekt, Catharina A. Hartman, Rona J. Strawbridge, Jouke-Jan Hottenga, Jaspal S. Kooner, Nilesh J. Samani, Kristin L. Ayers, A. Mesut Erzurumluoglu, Joshua C. Bis, Archie Campbell, Dan E. Arking, Germaine C. Verwoert, John Attia, Samuli Ripatti, Yuri Milaneschi, Caterina Barbieri, Fabiola M. Del Greco, C M Lindgren, Peter K. Joshi, Helen R. Warren, Nicholas J. Wareham, Simon Thom, Seppo Koskinen, Tamara B. Harris, Ilaria Gandin, Kent D. Taylor, Andrew D. Morris, Anna Morgan, Chiara Batini, Terho Lehtimäki, Walter Palmas, David Conen, Harold Snieder, Martin H. de Borst, Sarah E. Harris, Igor Rudan, Ruth J. F. Loos, Claudia Langenberg, Anuj Goel, Christopher P. Nelson, Peter S. Braund, Rossella Sorice, Yasaman Saba, Oscar H. Franco, Yongmei Liu, Mattias Frånberg, David S. Siscovick, Patricia B. Munroe, Rainer Rettig, Michela Traglia, Daniel Levy, Li Lin, Michael R. Barnes, Elin Org, Anne-Claire Vergnaud, Andres Metspalu, Stéphanie Debette, Yusuf Demirkale, John M. C. Connell, Jian'an Luan, Paolo Gasparini, Tim D. Spector, Marina Ciullo, Antti-Pekka Sarin, Ian J. Deary, Teemu J. Niiranen, Marty Larson, Heather J. Cordell, Jerome I. Rotter, Sekar Kathiresan, Teresa Nutile, Andrew P. Morris, Denis C. Shields, Alan F. Wright, Lorna M. Lopez, Aki S. Havulinna, Gonçalo R. Abecasis, Edith Hofer, Siim Sõber, Sébastien Thériault, Ahmad Vaez, Albert Hofman, Gonneke Willemsen, Lynda M. Rose, John C. Chambers, Peter S. Sever, Maryam Abedi, André G. Uitterlinden, François Mach, Massimiliano Cocca, Sarah H Wild, Reinhold Schmidt, Jaume Marrugat, Marc A. Seelen, Maris Laan, Aude Saint Pierre, David C. Liewald, Pim van der Harst, Sandosh Padmanabhan, Martin Farrall, Georg Ehret, Albert V. Smith, Quang Tri Nguyen, Ulf Gyllensten, Helena Schmidt, Ganesh Chauhan, Jennifer E. Huffman, Morris A. Swertz, Jaakko Tuomilehto, Louise V. Wain, Meixia Ren, Erwin P. Bottinger, Roberto Elosua, Ivana Kolcic, Veikko Salomaa, Stella Trompet, Bernard Keavney, Claudia P. Cabrera, Bram P. Prins, Jennie Hui, Uwe Völker, Albertine J. Oldehinkel, Evangelos Evangelou, Pekka Jousilahti, Dorret I. Boomsma, Harry Campbell, Shih-Jen Hwang, Jie Yao, Francis S. Collins, Chrysovalanto Mamasoula, Kati Kristiansson, Markus Perola, Renée de Mutsert, Xiuqing Guo, Antti Jula, Daniela Toniolo, Ruifang Li-Gao, Åsa Johansson, Nick Shrine, Teresa Ferreira, Lars Lind, David J. Stott, Tineka Blake, Daniela Ruggiero, Mike A. Nalls, Erik Ingelsson, Colin N. A. Palmer, Christopher Newton-Cheh, Marjo-Riitta Järvelin, Guillaume Paré, Joris Deelen, Morris Brown, Gail Davies, Annette Peters, Ioanna Tzoulaki, Alex S. F. Doney, Najaf Amin, Lenore J. Launer, Hugh Watkins, Yingchang Lu, Wain, Lv, Vaez, A, Jansen, R, Joehanes, R, van der Most, Pj, Erzurumluoglu, Am, O'Reilly, Pf, Cabrera, Cp, Warren, Hr, Rose, Lm, Verwoert, Gc, Hottenga, Jj, Strawbridge, Rj, Esko, T, Arking, De, Hwang, Sj, Guo, X, Kutalik, Z, Trompet, S, Shrine, N, Teumer, A, Ried, J, Bis, Jc, Smith, Av, Amin, N, Nolte, Im, Lyytikäinen, Lp, Mahajan, A, Wareham, Nj, Hofer, E, Joshi, Pk, Kristiansson, K, Traglia, M, Havulinna, A, Goel, A, Nalls, Ma, Sõber, S, Vuckovic, Dragana, Luan, J, Del Greco, M. F, Ayers, Kl, Marrugat, J, Ruggiero, D, Lopez, Lm, Niiranen, T, Enroth, S, Jackson, Au, Nelson, Cp, Huffman, Je, Zhang, W, Marten, J, Gandin, I, Harris, Se, Zemunik, T, Lu, Y, Evangelou, E, Shah, N, de Borst, Mh, Mangino, M, Prins, Bp, Campbell, A, Li Gao, R, Chauhan, G, Oldmeadow, C, Abecasis, G, Abedi, M, Barbieri, Cm, Barnes, Mr, Batini, C, Beilby, J, Blake, T, Boehnke, M, Bottinger, Ep, Braund, P, Brown, M, Brumat, M, Campbell, H, Chambers, Jc, Cocca, M, Collins, F, Connell, J, Cordell, Hj, Damman, Jj, Davies, G, de Geus, Ej, de Mutsert, R, Deelen, J, Demirkale, Y, Doney, Asf, Dörr, M, Farrall, M, Ferreira, T, Frånberg, M, Gao, H, Giedraitis, V, Gieger, C, Giulianini, F, Gow, Aj, Hamsten, A, Harris, Tb, Hofman, A, Holliday, Eg, Hui, J, Jarvelin, Mr, Johansson, Å, Johnson, Ad, Jousilahti, P, Jula, A, Kähönen, M, Kathiresan, S, Khaw, Kt, Kolcic, I, Koskinen, S, Langenberg, C, Larson, M, Launer, Lj, Lehne, B, Liewald, Dcm, Lin, L, Lind, L, Mach, F, Mamasoula, C, Menni, C, Mifsud, B, Milaneschi, Y, Morgan, Anna, Morris, Ad, Morrison, Ac, Munson, Pj, Nandakumar, P, Nguyen, Qt, Nutile, T, Oldehinkel, Aj, Oostra, Ba, Org, E, Padmanabhan, S, Palotie, A, Paré, G, Pattie, A, Penninx, Bwjh, Poulter, N, Pramstaller, Pp, Raitakari, Ot, Ren, M, Rice, K, Ridker, Pm, Riese, H, Ripatti, S, Robino, A, Rotter, Ji, Rudan, I, Saba, Y, Saint Pierre, A, Sala, Cf, Sarin, Ap, Schmidt, R, Scott, R, Seelen, Ma, Shields, Dc, Siscovick, D, Sorice, R, Stanton, A, Stott, Dj, Sundström, J, Swertz, M, Taylor, Kd, Thom, S, Tzoulaki, I, Tzourio, C, Uitterlinden, Ag, Völker, U, Vollenweider, P, Wild, S, Willemsen, G, Wright, Af, Yao, J, Thériault, S, Conen, D, Attia, J, Sever, P, Debette, S, Mook Kanamori, Do, Zeggini, E, Spector, Td, van der Harst, P, Palmer, Cna, Vergnaud, Ac, Loos, Rjf, Polasek, O, Starr, Jm, Girotto, Giorgia, Hayward, C, Kooner, J, Lindgren, Cm, Vitart, V, Samani, Nj, Tuomilehto, J, Gyllensten, U, Knekt, P, Deary, Ij, Ciullo, M, Elosua, R, Keavney, Bd, Hicks, Aa, Scott, Ra, Gasparini, Paolo, Laan, M, Liu, Y, Watkins, H, Hartman, Ca, Salomaa, V, Toniolo, D, Perola, M, Wilson, Jf, Schmidt, H, Zhao, Jh, Lehtimäki, T, van Duijn, Cm, Gudnason, V, Psaty, Bm, Peters, A, Rettig, R, James, A, Jukema, Jw, Strachan, Dp, Palmas, W, Metspalu, A, Ingelsson, E, Boomsma, Di, Franco, Oh, Bochud, M, Newton Cheh, C, Munroe, Pb, Elliott, P, Chasman, Di, Chakravarti, A, Knight, J, Morris, Ap, Levy, D, Tobin, Md, Snieder, H, Caulfield, Mj, Ehret, G. b., Home Office, Medical Research Council (MRC), National Institute for Health Research, Imperial College Healthcare NHS Trust- BRC Funding, British Heart Foundation, Life Course Epidemiology (LCE), Groningen Kidney Center (GKC), Lifestyle Medicine (LM), Vascular Ageing Programme (VAP), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Groningen Institute for Organ Transplantation (GIOT), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Cardiovascular Centre (CVC), Epidemiology, Gastroenterology & Hepatology, Clinical Genetics, Internal Medicine, Erasmus MC other, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Epidemiology and Data Science, Division 6, APH - Mental Health, APH - Digital Health, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and APH - Methodology
Subjects: 0301 basic medicine, cardiovascular risk, Netherlands Twin Register (NTR), hypertension, NETHERLANDS, Sistema cardiovascular -- Malalties, GWAS, blood pressure, complex traits, eSNP, Locus (genetics), Genome-wide association study, Disease, Biology, PERIPHERAL-BLOOD, 1102 Cardiovascular Medicine And Haematology, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Genetic variation, Internal Medicine, Journal Article, Cardiac and Cardiovascular Systems, 1000 Genomes Project, Gene, CENTRIC ARRAY, METAANALYSIS, Genetics, ddc:616, Kardiologi, PULSE PRESSURE, COMMON VARIANTS, 1103 Clinical Sciences, ta3121, 3. Good health, INDIVIDUALS, 030104 developmental biology, Blood pressure, TARGET, Cardiovascular System & Hematology, complex trait, GWAS, blood pressure, cardiovascular risk, complex traits, eSNP, hypertension, Hipertensió, Imputation (genetics), TRAITS
Abstract: Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project–based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7 , TNXB , LRP12 , LOC283335 , SEPT9 , and AKT2 , and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA . Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.
Published: 2017

20. Novel blood pressure locus and gene discovery using GWAS and expression datasets from blood and the kidney

Author: Ganesh Chauhan, Dragana Vuckovic, Yingchang Lu, Bernard Keavney, Patricia B. Munroe, Tim D. Spector, Tamara B. Harris, Chiara Batini, Harold Snieder, Yusuf Demirkale, Ulf Gyllensten, Heather J. Cordell, Christopher Newton-Cheh, Anne-Claire Vergnaud, Christophe Tzourio, Giorgia Girotto, Morris A. Swertz, John C. Chambers, Xiuqing Guo, Caterina Barbieri, Joris Deelen, Morris Brown, Igor Rudan, Christopher P. Nelson, Paul Knekt, Antti-Pekka Sarin, Peter Vollenweider, Lynda M. Rose, Ozren Polasek, Nilesh J. Samani, Murielle Bochud, James F. Wilson, Anna Morgan, Gail Davies, Ian J. Deary, Massimiliano Cocca, Antti Jula, Ioanna Tzoulaki, Jaspal S. Kooner, Sarah H Wild, Peter S. Braund, John M. Starr, Simon Thom, Christian Gieger, Rainer Rettig, John M. C. Connell, Marina Ciullo, Jian'an Luan, Rodney J. Scott, Franco Giulianini, Brenda W.J.H. Penninx, Mika Kähönen, Alison Pattie, Nabi Shah, Weihua Zhang, Ruth J. F. Loos, Maris Laan, Martin Farrall, Rick Jansen, Albert V. Smith, Sarah E. Harris, Alex S. F. Doney, Najaf Amin, Lenore J. Launer, Paul M. Ridker, John Attia, Alanna C. Morrison, Kay-Tee Khaw, Jaume Marrugat, Hugh Watkins, David C. Liewald, Pim van der Harst, Benjamin Lehne, Jennifer E. Huffman, Meixia Ren, Zoltán Kutalik, Lars Lind, Walter Palmas, Teresa Ferreira, David J. Stott, Janina S. Ried, Bruce M. Psaty, Paul F. O'Reilly, Massimo Mangino, Tõnu Esko, Jonathan Marten, Nick Shrine, Anders Hamsten, Tineka Blake, Yuri Milaneschi, Jing Hua Zhao, David Conen, Kristin L. Ayers, Germaine C. Verwoert, Veikko Salomaa, Olli T. Raitakari, Jaakko Tuomilehto, Louise V. Wain, Jennie Hui, Elin Org, Gonçalo R. Abecasis, Vilmundur Gudnason, Andrew A. Hicks, Rossella Sorice, Borbala Mifsud, Helen R. Warren, Jerome I. Rotter, Erwin P. Bottinger, Roberto Elosua, Antonietta Robino, Ilaria Gandin, Andres Metspalu, Marjo-Riitta Järvelin, Guillaume Paré, Anne U. Jackson, Jie Yao, Kent D. Taylor, Denis C. Shields, Andrew D. Morris, Daniela Ruggiero, Samuli Ripatti, C M Lindgren, Mike A. Nalls, Erik Ingelsson, Michela Traglia, Jeffrey Damman, J. Wouter Jukema, Catharina A. Hartman, Eco J. C. de Geus, Colin N. A. Palmer, Peter J. van der Most, Neil Poulter, Robert A. Scott, Anuj Goel, Aude Saint Pierre, Annette Peters, Paul Elliott, Daniel I. Chasman, Marco Brumat, Dennis O. Mook-Kanamori, Priyanka Nandakumar, Roby Joehanes, Cornelia M. van Duijn, Joshua C. Bis, Eleftheria Zeggini, Archie Campbell, Ivana Kolcic, Terho Lehtimäki, Mattias Frånberg, David S. Siscovick, Dan E. Arking, Shih-Jen Hwang, Stella Trompet, Christopher Oldmeadow, A. Mesut Erzurumluoglu, Nicholas J. Wareham, Alice Stanton, Chrysovalanto Mamasoula, Seppo Koskinen, Uwe Völker, Albertine J. Oldehinkel, Evangelos Evangelou, Pekka Jousilahti, Dorret I. Boomsma, Harry Campbell, Peter J. Munson, Aarno Palotie, Daniela Toniolo, He Gao, Ruifang Li-Gao, Claudia Langenberg, Kati Kristiansson, Åsa Johansson, Johan Sundström, Francis S. Collins, Alan J. Gow, Caroline Hayward, Markus Perola, Renée de Mutsert, Alan James, Ben A. Oostra, Alexander Teumer, Joanne Knight, Vilmantas Giedraitis, Marty Larson, Helena Schmidt, Sébastien Thériault, Peter S. Sever, Maryam Abedi, André G. Uitterlinden, Marc A. Seelen, Georg Ehret, Cristina Menni, Anubha Mahajan, Elizabeth G. Holliday, Ilja M. Nolte, Stéphanie Debette, Paolo Gasparini, Teemu J. Niiranen, Stefan Enroth, Mark J. Caulfield, Andrew P. Morris, Aki S. Havulinna, Cinzia Sala, Peter P. Pramstaller, Marcus Dörr, Quang Tri Nguyen, Claudia P. Cabrera, Bram P. Prins, Peter K. Joshi, Sekar Kathiresan, Lorna M. Lopez, Reinhold Schmidt, Sandosh Padmanabhan, Teresa Nutile, Gonneke Willemsen, François Mach, Michael Boehnke, John Beilby, Leo-Pekka Lyytikäinen, Alan F. Wright, Edith Hofer, Siim Sõber, Ahmad Vaez, Albert Hofman, Martin H. de Borst, Oscar H. Franco, Yongmei Liu, Tatijana Zemunik, Kenneth Rice, Veronique Vitart, Aravinda Chakravarti, Jouke-Jan Hottenga, Fabiola M. Del Greco, Yasaman Saba, Daniel Levy, Li Lin, Michael R. Barnes, Rona J. Strawbridge, Harriëtte Riese, Andrew D. Johnson, David P. Strachan, and Martin D. Tobin
Subjects: Genetics, 0303 health sciences, Genomics, Locus (genetics), Genome-wide association study, Biology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Blood pressure, Genetic variation, 1000 Genomes Project, Gene, 030217 neurology & neurosurgery, Imputation (genetics), 030304 developmental biology
Abstract: Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150,134 European ancestry individuals and sought significant evidence for independent replication in a further 228,245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9 and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA. Combining large whole-blood gene expression resources totaling 12,607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in BP regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.
Published: 2017
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21. An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans

Author: Rob M. van Dam, Francis S. Collins, Konstantin Strauch, Raimund Erbel, Rafn Benediktsson, Philippe Froguel, Kyle J. Gaulton, Peter Donnelly, Torben Hansen, Longda Jiang, Lennart C. Karssen, Rona J. Strawbridge, David J. Hunter, Leena Kinnunen, Thomas Meitinger, Michael Stumvoll, Stéphane Cauchi, Ching-Ti Liu, Olga McLeod, Oluf Pedersen, Michael Boehnke, Denis Rybin, Karl Gertow, Tõnu Esko, Bernhard O. Boehm, Sonali Pechlivanis, Bo Isomaa, Anne U. Jackson, Clement Ma, Yingchang Lu, Nicola D. Kerrison, Ruth J. F. Loos, Caroline S. Fox, Chiara Scapoli, Jian'an Luan, Martina Müller-Nurasyid, Domenico Palli, Anke Tönjes, Natalie R. van Zuydam, Neil Robertson, Barbara Thorand, Natalia Pervjakova, Andrew R. Wood, Karin Leander, Unnur Thorsteinsdottir, Sara M. Willems, Karen L. Mohlke, Robert A. Scott, Markus M. Nöthen, Ulf de Faire, Qi Sun, Eric Boerwinkle, Roman Wennauer, Douglas M. Ruderfer, Marika Kaakinen, Nigel W. Rayner, Jaakko Tuomilehto, Nisa M. Maruthur, Richard N. Bergman, Janina S. Ried, Himanshu Chheda, Josée Dupuis, Juan Tajes-Fernandes, Steve E. Humphries, Reedik Mägi, Gonçalo R. Abecasis, B F Voight, David Couper, Cornelia M. van Duijn, Samuli Ripatti, Yeji Lee, Heikki A. Koistinen, Christian Dina, Andres Metspalu, Lu Qi, James S. Pankow, Han Chen, Damiano Baldassarre, Mattias Frånberg, Gerald Steinbach, Inga Prokopenko, Matthias Blüher, Jose C. Florez, Julia Meyer, Niels Grarup, Anders Hamsten, Valeriya Lyssenko, James B. Meigs, Pritam Chanda, Leif Groop, Sarah Edkins, Anubha Mahajan, Gunnar Sigurðsson, Marilyn C. Cornelis, Christian Gieger, Nancy L. Pedersen, Andrew T. Hattersley, Paul W. Franks, Nicholas J. Wareham, Stefan Gustafsson, Katharine R. Owen, Peter Kovacs, Andrew D. Johnson, Lori L. Bonnycastle, Tiinamaija Tuomi, Aurelio Barricarte Gurrea, Tune H. Pers, Eric J.G. Sijbrands, Phoenix Kwan, Emmi Tikkanen, Elisabeth M. van Leeuwen, Stéphane Lobbens, Claudia Langenberg, E. Eury, Thomas W. Mühleisen, Lewin Eisele, Veikko Salomaa, Satu Mӓnnistö, Christian Fuchsberger, Evelin Mihailov, David Altshuler, Timothy M. Frayling, Peter Almgren, Harald Grallert, Hans A. Kestler, Beverley Balkau, Erik Ingelsson, Colin N. A. Palmer, Yvonne T. van der Schouw, Michael Roden, Thomas Sparsø, Karl-Heinz Jöckel, Johan G. Eriksson, Inês Barroso, John D. Eicher, Bengt Sennblad, Bruna Gigante, Andrew D. Morris, Panagiotis Deloukas, Man Li, Allan Linneberg, Astradur B. Hreidarsson, Lars Lannfelt, Elena Tremoli, Liming Liang, Omri Gottesman, Letizia Marullo, Peter S. Chines, Kari Stefansson, Mark I. McCarthy, Andrew P. Morris, Erwin P. Bottinger, Augustine Kong, Torben Jørgensen, Tanya M. Teslovich, Frank B. Hu, Dorothée Thuillier, Peter Kraft, Heiner Boeing, Laura J. Scott, Gudmar Thorleifsson, Lars Lind, John R. B. Perry, Heather M. Stringham, Susanne Moebus, Valgerdur Steinthorsdottir, Cecilia M. Lindgren, Guillaume Charpentier, Eleftheria Zeggini, Leena Peltonen, Loic Yengo, Norman Klopp, Teresa Ferreira, Christian Theil Have, Marit E. Jørgensen, Epidemiology, Erasmus MC other, Internal Medicine, Luan, Jian'an [0000-0003-3137-6337], Perry, John [0000-0001-6483-3771], Barroso, Ines [0000-0001-5800-4520], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Commission of the European Communities, and Wellcome Trust
Subjects: PROVIDES, 0301 basic medicine, SUSCEPTIBILITY LOCI, endocrine system diseases, Endocrinology, Diabetes and Metabolism, PATHOPHYSIOLOGY, European Continental Ancestry Group, Medizin, Genome-wide association study, Biology, Quantitative trait locus, Bioinformatics, White People, GENETIC ARCHITECTURE, NO, Endocrinology & Metabolism, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Diabetes Mellitus, Type 2, European Continental Ancestry Group, Gene Expression Regulation, Genetic Variation, Genome-Wide Association Study, Humans, Diabetes Mellitus, Internal Medicine, Journal Article, Glucose homeostasis, Humans, 1000 Genomes Project, Allele frequency, METAANALYSIS, 11 Medical and Health Sciences, RISK, Genetics, Science & Technology, RECEPTOR, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Haplotype, Genetic Variation, nutritional and metabolic diseases, Genetic architecture, 030104 developmental biology, Diabetes Mellitus, Type 2, Gene Expression Regulation, RARE VARIANTS, LOW-FREQUENCY, Life Sciences & Biomedicine, Type 2, 030217 neurology & neurosurgery, Imputation (genetics), FASTING GLUCOSE, Genome-Wide Association Study
Abstract: To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 × 10−8), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action–associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.
Published: 2017

22. Publisher Correction: Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits

Author: Aravinda Chakravarti, Jennifer E. Huffman, Meixia Ren, Veikko Salomaa, Christopher Newton-Cheh, Johan Sundström, Alan L. James, Joris Deelen, Raha Pazoki, Michela Traglia, Tõnu Esko, Seppo Koskinen, Christopher J. O'Donnell, Csaba P. Kovesdy, Daniel I. Chasman, Paul F. O'Reilly, Roby Joehanes, Paul M. Ridker, G. Abecasis, Lars Lind, Dragana Vuckovic, Yingchang Lu, Antonietta Robino, Anders Hamsten, Muralidharan Sargurupremraj, Caterina Barbieri, Anne U. Jackson, Anna Morgan, Claudia Langenberg, Peter S. Braund, Rainer Rettig, Murielle Bochud, Vilmundur Gudnason, Eleftheria Zeggini, David J. Stott, Joop Jukema, Nick Shrine, Jun Ding, Olle Melander, Massimo Mangino, Borbala Mifsud, Frank H. Collins, Liewald Dcm., Tineka Blake, Peter K. Joshi, Yan V. Sun, Aarno Palotie, Maciej Tomaszewski, Jarvelin M-R., Kati Kristiansson, L. J. Launer, Sara M. Willems, Ian J. Deary, Christophe Tzourio, Alan J. Gow, Caroline Hayward, Guillaume Paré, Christopher Oldmeadow, John M. Starr, Paul Elliott, Morris A. Swertz, C M van Duijn, Sekar Kathiresan, Lorna M. Lopez, Neil R Poulter, Mike A. Nalls, Erik Ingelsson, Eric Boerwinkle, Catharina A. Hartman, Giorgia Girotto, Ben A. Oostra, Markus Perola, Paul Knekt, Lyytikäinen L-P., T.B. Harris, J. C. Bis, Harriëtte Riese, J. Marrugat, Samuli Ripatti, Howson Jmm., Archie Campbell, C M Lindgren, Adam S. Butterworth, Xiuqing Guo, Lin W-Y., Priyanka Nandakumar, David Mosen-Ansorena, Alison Pattie, Marco Brumat, Annette Peters, Georgios Ntritsos, Ivana Kolcic, Alexander Teumer, Ulf Gyllensten, Joanne Knight, Stella Trompet, K. Witkowska, Hottenga J-J., Tim D. Spector, Maris Laan, Vilmantas Giedraitis, Bram P. Prins, Loos Rjf., M. H. de Borst, Antti Jula, Lynda M. Rose, Massimiliano Cocca, Daniela Toniolo, Igor Rudan, P. J. van der Most, Fu Liang Ng, Heather J. Cordell, Walter Palmas, John Danesh, John Attia, Dan E. Arking, Ganesh Chauhan, C Gieger, P. van der Harst, Penninx Bwjh., Kristin L. Ayers, Germaine C. Verwoert, Bruce M. Psaty, Jaspal S. Kooner, Ruifang Li-Gao, Benjamin Lehne, Khaw K-T., Sandosh Padmanabhan, Franco Giulianini, Erwin P. Bottinger, Roberto Elosua, Christopher P. Nelson, Ozren Polasek, D.R. Velez Edwards, Martin Farrall, Ioanna Tzoulaki, Peter Vollenweider, Uwe Völker, Albertine J. Oldehinkel, Åsa Johansson, Helen R. Warren, Evan Tzanis, Albert V. Smith, Hwang S-J., Teresa Ferreira, E.J.C. de Geus, Evangelos Evangelou, Niek Verweij, R. J. Scott, Pekka Jousilahti, Elin Org, Stefan Enroth, Dorret I. Boomsma, Harry Campbell, Andrew D. Johnson, David Conen, James F. Wilson, Edward G. Lakatta, Anuj Goel, Raymond Noordam, Najaf Amin, David P. Strachan, Martin D. Tobin, Francesco Cucca, Doney Asf., Todd L. Edwards, Jerome I. Rotter, Mika Kähönen, Hugh Watkins, Rossella Sorice, John M. C. Connell, David S. Siscovick, Sébastien Thériault, Jian'an Luan, Marty Larson, Philippe Amouyel, A C Morrison, Louise V. Wain, Reedik Mägi, Jonathan Marten, Thibaud Boutin, Nabi Shah, Weihua Zhang, Palmer Cna., Daniela Ruggiero, Zhao J-H., Olli T. Raitakari, Bernard Keavney, Peter S. Sever, Philip S. Tsao, Jie Yao, André G. Uitterlinden, Marina Evangelou, Zoltán Kutalik, Robert A. Scott, Helena Schmidt, J. Tuomilehto, Nilesh J. Samani, Quang Tri Nguyen, John Michael Gaziano, Georg Ehret, Praveen Surendran, Terho Lehtimäki, Mark J. Caulfield, Denis C. Shields, Rick Jansen, Sarin A-P., Alice Stanton, Mattias Frånberg, Cumhur Y Demirkale, Stéphanie Debette, Paolo Gasparini, Ilaria Gandin, Simon Thom, Kent D. Taylor, Andrew D. Morris, Claudia P. Cabrera, Teemu J. Niiranen, Nicholas J. Wareham, Andrew P. Morris, Yasaman Saba, Daniel Levy, Aki S. Havulinna, Kelly Cho, Sarah E. Harris, Li Lin, Janina S. Ried, Michael R. Barnes, Sarah H. Wild, Patricia B. Munroe, Vergnaud A-C., Lorenz Risch, Rona J. Strawbridge, Y. Milaneschi, John C. Chambers, Yong Qian, Cristina Menni, Anubha Mahajan, Peter Almgren, Gary Davies, Jacklyn N. Hellwege, Elizabeth G. Holliday, A. Metspalu, Ilja M. Nolte, Peter J. Munson, He Gao, Marcus Dörr, Cinzia Sala, Peter P. Pramstaller, Teresa Nutile, Wilson Pwf., Gonneke Willemsen, Markku Laakso, Chiara Batini, Harold Snieder, Ibrahim Karaman, Adriana M. Hung, Reinhold Schmidt, R. de Mutsert, Michael Boehnke, Lili Milani, Alan F. Wright, Edith Hofer, Siim Sõber, Ahmad Vaez, Albert Hofman, Oscar H. Franco, Yongmei Liu, Tatijana Zemunik, Kenneth Rice, Veronique Vitart, Marina Ciullo, Niki Dimou, Morris J. Brown, Crysovalanto Mamasoula, A.M. Erzurumluoglu, Andrew A. Hicks, Ayush Giri, Dennis O. Mook-Kanamori, Home Office, UNIVERSITY OF OULU, Commission of the European Communities, Medical Research Council (MRC), Action on Hearing Loss, British Heart Foundation, National Institute for Health Research, Imperial College Healthcare NHS Trust- BRC Funding, and UK DRI Ltd
Subjects: Genetics & Heredity, 0301 basic medicine, Netherlands Twin Register (NTR), Science & Technology, computer.internet_protocol, Million Veteran Program, Genome-wide association study, Computational biology, 06 Biological Sciences, Biology, Genetic analysis, 03 medical and health sciences, 030104 developmental biology, Genetics, Genome informatics, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Life Sciences & Biomedicine, computer, 11 Medical and Health Sciences, XML, Developmental Biology
Abstract: In the version of this article originally published, the name of author Martin H. de Borst was coded incorrectly in the XML. The error has now been corrected in the HTML version of the paper.
Published: 2018

23. A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Author: Niina Eklund, Robert C. Kaplan, Niek Verweij, Marcus Richards, Nancy L. Heard-Costa, Angelo Tremblay, Lu Qi, Andres Metspalu, Mark A. Sarzynski, Charleston W. K. Chiang, Tõnu Esko, Jaana Lindström, Pirro G. Hysi, Torben Hansen, James F. Wilson, Serena Sanna, Marie-Claude Vohl, Lynda M. Rose, Daniele Cusi, Megan T. Smith, Anne U. Jackson, Jing Hua Zhao, Anubha Mahajan, Nele Friedrich, Marcel Bruinenberg, Lori L. Bonnycastle, Ilja M. Nolte, Timothy M. Frayling, Weihua Zhang, Lavinia Paternoster, Jenny van Dongen, Torben Jørgensen, Aarno Palotie, Jana V. van Vliet-Ostaptchouk, Martin Farrall, Konstantin Strauch, Jan Smit, Zoltán Kutalik, Anne E. Justice, Elisabeth Widen, Tuomo Rankinen, Timo A. Lakka, Maria Dimitriou, Louis Pérusse, Peter J. van der Most, Yun Ju Sung, George Dedoussis, Caroline Hayward, Tom Wilsgaard, Peter P. Pramstaller, Maria Karaleftheri, Seppo Koskinen, Clive Osmond, Panos Deloukas, David J. Hunter, Kathleen Stirrups, Nicola Glorioso, Andrew T. Hattersley, Hugh Watkins, Sven Bergmann, Eric Boerwinkle, Catharina A. Hartman, Anke Tönjes, Daniel I. Chasman, May E. Montasser, Alan James, Ben A. Oostra, Nigel W. Rayner, Massimo Mangino, Ron T. Gansevoort, Cristina Barlassina, Johanna Kuusisto, Andrew A. Hicks, Roberto Lorbeer, Tomi Laitinen, Narisu Narisu, Stefan R. Bornstein, Gemma Cadby, Johan G. Eriksson, Gudmar Thorleifsson, Erika Salvi, Jari Lahti, Cornelia M. van Duijn, Janina M. Jeff, Heather M. Stringham, Bruce M. Psaty, Thomas W. Winkler, Paul M. Ridker, Unnur Thorsteinsdottir, Lyle J. Palmer, Alexander Teumer, Jürgen Gräßler, Allan Linneberg, Francesca D'Avila, Markku Heliövaara, Harald Grallert, Ivana Kolcic, Kari E. North, Eleftheria Zeggini, James S. Pankow, Alena Standáková, Marjo-Riitta Järvelin, Ozren Polasek, Krista Fischer, Valeriya Lyssenko, Thorkild I. A. Sørensen, André G. Uitterlinden, Stavroula Kanoni, Caroline S. Fox, Sophie R. Wang, Treva Rice, Maria Grazia Pilia, Olli T. Raitakari, Claudia Langenberg, Thomas Sparsø, Emmanouil Tsafantakis, Irene Pichler, Kathy Ryan, Eero Jokinen, Mika Kähönen, Leif Groop, Irene Mateo Leach, Gabriele Müller, Annette Peters, Peter Vollenweider, Oddgeir L. Holmen, David Schlessinger, Paul Knekt, M. Carola Zillikens, Evelin Mihailov, Erkki Vartiainen, Nicholas J. Wareham, Francis S. Collins, Sirkka Keinänen-Kiukaanniemi, Mark I. McCarthy, Joel N. Hirschhorn, Frank B. Hu, Janina S. Ried, Valgerdur Steinthorsdottir, Shapour Jalilzadeh, Peter Kovacs, Anuj Goel, Pim van der Harst, Peter Schwarz, Mathias Gorski, Jorma Viikari, Uwe Völker, Cecilia M. Lindgren, Theodosios Kyriakou, Morris A. Swertz, Inga Prokopenko, Ken K. Ong, Leena Kinnunen, Markus Perola, Kristian Hveem, Matthias Blüher, Rebecca Mills, Albertine J. Oldehinkel, Anders Hamsten, Mattias Lorentzon, Joel Eriksson, Karen L. Mohlke, Rasmus Ribel-Madsen, Pekka Jousilahti, Paolo Manunta, Eva Albrecht, Jeffrey R. O'Connell, Wendy L. McArdle, Amy J. Swift, Dorret I. Boomsma, Harry Campbell, Fracensco Cucca, Aaron Isaacs, Andrew Wong, Georg Homuth, Laura M. Yerges-Armstrong, Carolina Medina-Gomez, Kay-Tee Khaw, Claes Ohlsson, Claude Bouchard, John Blangero, Aliki-Eleni Farmaki, Lorraine Southam, Anette P. Gjesing, Traci M. Bartz, Dabeeru C. Rao, Andrew P. Morris, David P. Strachan, Nita G. Forouhi, Eco J. C. de Geus, Jaakko Tuomilehto, Antti Jula, Ryan W. Walker, Mary F. Feitosa, Reedik Mägi, Aki S. Havulinna, Inger Njølstad, Alan R. Shudiner, Jennifer E. Huffman, Peter Lichtner, Richard N. Bergman, Mariaelisa Graff, Diana Kuh, Tim D. Spector, Robert Luben, Veikko Salomaa, Christian Gieger, Jaspal S. Kooner, Teresa Ferreira, Jennifer L. Bragg-Gresham, Sylvain Sebert, Terho Lehtimäki, Heikki A. Koistinen, Alexandra M. Lewin, Alexessander Couto Alves, Peter S. Chines, Lise Lotte N. Husemoen, Salome Scholtens, Yii-Der Ida Chen, Kati Kristiansson, Barbara McKnight, Sara M. Willems, Rainer Rauramaa, Satu Männistö, Stephan J. L. Bakker, Angela Döring, Audrey Y. Chu, Niels Grarup, Matti Uusitupa, Hannu Puolijoki, L. Adrienne Cupples, Veronique Vitart, Marie Neergaard Harder, Jouke-Jan Hottenga, Kari Stefansson, Alan F. Wright, Igor Rudan, Keri L. Monda, Jian'an Luan, Robert A. Scott, Albert Hofman, Tarunveer S. Ahluwalia, Liesbeth Vandenput, Maija Hassinen, Sarah H. Wild, Iris M. Heid, Brenda W.J.H. Penninx, John C. Chambers, Claire Bellis, Nicholas D. Hastie, Ruth J. F. Loos, Martina Müller-Nurasyid, Johanne Marie Justesen, Gérard Waeber, Jennie Hui, Gonçalo R. Abecasis, Ishminder K. Kooner, Harold Snieder, Judith M. Vonk, Ioanna Tachmazidou, Ronald P. Stolk, Michael Stumvoll, Till Ittermann, Oluf Pedersen, Ingrid B. Borecki, Gonneke Willemsen, Jagvir Grewal, Markku Laakso, Arthur W. Musk, Eero Kajantie, Hans L. Hillege, Michael Boehnke, Cristina Venturini, Lili Milani, John Beilby, Fernando Rivadeneira, Biochemie, RS: FHML MaCSBio, RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, Goel, Anuj [0000-0003-2307-4021], Jackson, Anne U [0000-0002-9672-2547], Kristiansson, Kati [0000-0003-4688-107X], Medina-Gomez, Carolina [0000-0001-7999-5538], Nolte, Ilja M [0000-0001-5047-4077], Prokopenko, Inga [0000-0003-1624-7457], Teumer, Alexander [0000-0002-8309-094X], Wong, Andrew [0000-0003-2079-4779], Beilby, John [0000-0002-4915-2254], Bergmann, Sven [0000-0002-6785-9034], Strachan, David P [0000-0001-7854-1366], Apollo - University of Cambridge Repository, Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Groningen Energy & Sustainability Programme, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Research Institute for Asthma and COPD (GRIAC), Center for Liver, Digestive and Metabolic Diseases (CLDM), Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Children's Hospital, Lastentautien yksikkö, Clinicum, Institute for Molecular Medicine Finland, Behavioural Sciences, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Department of Medicine, Endokrinologian yksikkö, Aarno Palotie / Principal Investigator, Elisabeth Ingrid Maria Widen / Principal Investigator, University of Helsinki, Leif Groop Research Group, Quantitative Genetics, HUS Children and Adolescents, Developmental Psychology Research Group, Complex Disease Genetics, Genomics of Neurological and Neuropsychiatric Disorders, Genomic Discoveries and Clinical Translation, School of Medicine / Clinical Medicine, School of Medicine / Biomedicine,School of Medicine / Clinical Nutrition, Ried, Janina S., Jeff, Janina M., Chu, Audrey Y., Bragg Gresham, Jennifer L., Van Dongen, Jenny, Huffman, Jennifer E., Ahluwalia, Tarunveer S., Cadby, Gemma, Eklund, Niina, Eriksson, Joel, Esko, Toñu, Feitosa, Mary F., Goel, Anuj, Gorski, Mathia, Hayward, Caroline, Heard Costa, Nancy L., Jackson, Anne U., Jokinen, Eero, Kanoni, Stavroula, Kristiansson, Kati, Kutalik, Zoltán, Lahti, Jari, Luan, Jian'An, Mägi, Reedik, Mahajan, Anubha, Mangino, Massimo, Medina Gomez, Carolina, Monda, Keri L., Nolte, Ilja M., Pérusse, Loui, Prokopenko, Inga, Qi, Lu, Rose, Lynda M., Salvi, Erika, Smith, Megan T., Snieder, Harold, Standáková, Alena, Ju Sung, Yun, Tachmazidou, Ioanna, Teumer, Alexander, Thorleifsson, Gudmar, Van Der Harst, Pim, Walker, Ryan W., Wang, Sophie R., Wild, Sarah H., Willems, Sara M., Wong, Andrew, Zhang, Weihua, Albrecht, Eva, Couto Alves, Alexessander, Bakker, Stephan J. L., Barlassina, Cristina, Bartz, Traci M., Beilby, John, Bellis, Claire, Bergman, Richard N., Bergmann, Sven, Blangero, John, Blüher, Matthia, Boerwinkle, Eric, Bonnycastle, Lori L., Bornstein, Stefan R., Bruinenberg, Marcel, Campbell, Harry, Chen, Yii Der Ida, Chiang, Charleston W. K., Chines, Peter S., Collins, Francis S, Cucca, Fracensco, Cupples, L. Adrienne, D'Avila, Francesca, De Geus, Eco J. C., Dedoussis, George, Dimitriou, Maria, Döring, Angela, Eriksson, Johan G., Farmaki, Aliki Eleni, Farrall, Martin, Ferreira, Teresa, Fischer, Krista, Forouhi, Nita G., Friedrich, Nele, Gjesing, Anette Prior, Glorioso, Nicola, Graff, Mariaelisa, Grallert, Harald, Grarup, Niel, Gräßler, Jürgen, Grewal, Jagvir, Hamsten, Ander, Harder, Marie Neergaard, Hartman, Catharina A., Hassinen, Maija, Hastie, Nichola, Hattersley, Andrew Tym, Havulinna, Aki S., Heliövaara, Markku, Hillege, Han, Hofman, Albert, Holmen, Oddgeir, Homuth, Georg, Hottenga, Jouke Jan, Hui, Jennie, Husemoen, Lise Lotte, Hysi, Pirro G., Isaacs, Aaron, Ittermann, Till, Jalilzadeh, Shapour, James, Alan L., Jørgensen, Torben, Jousilahti, Pekka, Jula, Antti, Marie Justesen, Johanne, Justice, Anne E., Kähönen, Mika, Karaleftheri, Maria, Tee Khaw, Kay, Keinanen Kiukaanniemi, Sirkka M., Kinnunen, Leena, Knekt, Paul B., Koistinen, Heikki A., Kolcic, Ivana, Kooner, Ishminder K., Koskinen, Seppo, Kovacs, Peter, Kyriakou, Theodosio, Laitinen, Tomi, Langenberg, Claudia, Lewin, Alexandra M., Lichtner, Peter, Lindgren, Cecilia M., Lindström, Jaana, Linneberg, Allan, Lorbeer, Roberto, Lorentzon, Mattia, Luben, Robert, Lyssenko, Valeriya, Männistö, Satu, Manunta, Paolo, Leach, Irene Mateo, Mcardle, Wendy L., Mcknight, Barbara, Mohlke, Karen L., Mihailov, Evelin, Milani, Lili, Mills, Rebecca, Montasser, May E., Morris, Andrew P., Müller, Gabriele, Musk, Arthur W., Narisu, Narisu, Ong, Ken K., Oostra, Ben A., Osmond, Clive, Palotie, Aarno, Pankow, James S., Paternoster, Lavinia, Penninx, Brenda W., Pichler, Irene, Pilia, Maria G., Polašek, Ozren, Pramstaller, Peter P., Raitakari, Olli T, Rankinen, Tuomo, Rao, D. C., Rayner, Nigel W., Ribel Madsen, Rasmu, Rice, Treva K., Richards, Marcu, Ridker, Paul M., Rivadeneira, Fernando, Ryan, Kathy A., Sanna, Serena, Sarzynski, Mark A., Scholtens, Salome, Scott, Robert A., Sebert, Sylvain, Southam, Lorraine, Sparsø, Thomas Hempel, Steinthorsdottir, Valgerdur, Stirrups, Kathleen, Stolk, Ronald P., Strauch, Konstantin, Stringham, Heather M., Swertz, Morris A., Swift, Amy J., Tönjes, Anke, Tsafantakis, Emmanouil, Van Der Most, Peter J., Van Vliet Ostaptchouk, Jana V., Vandenput, Liesbeth, Vartiainen, Erkki, Venturini, Cristina, Verweij, Niek, Viikari, Jorma S., Vitart, Veronique, Vohl, Marie Claude, Vonk, Judith M., Waeber, Gérard, Widén, Elisabeth, Willemsen, Gonneke, Wilsgaard, Tom, Winkler, Thomas W., Wright, Alan F., Yerges Armstrong, Laura M., Zhao, Jing Hua, Carola Zillikens, M., Boomsma, Dorret I., Bouchard, Claude, Chambers, John C., Chasman, Daniel I., Cusi, Daniele, Gansevoort, Ron T., Gieger, Christian, Hansen, Torben, Hicks, Andrew A., Hu, Frank, Hveem, Kristian, Jarvelin, Marjo Riitta, Kajantie, Eero, Kooner, Jaspal S., Kuh, Diana, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A., Lehtimäki, Terho, Metspalu, Andre, Njølstad, Inger, Ohlsson, Clae, Oldehinkel, Albertine J., Palmer, Lyle J., Pedersen, Oluf, Perola, Marku, Peters, Annette, Psaty, Bruce M., Puolijoki, Hannu, Rauramaa, Rainer, Rudan, Igor, Salomaa, Veikko, Schwarz, Peter E. H., Shudiner, Alan R., Smit, Jan H., Sørensen, Thorkild I. A., Spector, Timothy D., Stefansson, Kari, Stumvoll, Michael, Tremblay, Angelo, Tuomilehto, Jaakko, Uitterlinden, André G., Uusitupa, Matti, Völker, Uwe, Vollenweider, Peter, Wareham, Nicholas J., Watkins, Hugh, Wilson, James F., Zeggini, Eleftheria, Abecasis, Goncalo R., Boehnke, Michael, Borecki, Ingrid B., Deloukas, Pano, Van Duijn, Cornelia M., Fox, Caroline, Groop, Leif C., Heid, Iris M., Hunter, David J., Kaplan, Robert C., Mccarthy, Mark I., North, Kari E., O'Connell, Jeffrey R., Schlessinger, David, Thorsteinsdottir, Unnur, Strachan, David P., Frayling, Timothy, Hirschhorn, Joel N., Müller Nurasyid, Martina, Loos, Ruth J. F., Internal medicine, Psychiatry, EMGO - Mental health, Public Health, Epidemiology, Surgery, Internal Medicine, Erasmus MC other, and Child and Adolescent Psychiatry / Psychology
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), Statistical methods, General Physics and Astronomy, Genome-wide association study, Genome-wide association studies, Mice, HEIGHT, Body Size, Mass index, 2. Zero hunger, Genetics, Principal Component Analysis, Multidisciplinary, VDP::Medisinske Fag: 700::Helsefag: 800::Samfunnsmedisin, sosialmedisin: 801, Anthropometry, Chemistry (all), Phenotype, Common, gene, body, shape, Multidisciplinary Sciences, Principal component analysis, Trait, Science & Technology - Other Topics, DIET-INDUCED OBESITY, Waist, Genotype, 515 Psychology, Science, EARLY-ONSET, Snp, BIOLOGY, HIP RATIO, Genome-wide association studies Statistical methods, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Physics and Astronomy (all), MASS INDEX, DISEASE ASSOCIATIONS, RESOURCE, MD Multidisciplinary, Humans, GENOME-WIDE ASSOCIATION, Biochemistry, Genetics and Molecular Biology (all), Science & Technology, Models, Genetic, ta1184, FAT DISTRIBUTION, General Chemistry, ta3121, 030104 developmental biology, 3121 General medicine, internal medicine and other clinical medicine, 3111 Biomedicine, VDP::Medical disciplines: 700::Health sciences: 800::Community medicine, Social medicine: 801, Body mass index, Genome-Wide Association Study
Abstract: Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways., published version, peerReviewed
Published: 2016

24. Dilution of candidates: the case of iron-related genes in restless legs syndrome

Author: Bertram Müller-Myhsok, H-Erich Wichmann, Darina Czamara, Janina S. Ried, Thomas Meitinger, G. Martin Fiedler, Angela Döring, Birgit Högl, Michael Specht, Birgit Frauscher, Holger Prokisch, Claudia Trenkwalder, Barbara Schormair, Peter Lichtner, Juliane Winkelmann, Katharina Heim, Annette Peters, Konrad Oexle, Joachim Thiery, and Christian Gieger
Subjects: Iron, Population, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Article, Restless Legs Syndrome, Iron Parameters, Meis1 Haplotype, Power Calculation, Linear Regression, Logistic Regression, 03 medical and health sciences, 0302 clinical medicine, Receptors, Transferrin, mental disorders, Genetics, medicine, Humans, Hemochromatosis Protein, Myeloid Ecotropic Viral Integration Site 1 Protein, education, Gene, Genetic Association Studies, Genetics (clinical), 030304 developmental biology, Soluble transferrin receptor, Adenosine Triphosphatases, Homeodomain Proteins, chemistry.chemical_classification, 0303 health sciences, education.field_of_study, biology, medicine.diagnostic_test, Histocompatibility Antigens Class I, Transferrin, Case-control study, Membrane Proteins, Neoplasm Proteins, Ferritin, chemistry, Case-Control Studies, Ferritins, biology.protein, Serum iron, Katanin, 030217 neurology & neurosurgery
Abstract: Restless legs syndrome (RLS) is a common multifactorial disease. Some genetic risk factors have been identified. RLS susceptibility also has been related to iron. We therefore asked whether known iron-related genes are candidates for association with RLS and, vice versa, whether known RLS-associated loci influence iron parameters in serum. RLS/control samples (n=954/1814 in the discovery step, 735/736 in replication 1, and 736/735 in replication 2) were tested for association with SNPs located within 4 Mb intervals surrounding each gene from a list of 111 iron-related genes using a discovery threshold of P=5 × 10(-4). Two population cohorts (KORA F3 and F4 with together n=3447) were tested for association of six known RLS loci with iron, ferritin, transferrin, transferrin-saturation, and soluble transferrin receptor. Results were negative. None of the candidate SNPs at the iron-related gene loci was confirmed significantly. An intronic SNP, rs2576036, of KATNAL2 at 18q21.1 was significant in the first (P=0.00085) but not in the second replication step (joint nominal P-value=0.044). Especially, rs1800652 (C282Y) in the HFE gene did not associate with RLS. Moreover, SNPs at the known RLS loci did not significantly affect serum iron parameters in the KORA cohorts. In conclusion, the correlation between RLS and iron parameters in serum may be weaker than assumed. Moreover, in a general power analysis, we show that genetic effects are diluted if they are transmitted via an intermediate trait to an end-phenotype. Sample size formulas are provided for small effect sizes.European Journal of Human Genetics advance online publication, 29 August 2012; doi:10.1038/ejhg.2012.193.
Published: 2012

25. PSEA: Phenotype Set Enrichment Analysis-A New Method for Analysis of Multiple Phenotypes

Author: Karsten Suhre, Annette Peters, H-Erich Wichmann, Norman Klopp, Konrad Oexle, Thomas Meitinger, Angela Döring, Janina S. Ried, Christian Gieger, Christa Meisinger, and Juliane Winkelmann
Subjects: Genetics, 0303 health sciences, education.field_of_study, Epidemiology, 030305 genetics & heredity, Population, Univariate, Genome-wide association study, Biology, Phenotype, 03 medical and health sciences, Pleiotropy, Genotype, Identification (biology), education, Genetics (clinical), 030304 developmental biology, Genetic association
Abstract: Most genome-wide association studies (GWAS) are restricted to one phenotype, even if multiple related or unrelated phenotypes are available. However, an integrated analysis of multiple phenotypes can provide insight into their shared genetic basis and may improve the power of association studies. We present a new method, called "phenotype set enrichment analysis" (PSEA), which uses ideas of gene set enrichment analysis for the investigation of phenotype sets. PSEA combines statistics of univariate phenotype analyses and tests by permutation. It does not only allow analyzing predefined phenotype sets, but also to identify new phenotype sets. Apart from the application to situations where phenotypes and genotypes are available for each person, the method was adjusted to the analysis of GWAS summary statistics. PSEA was applied to data from the population-based cohort KORA F4 (N = 1,814) using iron-related and blood count traits. By confirming associations previously found in large meta-analyses on these traits, PSEA was shown to be a reliable tool. Many of these associations were not detectable by GWAS on single phenotypes in KORA F4. Therefore, the results suggest that PSEA can be more powerful than a single phenotype GWAS for the identification of association with multiple phenotypes. PSEA is a valuable method for analysis of multiple phenotypes, which can help to understand phenotype networks. Its flexible design enables both the use of prior knowledge and the generation of new knowledge on connection of multiple phenotypes. A software program for PSEA based on GWAS results is available upon request.
Published: 2012

26. Novel association to the proprotein convertase PCSK7 gene locus revealed by analysing soluble transferrin receptor (sTfR) levels

Author: G. Martin Fiedler, H.-Erich Wichmann, Joachim Thiery, Martin Gögele, Thomas Meitinger, Luigi Ferrucci, Irene Pichler, Thomas Illig, Angela Döring, Peter Lichtner, Toshiko Tanaka, Harry Campbell, Stefania Bandinelli, Juliane Winkelmann, Caroline Hayward, Mathias Bruegel, Christian Gieger, Igor Rudan, Andrew A. Hicks, Janina S. Ried, Bertram Müller-Myhsok, Alan F. Wright, Peter P. Pramstaller, Cosetta Minelli, Konrad Oexle, and Christine Schwienbacher
Subjects: Adult, Male, Transferrin Saturation Measurement, medicine.medical_specialty, TMPRSS6, Adolescent, Iron, Genome-wide association, Iron homeostasis, Common variants, Hemojuvelin, Hemochromatosis, Metabolism, Consortium, Mutations, Overload, Transferrin receptor, Cohort Studies, Gene product, Young Adult, Internal medicine, Receptors, Transferrin, Genetics, medicine, Humans, Subtilisins, Molecular Biology, Genetics (clinical), Aged, Soluble transferrin receptor, Aged, 80 and over, biology, Transferrin saturation, Association Studies Articles, General Medicine, Middle Aged, Proprotein convertase, Ferritin, Endocrinology, Biochemistry, biology.protein, Female, Genome-Wide Association Study
Abstract: The level of body iron storage and the erythropoietic need for iron are indicated by the serum levels of ferritin and soluble transferrin receptor (sTfR), respectively. A meta-analysis of five genome-wide association studies on sTfR and ferritin revealed novel association to the PCSK7 and TMPRSS6 loci for sTfR and the HFE locus for both parameters. The PCSK7 association was the most significant (rs236918, P = 1.1 x 10E-27) suggesting that proprotein convertase 7, the gene product of PCSK7, may be involved in sTfR generation and/or iron homeostasis. Conditioning the sTfR analyses on transferrin saturation abolished the HFE signal and substantially diminished the TMPRSS6 signal while the PCSK7 association was unaffected, suggesting that the former may be mediated by transferrin saturation whereas the PCSK7-associated effect on sTfR generation appears to be more direct.
Published: 2010

27. Sixteen new lung function signals identified through 1000 Genomes Project reference panel imputation

Author: Arthur W. Musk, John P. Kemp, Ioanna Ntalla, Igor Rudan, Suzanne Miller, Anubha Mahajan, Samuli Ripatti, Nicholas J. Wareham, Alan F. Wright, Jennie Hui, Jing Hua Zhao, Jonathan Marten, Olli T. Raitakari, Henry Voelzke, John Beilby, John M. Starr, Robert A. Scott, Harry Campbell, Ma'en Obeidat, Deborah Jarvis, David C. Nickle, Markku Heliövaara, Nick Shrine, Lars Lind, David M. Evans, Richard Hubbard, John Henderson, Ozren Polasek, Panos Deloukas, James F. Wilson, María Soler Artigas, Ian P. Hall, Jennifer E. Huffman, Juan R. González, Joachim Heinrich, Mika Kähönen, Tim D. Spector, Neil C. Thomson, Christopher J Hammond, Marjo-Riitta Järvelin, Erik Ingelsson, Stefan Enroth, Ida Surakka, Andrew P. Morris, Ivana Kolcic, Louise V. Wain, Sarah H. Wild, Lynne J. Hocking, Wendy L. McArdle, Rajesh Rawal, Nina Hutri-Kähönen, Tatijana Zemunik, Åsa Johansson, Terho Lehtimäki, Christian Gieger, Veronique Vitart, Erik Melén, Sarah E. Harris, Medea Imboden, Holly Trochet, Momoko Horikoshi, Don D. Sin, Ian J. Deary, Pau Navarro, Alexessander Couto Alves, Ashok Kumar, Abdul Kader Kheirallah, Caroline Hayward, Stefan Karrasch, Alan James, Alexander Teumer, Ulf Gyllensten, Victoria E. Jackson, Eleftheria Zeggini, Ian D. Pavord, Holger Schulz, Anna-Liisa Hartikainen, Ana Viñuela, Anna Hansell, Nicole Probst-Hensch, Leo-Pekka Lyytikäinen, Pirro G. Hysi, Ian Sayers, Jonathan Marchini, Claudia Flexeder, David P. Strachan, Martin D. Tobin, Raquel Granell, Beate Stubbe, Corry-Anke Brandsma, Sven Glaeser, Janina S. Ried, Eva Albrecht, Yohan Bossé, Peter K. Joshi, Lorna M. Lopez, Sandosh Padmanabhan, Harald Grallert, Medical Research Council (MRC), Groningen Research Institute for Asthma and COPD (GRIAC), Institute for Molecular Medicine Finland, Clinicum, Department of Public Health, Biostatistics Helsinki, and Complex Disease Genetics
Subjects: Lung Diseases, Male, Vital capacity, UK BiLEVE, General Physics and Astronomy, Genome-wide association study, 0302 clinical medicine, Missing heritability problem, MISSING HERITABILITY, Forced Expiratory Volume, Genotype, SEQUENCE VARIANTS, WIDE ASSOCIATION, SUSCEPTIBILITY LOCUS, Lung, GENE-EXPRESSION, Genetics, Aged, 80 and over, 0303 health sciences, ARCHITECTURE, Multidisciplinary, Middle Aged, Aparell respiratori, 3. Good health, ddc, Multidisciplinary Sciences, Science & Technology - Other Topics, Female, Adult, European Continental Ancestry Group, Biology, OBSTRUCTIVE PULMONARY-DISEASE, Polymorphism, Single Nucleotide, White People, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, FEV1/FVC ratio, Young Adult, MD Multidisciplinary, Humans, SMOKING-BEHAVIOR, 1000 Genomes Project, Genetik, METAANALYSIS, 030304 developmental biology, Aged, Science & Technology, spirometry, lung function, genetics, ta1184, General Chemistry, ta3121, Heritability, 030228 respiratory system, 3121 General medicine, internal medicine and other clinical medicine, Pulmons, FORCED VITAL CAPACITY, Imputation (genetics), Genètica, Genome-Wide Association Study
Abstract: Lung function measures are used in the diagnosis of chronic obstructive pulmonary disease. In 38,199 European ancestry individuals, we studied genome-wide association of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC with 1000 Genomes Project (phase 1)-imputed genotypes and followed up top associations in 54,550 Europeans. We identify 14 novel loci (P, Genetic and environmental factors impact on lung function, important in the diagnosis of pulmonary diseases. Here the authors use imputation of genotypes to the 1000 Genomes Project reference panel to identify novel, low frequency variants associated with lung function.
Published: 2015

28. New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk

Author: Philippe Froguel, Pekka Jousilahti, Harry Campbell, Ellen M. Schmidt, Vasiliki Lagou, John Andrew Pospisilik, Ivana Kolcic, Igor Rudan, Mark A. Sarzynski, Brigitte Kühnel, Robin Haring, Paul Knekt, Christian Gieger, Eero Kajantie, Jian Yang, Tuomas O. Kilpeläinen, Hans L. Hillege, Niek Verweij, Sarah H Wild, Torben Hansen, Leena Taittonen, Michael Boehnke, Mark I. McCarthy, Joel N. Hirschhorn, Åsa K. Hedman, D. Timothy Bishop, James F. Wilson, Jian'an Luan, Leo-Pekka Lyytikäinen, Nita G. Forouhi, Mark Walker, Elodie Eury, Konstantin Strauch, Aroon D. Hingorani, Nam H. Cho, Peter Vollenweider, Erkki Vartiainen, Jong-Young Lee, Fredrik Karpe, Jiali Han, Joanne M. Jordan, Chen Lu, Henri Wallaschofski, Anna A. E. Vinkhuyzen, Alan R. Shuldiner, David J. Hunter, Mario Falchi, Aron S. Buchman, Caroline S. Fox, Robert A. Scott, Chan Soo Shin, Fernando Rivadeneira, Zari Dastani, Veikko Salomaa, Weihua Zhang, Rui Li, John C. Chambers, Thorkild I. A. Sørensen, André G. Uitterlinden, David A. Bennett, Marianna Sanna, Claire Bellis, Lars Bertram, Karl Michaëlsson, Yingchang Lu, Marie Loh, Loic Yengo, Bok-Ghee Han, Priya Srikanth, Laura Pascoe, Peter Wagner, Philip L. De Jager, Oscar H. Franco, Yongmei Liu, Stavroula Kanoni, Simone Gärtner, Ruth J. F. Loos, Eric E. Schadt, Claes Ohlsson, Cornelia M. van Duijn, Jorma S. A. Viikari, Stephan J. L. Bakker, Tamara B. Harris, Pirro G. Hysi, Samuli Ripatti, John R. B. Perry, Stefan A. Czerwinski, Tune H. Pers, Angela Döring, Ghazaleh Fatemifar, Tarunveer S. Ahluwalia, Liesbeth Vandenput, Carrie M. Nielson, Claudia Langenberg, Carolina Medina-Gomez, Mike A. Nalls, Erik Ingelsson, Barbara McKnight, Niels Grarup, L. Adrienne Cupples, Torben Jørgensen, Satu Männistö, Jianbo Na, Cristen J. Willer, Tuomo Rankinen, Irene Mateo Leach, Cecilia M. Lindgren, Marie-Claude Vohl, Ryan W. Walker, Yun Ju Sung, Joanne M. Murabito, Natasja M. van Schoor, Mika Kivimäki, Nicholas J. Wareham, Lei Yu, Markku Laakso, Julia A. Newton Bishop, Pim van der Harst, Qibin Qi, Veronique Bataille, Clive Osmond, Alan F. Wright, Audrey C. Choh, Charles C. White, Felix R. Day, Ron T. Gansevoort, Tiina Laatikainen, Ozren Polasek, Johan G. Eriksson, Mark M. Iles, Dena G. Hernandez, Meena Kumari, Dmitry Shungin, Jeffrey R. O'Connell, Joseph M. Zmuda, Antti Jula, Hyung Jin Choi, Albert Hofman, Steven R. Cummings, Youfang Liu, Vilmundur Gudnason, J. Brent Richards, Michael Stumvoll, Ayse Demirkan, Teresa Ferreira, Rosalie A. M. Dhonukshe-Rutten, Rahel Eckardt, Lude Franke, Karen L. Mohlke, Uzma Afzal, Kijoung Song, Till Ittermann, Janina S. Ried, Allan Linneberg, Nicholas D. Hastie, Laticia Oozageer, Johanna Kuusisto, John Blangero, Amélie Bonnefond, Panos Deloukas, Andrew P. Morris, Oluf Pedersen, Adam E. Locke, Emmi Tikkanen, Veronique Vitart, Aki S. Havulinna, Olli T. Raitakari, Inga Prokopenko, Peter Lichtner, Harm-Jan Westra, Katja Borodulin, Teemu Kuulasmaa, Lars Lind, Bradford Towne, Christine G. Lee, Mika Kähönen, Anke W. Enneman, Terrence S. Furey, Treva Rice, Abbas Dehghan, Jaspal S. Kooner, Dabeeru C. Rao, Terrence Forrester, Jing Hua Zhao, Xin Li, Mary F. Feitosa, Melissa E. Garcia, Tian Liu, Aarno Palotie, Eric S. Orwoll, Reedik Mägi, Daniel S. Evans, Elisabeth Widen, Tim D. Spector, Caroline Hayward, Annette Peters, Markku Heliövaara, Harald Grallert, Niina Eklund, Robert C. Kaplan, Ilja Demuth, Luigi Ferrucci, Kati Kristiansson, Amy Luke, Tõnu Esko, Ken K. Ong, Gregory J. Tranah, Angelo Tremblay, Ben A. Oostra, Stefan Gustafsson, Zhihong Zhu, Nina Smolej Narančić, Cameron D. Palmer, William R. Scott, Alexander Teumer, Anne U. Jackson, Markus Perola, Toshiko Tanaka, Lavinia Paternoster, Henry Völzke, Terho Lehtimäki, Dominik Spira, Karin M. A. Swart, Louis Pérusse, Matthias Blüher, Jari Lahti, M. Carola Zillikens, Kari E. North, Yvonne Boettcher, Douglas P. Kiel, Bamidele O. Tayo, Elisabeth Steinhagen-Thiessen, Diana L. Cousminer, Joanne E. Curran, Peter Kovacs, David M. Evans, Claude Bouchard, Alena Stančáková, Seppo Koskinen, Jack W. Kent, Alexander W. Drong, Massimo Mangino, Frédéric Fumeron, Richard S. Cooper, Juha Karjalainen, Nathalie van der Velde, Martin L. Buchkovich, Stéphane Lobbens, Cristina Menni, Anubha Mahajan, Nele Friedrich, Anke Tönjes, Colin A. McKenzie, Tom Forsén, Anne E. Justice, Lisette C. P. G. M. de Groot, Ingrid B. Borecki, Mingfeng Zhang, Tommy Cederholm, IOO, Internal medicine, Epidemiology and Data Science, EMGO - Musculoskeletal health, APH - Amsterdam Public Health, AMS - Amsterdam Movement Sciences, Geriatrics, Internal Medicine, Erasmus MC other, Epidemiology, Clinical Genetics, Institute for Molecular Medicine Finland, Clinicum, Department of General Practice and Primary Health Care, Behavioural Sciences, Samuli Olli Ripatti / Principal Investigator, Department of Public Health, Aarno Palotie / Principal Investigator, Johan Eriksson / Principal Investigator, Children's Hospital, Lastentautien yksikkö, University of Helsinki, Elisabeth Ingrid Maria Widen / Principal Investigator, Biostatistics Helsinki, Quantitative Genetics, Developmental Psychology Research Group, Complex Disease Genetics, Genomics of Neurological and Neuropsychiatric Disorders, Genomic Discoveries and Clinical Translation, Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Stem Cell Aging Leukemia and Lymphoma (SALL)
Subjects: 0301 basic medicine, Medicin och hälsovetenskap, Drosophila melanogaster/genetics, Nutrition and Disease, General Physics and Astronomy, Genome-wide association study, Medical and Health Sciences, Body fat percentage, Voeding en Ziekte, CUTANEOUS NEVI, Mass index, Human Nutrition & Health, Adiposity, INSULIN-RESISTANCE, Multidisciplinary, body fat, cardiometabolic traits, genome-wide association study, meta-analysis, biology, Disease genetics, Leptin, Humane Voeding & Gezondheid, COMMON VARIANTS, Public Health, Global Health, Social Medicine and Epidemiology, 3. Good health, Biological sciences, Cardiovascular diseases, Drosophila melanogaster, Gene Knockdown Techniques, ENERGY-BALANCE, Medical Genetics, medicine.medical_specialty, SUSCEPTIBILITY LOCI, Heart Diseases, 515 Psychology, Science, Quantitative Trait Loci, PROVIDES INSIGHTS, Quantitative trait locus, General Biochemistry, Genetics and Molecular Biology, Article, GENETIC ARCHITECTURE, 03 medical and health sciences, MASS INDEX, Insulin resistance, Internal medicine, MD Multidisciplinary, Genetics, medicine, Life Science, Animals, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Medicinsk genetik, VLAG, Global Nutrition, Wereldvoeding, Gene Expression Regulation/physiology, C-reactive protein, Metabolic diseases, General Chemistry, ta3121, medicine.disease, Onderwijsinstituut, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, Adiposity/genetics, Drosophila melanogaster/metabolism, Genome-Wide Association Study, Heart Diseases/genetics, Quantitative Trait Loci/genetics, 030104 developmental biology, Endocrinology, Gene Expression Regulation, 3121 General medicine, internal medicine and other clinical medicine, biology.protein, Lean body mass, IDENTIFIES COMMON
Abstract: To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P, A genome-wide association meta-analysis study here shows novel genetic loci to be associated to body fat percentage, and describes cross-phenotype association that further demonstrate a close relationship between adiposity and cardiovascular disease risk.
Published: 2015

29. The impact of low-frequency and rare variants on lipid levels

Author: Martina Müller-Nurasyid, Matthew Blades, Natalia Tšernikova, Tune H. Pers, Sara M. Willems, Christine Power, Momoko Horikoshi, Harald Grallert, Vilja Pietiäinen, Christian Gieger, Lude Franke, Brenda W.J.H. Penninx, Cornelia M. van Duijn, Samuli Ripatti, Joris Deelen, P. Eline Slagboom, Johannes Kettunen, Jorma Viikari, Jeanette Erdmann, Andres Metspalu, Dorret I. Boomsma, Vasiliki Lagou, Matti Pirinen, Antti-Pekka Sarin, Veikko Salomaa, Markus Perola, Elina Ikonen, Inga Prokopenko, Olli Kallioniemi, Sara Hägg, Anders Hamsten, Stefan Gustafsson, Lars Lind, Marjo-Riitta Järvelin, Valeriya Lyssenko, Elina Hyppönen, Christian Hengstenberg, Martin D. Tobin, Patrik K. E. Magnusson, Gudmar Thorleifsson, Aarno Palotie, John Patrick Mpindi, Unnur Thorsteinsdottir, Benjamin Miraglio, Claes Ladenvall, Annette Peters, Christopher P. Nelson, Heribert Schunkert, Ida Surakka, Johannes H. Smit, Reedik Mägi, Christina Willenborg, Erik Ingelsson, Gonneke Willemsen, Johan G. Eriksson, A Isaacs, Janina S. Ried, Jaakko Kaprio, Letizia Marullo, Lennart C. Karssen, Tõnu Esko, Eco J. C. de Geus, Jouke-Jan Hottenga, Leif Groop, Kari Stefansson, Olli T. Raitakari, Sanna Timonen, Terho Lehtimäki, Mark I. McCarthy, Nilesh J. Samani, Anubha Mahajan, Jeanine J. Houwing-Duistermaat, Anton J. M. de Craen, Nancy L. Pedersen, Juha Karjalainen, Elisabeth M. van Leeuwen, Harm-Jan Westra, Antti Jula, Evelin Mihailov, Johan Rung, Marian Beekman, Teresa Ferreira, Valgerdur Steinthorsdottir, Cecilia M. Lindgren, Andrew P. Morris, Aki S. Havulinna, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Lifestyle, Overweight and Diabetes, Psychiatry, NCA - Neurobiology of mental health, EMGO - Lifestyle, overweight and diabetes, Surakka, Ida, Horikoshi, Momoko, Mägi, Reedik, Sarin, Antti-Pekka, Hyppönen, Elina, Ripatti, Samuli, ENGAGE Consortium, Epidemiology, and General Practice
Subjects: Netherlands Twin Register (NTR), Linkage disequilibrium, LIVER, LOCI, Genome-wide association study, Linkage Disequilibrium, DISEASE, GLUCOSE, Gene Frequency, Lipid Metabolism/genetics, HETEROGENEITY, Dyslipidemias/genetics, 11 Medical and Health Sciences, Genetics, Genetics & Heredity, Single Nucleotide, ENGAGE Consortium, CD300, lipid genetics, Life Sciences & Biomedicine, Sequence Analysis, EXPRESSION, GENES, Mutation, Missense, Locus (genetics), Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, SEQUENCE, Article, SIALOMUCIN, Humans, 1000 Genomes Project, Polymorphism, GENOME-WIDE ASSOCIATION, Allele frequency, Dyslipidemias, Science & Technology, cholesterol, Sequence Analysis, DNA, DNA, IN-VITRO, ta3121, 06 Biological Sciences, Lipid Metabolism, Genetic Loci, Expression quantitative trait loci, Mutation, Missense, Imputation (genetics), Developmental Biology, Genome-Wide Association Study
Abstract: Using a genome-wide screen of 9.6 million genetic variants achieved through 1000 Genomes Project imputation in 62,166 samples,we identify association to lipid traits in 93 loci, including 79 previously identified loci with new lead SNPs and 10 new loci, 15 loci with a low-frequency lead SNP and 10 loci with a missense lead SNP, and 2 loci with an accumulation of rare variants. In six loci,SNPs with established function in lipid genetics (CELSR2, GCKR, LIPC and APOE) or candidate missense mutations with predicted damaging function (CD300LG and TM6SF2) explained the locus associations. The low-frequency variants increased the proportion of variance explained, particularly for low-density lipoprotein cholesterol and total cholesterol. Altogether, our results highlight the impact of low-frequency variants in complex traits and show that imputation offers a cost-effective alternative to resequencing. Refereed/Peer-reviewed
Published: 2015

30. Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error: the CREAM consortium

Author: Paul Mitchell, Arne Schillert, Tanja Zeller, Beate St Pourcain, Yi Lu, Christopher J Hammond, Nicholas G. Martin, René Höhn, Veluchamy A Barathi, Terri L. Young, Johannes R. Vingerling, Mario Pirastu, Veronique Vitart, André G. Uitterlinden, Virginie J. M. Verhoeven, Federico Murgia, Xin Zhou, Pirro G. Hysi, Christian Gieger, Jeremy A. Guggenheim, Robert Wojciechowski, Paul G. Sanfilippo, Alireza Mirshahi, Caroline Hayward, Terho Lehtimäki, Phillippa M. Cumberland, Caroline C W Klaver, Konrad Oexle, Tin Aung, Alan F. Wright, Eranga N. Vithana, Paul N. Baird, Qiao Fan, Ching-Yu Cheng, Andrew D. Paterson, Joan E. Bailey-Wilson, Thomas Meitinger, Mohammad Kamran Ikram, Janina S. Ried, Youchan Shin, Albert Hofman, David A. Mackey, Lennart C. Karssen, James F. Wilson, George McMahon, Najaf Amin, Ben A. Oostra, Brian W Fleck, Tien Yin Wong, Olavi Pärssinen, Cathy Williams, Kari-Matti Mäkelä, Kumari Neelam, Rosalynn Siantar, Yik Ying Teo, Alex W. Hewitt, Hoi Suen Wong, Olli T. Raitakari, Seyhan Yazar, Barbara E.K. Klein, Janice Lam, Shea Ping Yip, Ekaterina Yonova-Doing, Chiea Chuen Khor, Maurice Yap, David M. Evans, Harry Campbell, Goran Benčić, Jost B. Jonas, Yingfeng Zheng, Cristina Venturini, Claire L. Simpson, S. Mohsen Hosseini, Dwight Stambolian, E. Shyong Tai, Fernando Rivadeneira, Juho Wedenoja, John P. Kemp, Stuart MacGregor, Qing Li, Cornelia M. van Duijn, Ozren Polasek, Mika Kähönen, Ya Xing Wang, Kate Northstone, Jugnoo S Rahi, Seang-Mei Saw, Karl J. Lackner, Nicholas J. Timpson, Ophthalmology, Erasmus MC other, Epidemiology, Internal Medicine, Clinical Genetics, Department of Public Health, and Silmäklinikka
Subjects: Male, Refractive error, BLUE MOUNTAINS EYE, CORNEAL ASTIGMATISM, Spherical equivalent, Genome-wide association study, astigmatism, gene, SNP, DISEASE, Cohort Studies, 0302 clinical medicine, Statistics, Genetics(clinical), Neural Cell Adhesion Molecules, POPULATION, Genetics (clinical), Original Investigation, Genetics, 0303 health sciences, education.field_of_study, Age Factors, High Mobility Group Proteins, Middle Aged, 3142 Public health care science, environmental and occupational health, 3. Good health, Female, OPEN-ANGLE GLAUCOMA, Adult, Genetic Markers, EXPERIMENTALLY-INDUCED MYOPIA, Keratoconus, SUSCEPTIBILITY LOCI, Cell Adhesion Molecules, Neuronal, education, Population, Nerve Tissue Proteins, Astigmatism, Biology, White People, 03 medical and health sciences, AGE, Asian People, MAJOR LOCUS, medicine, Humans, 3125 Otorhinolaryngology, ophthalmology, 030304 developmental biology, Genetic association, Calcium-Binding Proteins, Heritability, medicine.disease, NONCODING RNAS, 030221 ophthalmology & optometry, Genome-Wide Association Study
Abstract: To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295); White Europeans aged
Published: 2015

31. Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High- Density Imputation

Author: Letizia Marullo, Jouke-Jan Hottenga, Kari Stefansson, Antti Jula, Johan Rung, Kyle J. Gaulton, Claes Ladenvall, Marian Beekman, Jeanine J. Houwing-Duistermaat, Anton J. M. de Craen, Nancy L. Pedersen, Teresa Ferreira, Jeanette Erdmann, Terho Lehtimӓki, Valgerdur Steinthorsdottir, Antti-Pekka Sarin, Christopher J. Groves, Anders Hamsten, Cecilia M. Lindgren, Veikko Salomaa, Unnur Thorsteinsdottir, Lennart C. Karssen, Valeriya Lyssenko, Cornelia M. van Duijn, Samuli Ripatti, Patrik K. E. Magnusson, Anubha Mahajan, Evelin Mihailov, Eco J. C. de Geus, P. Eline Slagboom, Martijn van de Bunt, Tõnu Esko, Andrew P. Morris, Aaron Isaacs, Sara Hӓgg, Jaakko Kaprio, Aki S. Havulinna, S Wiltshire, Sara M. Willems, Neil R. Robertson, Juan Fernandez, Momoko Horikoshi, Heribert Schunkert, Lars Lind, Erik Ingelsson, Yuri Milaneschi, Dorret I. Boomsma, Harald Grallert, Martina Müller-Nurasyid, Janina S. Ried, Gudmar Thorleifsson, Ida Surakka, Leif Groop, Joris Deelen, Martin D. Tobin, Jorma Viikari, Christian Gieger, Christian Herder, Natalia Pervjakova, Amanda J. Bennett, Matthew Blades, Annette Peters, Johannes H. Smit, Gonneke Willemsen, Markus Perola, Christina Willenborg, Thomas W. Winkler, Reedik Mӓgi, Iris M. Heid, Brenda W.J.H. Penninx, Michael Roden, Chris Power, Inga Prokopenko, Christopher P. Nelson, Elisabeth M. van Leeuwen, Mark I. McCarthy, Nilesh J. Samani, Johan G. Eriksson, Andres Metspalu, Olli T. Raitakari, Elina Hyppönen, Christian Hengstenberg, Gibson, Greg, Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Lifestyle, Overweight and Diabetes, Institute for Molecular Medicine Finland, Clinicum, Jaakko Kaprio / Principal Investigator, Department of Public Health, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Leif Groop Research Group, Samuli Olli Ripatti / Principal Investigator, Biostatistics Helsinki, Quantitative Genetics, Complex Disease Genetics, Genetic Epidemiology, Psychiatry, NCA - Neurobiology of mental health, EMGO - Lifestyle, overweight and diabetes, Epidemiology, General Practice, Dermatology, Immunology, Horikoshi, Momoko, Mägi, Reedik, van de Bunt, Martijn, Surakka, Ida, Hypponen, Elina, Morris, Andrew P, and ENGAGE Consortium
Subjects: Netherlands Twin Register (NTR), Cancer Research, RARE GENETIC-VARIATION, Obesity/genetics, Genome-wide association study, Body Mass Index, Germinal Center Kinases, 0302 clinical medicine, quantitative trait locus, Gene Frequency, genetic variability, 2.1 Biological and endogenous factors, Aetiology, Association mapping, Genetics (clinical), 2. Zero hunger, Genetics, G6PC2 gene, Genetics & Heredity, 0303 health sciences, INSULIN-RESISTANCE, Glycemic Index/genetics, Chromosome Mapping, Single Nucleotide, ENGAGE Consortium, Protein-Serine-Threonine Kinases, Polymorphism, Single Nucleotide/genetics, ddc, 3. Good health, fine-mapping, Gene Frequency/genetics, Glucose-6-Phosphatase, LOW-FREQUENCY, RSPO3 gene, Life Sciences & Biomedicine, Single Nucleotide/genetics, Medical Genetics, Research Article, Biotechnology, lcsh:QH426-470, Protein-Serine-Threonine Kinases/genetics, Thrombospondins/genetics, Quantitative Trait Loci, Locus (genetics), Biology, Endocrinology and Diabetes, Protein Serine-Threonine Kinases, GENOTYPE IMPUTATION, Polymorphism, Single Nucleotide, ASIAN POPULATIONS, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Humans, Genetic Predisposition to Disease, Obesity, 1000 Genomes Project, GENOME-WIDE ASSOCIATION, Polymorphism, Molecular Biology, Allele frequency, Ecology, Evolution, Behavior and Systematics, Metabolic and endocrine, 030304 developmental biology, Genetic association, Medicinsk genetik, Nutrition, Science & Technology, Body mass index, Molecular genetics, Quantitative trait loci, Genome-wide association studies, Quality control, Genomic signal processing, Meta-analysis, Human Genome, gene mapping, ta3121, Minor allele frequency, BODY-MASS INDEX, lcsh:Genetics, Glucose-6-Phosphatase/genetics, Glycemic Index, glycemic control, TYPE-2 DIABETES RISK, 3111 Biomedicine, GCK gene, WAIST-HIP RATIO, Quantitative Trait Loci/genetics, Thrombospondins, 030217 neurology & neurosurgery, Imputation (genetics), FASTING GLUCOSE, Genome-Wide Association Study, Developmental Biology
Abstract: Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency ≥0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated., Author Summary Human genetic studies have demonstrated that quantitative human anthropometric and metabolic traits, including body mass index, waist-hip ratio, and plasma concentrations of glucose and insulin, are highly heritable, and are established risk factors for type 2 diabetes and cardiovascular diseases. Although many regions of the genome have been associated with these traits, the specific genes responsible have not yet been identified. By making use of advanced statistical “imputation” techniques applied to more than 87,000 individuals of European ancestry, and publicly available “reference panels” of more than 37 million genetic variants, we have been able to identify novel regions of the genome associated with these glycaemic and obesity-related traits and localise genes within these regions that are most likely to be causal. This improved understanding of the biological mechanisms underlying glycaemic and obesity-related traits is extremely important because it may advance drug development for downstream disease endpoints, ultimately leading to public health benefits.
Published: 2015

32. Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis

Author: Supinda Bunyavanich, Mayumi Tamari, Ronny Myhre, Birgit Kalb, Benjamin A. Raby, Xuejun Zhang, Wendy L. McArdle, Daniel Glass, Gabrielle A. Lockett, Chao Tian, Adnan Custovic, Frank Geller, Albert M. Levin, Susanne Lau, Nicole Probst-Hensch, Marie Standl, Tim D. Spector, Elke Rodriguez, Badri Pahukasahasram, Craig E. Pennell, Carole Ober, Alexessander Couto Alves, George Davey Smith, Cheng-Jian Xu, James J. Yang, Nicholas G. Martin, Elisabeth Altmaier, Feng Li Xiao, Regina Foelster-Holst, Lise Lotte N. Husemoen, Atsushi Takahashi, Angela Simpson, Markus M. Noethen, Grainne M. O'Regan, Patrick M. A. Sleiman, Anja Bauerfeind, Linda E. Campbell, Jacob P. Thyssen, Caoimhe M. R. Fahy, Ingo Marenholz, André G. Uitterlinden, Jorge Esparza-Gordillo, Albert Hofman, John A. Curtin, John P. Kemp, Jie Zheng, Melanie C. Matheson, Suzanne G.M.A. Pasmans, Christian Gieger, Pirro G. Hysi, Esteban G. Burchard, Eskil Kreiner-Møller, Keith M. Godfrey, Erik Melén, Jin Li, Hans Bisgaard, Michael Kurek, X. Zheng, Min Ae Lee-Kirsch, Lavinia Paternoster, Mads Melbye, Juha Pekkanen, Natalia Vilor-Tejedor, Elisabeth Thiering, Carsten Oliver Schmidt, Anja Matanovic, W.H. Irwin McLean, Wenche Nystad, Carla M. T. Tiesler, Sheila J. Barton, Michiaki Kubo, Klaus Bønnelykke, Guy B. Marks, Stephan Weidinger, Deborah A. Meyers, David P. Strachan, Bjarke Feenstra, Wolfgang Lieb, Thomas Keil, Celeste Eng, Elisabeth Mangold, Christel M. Middeldorp, Cristina Venturini, Niels J. Elbert, Jouke-Jan Hottenga, Xian Bo Zuo, Georg Homuth, L. Keoki Williams, Sylvain Sebert, Maria Pino-Yanes, Mariona Bustamante, Scott T. Weiss, Donglei Hu, Allan Linneberg, Ashok Kumar, Ivan Curjuric, Johannes Waage, Joachim Heinrich, Philip J. Thompson, Johan C. de Jongste, Fernando Rivadeneira, Veronique Bataille, David M. Evans, Joyce Y. Tung, Bo Jacobsson, Natalija Novak, Sara J. Brown, Andre Franke, Medea Imboden, Lisbeth Carstensen, Maeve A. McAleer, Jordi Sunyer, Momoko Horikoshi, Hakon Hakonarson, Liesbeth Duijts, Juan R. González, Scott Huntsman, Xianyong Yin, Melanie Hotze, Niels Grarup, Carol A. Wang, Norbert Huebner, Tomomitsu Hirota, Rachel A. Myers, Milan Macek, Cilla Soederhaell, Maria M. Groen-Blokhuis, Herman T. den Dekker, Dorret I. Boomsma, Franz Rueschendorf, Deborah Jarvis, Alan D. Irvine, Sven Cichon, Manuel A. R. Ferreira, Janina S. Ried, Young-Ae Lee, Andreas Arnold, H. Baurecht, Gerard H. Koppelman, David A. Hinds, Colin F. Robertson, Liangdan Sun, Vincent W. V. Jaddoe, Dirkje S. Postma, Marjo-Riitta Järvelin, Annette Peters, John W. Holloway, Caroline L Relton, A. John Henderson, Jonas Bacelis, Psychiatry, EMGO - Musculoskeletal health, NCA - Neurobiology of mental health, Groningen Research Institute for Asthma and COPD (GRIAC), Epidemiology, Pediatrics, Internal Medicine, Erasmus MC other, Dermatology, Gastroenterology & Hepatology, Child and Adolescent Psychiatry / Psychology, Public Health, Biological Psychology, EMGO+ - Musculoskeletal Health, and Neuroscience Campus Amsterdam - Neurobiology of Mental Health
Subjects: Netherlands Twin Register (NTR), Candidate gene, T-Lymphocytes, Genome-wide association study, VARIANTS, Genome-wide association studies, EArly Genetics and Lifecourse Epidemiology (EAGLE) Eczema Consortium, Risk Factors, Ethnicity, health care economics and organizations, Genetics & Heredity, Genetics, PSORIASIS, 11 Medical And Health Sciences, Atopic dermatitis, 3. Good health, Life Sciences & Biomedicine, Dermatitis atòpica, Genetic Markers, medicine.medical_specialty, SUSCEPTIBILITY LOCI, education, Biology, Australian Asthma Genetics Consortium (AAGC), Polymorphism, Single Nucleotide, Article, Dermatitis, Atopic, GENETIC ARCHITECTURE, SDG 3 - Good Health and Well-being, Molecular genetics, medicine, Humans, FILAGGRIN, Genetic Predisposition to Disease, JAPANESE POPULATION, Genomes, METAANALYSIS, Genetic association, Science & Technology, Case-control study, Grups ètnics, INTERLEUKIN-7 RECEPTOR, 06 Biological Sciences, medicine.disease, Immunity, Innate, Genetic architecture, Genetic Loci, Genetic marker, Case-Control Studies, Immunology, ASTHMA, Genètica, Developmental Biology, Genome-Wide Association Study, INFLAMMATORY-BOWEL-DISEASE
Abstract: Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified ten new risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with new secondary signals at four of these loci). Notably, the new loci include candidate genes with roles in the regulation of innate host defenses and T cell function, underscoring the important contribution of (auto)immune mechanisms to atopic dermatitis pathogenesis. This research was specifically funded by an MRC Population Health Scientist Fellowship awarded to Dr L Paternoster (MR/J012165/1). D.M.E. is supported by an Australian Research Council Future Fellowship (FT130101709) and a Medical Research Council program grant (MC_UU_12013/4)
Published: 2015

33. Novel genetic associations with serum level metabolites identified by phenotype set enrichment analyses

Author: Thomas Illig, H-Erich Wichmann, Konstantin Strauch, Nicole Soranzo, Christian Gieger, Fabian J. Theis, So-Youn Shin, Karsten Suhre, Jan Krumsiek, Janina S. Ried, Tim D. Spector, and Jerzy Adamski
Subjects: Genotype, Metabolite, Population, Biology, Polymorphism, Single Nucleotide, Cohort Studies, chemistry.chemical_compound, Metabolomics, Genetics, Metabolome, Humans, education, Molecular Biology, Gene, Genetics (clinical), Genetic Association Studies, Genetic association, education.field_of_study, Association Studies Articles, Computational Biology, Reproducibility of Results, General Medicine, Phenotype, ddc, chemistry, Genetic Loci, Biomarkers
Abstract: Availability of standardized metabolite panels and genome-wide single nucleotide polymorphism (SNP) data endorse the comprehensive analysis of gene-metabolite association. Currently, many studies use genome-wide association analysis to investigate the genetic effects on single metabolites (mGWAS) separately. Such studies have identified several loci that are associated not only with one but with multiple metabolites, facilitated by the fact that metabolite panels often include metabolites of the same or related pathways. Strategies that analyse several phenotypes in a combined way were shown to be able to detect additional genetic loci. One of those methods is the phenotype set enrichment analysis (PSEA) that tests sets of metabolites for enrichment at genes. Here we applied PSEA on two different panels of serum metabolites together with genome-wide data. All analyses were performed as a two-step identification-validation approach, using data from the population-based KORA cohort and the TwinsUK study. In addition to confirming genes that were already known from mGWAS, we were able to identify and validate twelve new genes. Knowledge about gene function was supported by the enriched metabolite sets. For loci with unknown gene functions, the results suggest a function that is interrelated with the metabolites, and hint at the underlying pathways.
Published: 2014

34. Simulation of Finnish population history, guided by empirical genetic data, to assess power of rare-variant tests in Finland

Author: Mark A. DePristo, Gil McVean, Jacquelyn Murphy, Kyle J. Gaulton, Jasmina Kravic, Martin Hrabé de Angelis, Noël P. Burtt, Ryan Poplin, Jeff Chen, Peter S. Chines, Tiinamaija Toumi, David Buck, Khalid Shakir, Pierre Fontanillas, Richard N. Bergman, Neil Robertson, Leif Groop, Tim M. Strom, Martina Müller-Nurasyid, Loukas Moutsianas, Christian Fuchsberger, Charleston W. K. Chiang, Thomas Meitinger, Jennifer Kriebel, Richard D. Pearson, Christa Meisinger, Gonçalo R. Abecasis, Jaakko Tuomilehto, Ashok Kumar, Janina S. Ried, Anubha Mahajan, Andrew T. Hattersley, Adam E. Locke, Wolfgang Rathmann, Inga Prokopenko, Adrian Tan, Annette Peters, Lori L. Bonnycastle, Andrew D. Morris, Christopher Hartl, Peter Donnelly, Vineeta Agarwala, Will Rayner, Jason Flannick, Timothy M. Frayling, Cornelia Huth, Martijn van de Bunt, David Altshuler, Harald Grallert, Stacey Gabriel, Michael Boehnke, Laura J. Scott, Tim D. Spector, Thomas W. Blackwell, Heather M. Stringham, Phoenix Kwan, Alisa Manning, Tanya M. Teslovich, Sophie R. Wang, Jeroen R. Huyghe, Francis S. Collins, Kerrin S. Small, Cecilia M. Lindgren, Gerton Lunter, Mark I. McCarthy, Joel N. Hirschhorn, Timothy Fennell, Todd Green, Clement Ma, Manny Rivas, Claes Ladenvall, Bo Isomaa, Anne U. Jackson, Hyun Min Kang, Eric Banks, Michael L. Stitzel, Xueling Sim, John R. B. Perry, Bryan Howie, Konstantin Strauch, Goo Jun, Karen L. Mohlke, and Christian Gieger
Subjects: Genetics, Multifactorial Inheritance, Models, Genetic, Population, Population genetics, Biology, Genetic architecture, Founder Effect, White People, Article, Diabetes Mellitus, Type 2, Evolutionary biology, Genetic model, Humans, Genetics(clinical), Computer Simulation, Exome, Genotyping, Genetics (clinical), Exome sequencing, Finland, Genetic association, Founder effect
Abstract: Finnish samples have been extensively utilized in studying single-gene disorders, where the founder effect has clearly aided in discovery, and more recently in genome-wide association studies of complex traits, where the founder effect has had less obvious impacts. As the field starts to explore rare variants' contribution to polygenic traits, it is of great importance to characterize and confirm the Finnish founder effect in sequencing data and to assess its implications for rare-variant association studies. Here, we employ forward simulation, guided by empirical deep resequencing data, to model the genetic architecture of quantitative polygenic traits in both the general European and the Finnish populations simultaneously. We demonstrate that power of rare-variant association tests is higher in the Finnish population, especially when variants' phenotypic effects are tightly coupled with fitness effects and therefore reflect a greater contribution of rarer variants. SKAT-O, variable-threshold tests, and single-variant tests are more powerful than other rare-variant methods in the Finnish population across a range of genetic models. We also compare the relative power and efficiency of exome array genotyping to those of high-coverage exome sequencing. At a fixed cost, less expensive genotyping strategies have far greater power than sequencing; in a fixed number of samples, however, genotyping arrays miss a substantial portion of genetic signals detected in sequencing, even in the Finnish founder population. As genetic studies probe sequence variation at greater depth in more diverse populations, our simulation approach provides a framework for evaluating various study designs for gene discovery.
Published: 2013

35. Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels

Author: Eva Albrecht, Medea Imboden, Jennifer E. Huffman, James F. Wilson, Eva Reischl, David P. Strachan, Ozren Polasek, Ian P. Hall, Beate Koch, Thierry Rochat, Holger Schulz, Ian J. Deary, Sune F. Nielsen, Ilaria Ferrarotti, Ashok Kumar, Erich W. Russi, Igor Rudan, Margot Haun, Florian Kronenberg, Ivan Curjuric, Gian Andri Thun, Andrew J. Sandford, Marjo-Riitta Järvelin, Morten Dahl, Ke Hao, Ma'en Obeidat, Jennie Hui, Stefan Enroth, Børge G. Nordestgaard, Caroline Hayward, Alan James, Alexander Teumer, Ulf Gyllensten, Maurizio Luisetti, Martin D. Tobin, Victoria E. Jackson, Alexessander Couto Alves, Wim Timens, Nicole Probst-Hensch, Michele Zorzetto, Yohan Bossé, Lorna M. Lopez, Janina S. Ried, Groningen Research Institute for Asthma and COPD (GRIAC), Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Medical Research Council (MRC)
Subjects: Cancer Research, Medicin och hälsovetenskap, Pulmonology, Chronic Obstructive Pulmonary Diseases, Epidemiology, Denmark, Genome-wide association study, SUSCEPTIBILITY, gene, serpina, Medical and Health Sciences, AIR-FLOW OBSTRUCTION, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, Gene Frequency, MOLECULAR CHARACTERIZATION, Lung, Genetics (clinical), ALPHA(1)-ANTITRYPSIN, POPULATION, Genetics, Genetics & Heredity, 0303 health sciences, education.field_of_study, 3. Good health, DEFICIENCY, LUNG-FUNCTION, RARE VARIANTS, Genetic Epidemiology, Multigene Family, Perspective, Medicine, Life Sciences & Biomedicine, Research Article, lcsh:QH426-470, Genotype, Population, Single-nucleotide polymorphism, Locus (genetics), Biology, Polymorphism, Single Nucleotide, OBSTRUCTIVE PULMONARY-DISEASE, 03 medical and health sciences, ALPHA-1-ANTITRYPSIN PHENOTYPES, Genome-Wide Association Studies, SNP, Humans, Genetic Predisposition to Disease, Allele, GENOME-WIDE ASSOCIATION, education, Molecular Biology, Allele frequency, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Clinical Genetics, 0604 Genetics, Science & Technology, Computational Biology, Smoking Related Disorders, Human Genetics, AIR-POLLUTION, MZ HETEROZYGOTES, Minor allele frequency, lcsh:Genetics, 030228 respiratory system, alpha 1-Antitrypsin, Genetics of Disease, Genetic Polymorphism, Population Genetics, Genome-Wide Association Study, Developmental Biology
Abstract: Several infrequent genetic polymorphisms in the SERPINA1 gene are known to substantially reduce concentration of alpha1-antitrypsin (AAT) in the blood. Since low AAT serum levels fail to protect pulmonary tissue from enzymatic degradation, these polymorphisms also increase the risk for early onset chronic obstructive pulmonary disease (COPD). The role of more common SERPINA1 single nucleotide polymorphisms (SNPs) in respiratory health remains poorly understood. We present here an agnostic investigation of genetic determinants of circulating AAT levels in a general population sample by performing a genome-wide association study (GWAS) in 1392 individuals of the SAPALDIA cohort. Five common SNPs, defined by showing minor allele frequencies (MAFs) >5%, reached genome-wide significance, all located in the SERPINA gene cluster at 14q32.13. The top-ranking genotyped SNP rs4905179 was associated with an estimated effect of β = −0.068 g/L per minor allele (P = 1.20*10−12). But denser SERPINA1 locus genotyping in 5569 participants with subsequent stepwise conditional analysis, as well as exon-sequencing in a subsample (N = 410), suggested that AAT serum level is causally determined at this locus by rare (MAF, Author Summary Low levels of alpha1-antitrypsin (AAT) in the blood are a well-established risk factor for accelerated loss in lung function and chronic obstructive pulmonary disease. While a few infrequent genetic polymorphisms are known to influence the serum levels of this enzyme, the role of common genetic variants has not been examined so far. The present genome-wide scan for associated variants in approximately 1400 Swiss inhabitants revealed a chromosomal locus containing the functionally established variants of AAT deficiency and variants previously associated with lung function and emphysema. We used dense genotyping of this genetic region in more than 5500 individuals and subsequent conditional analyses to unravel which of these associated variants contribute independently to the phenotype's variability. All associations of common variants could be attributed to the rarer functionally established variants, a result which was then replicated in an independent population-based Danish cohort. Hence, this locus represents a textbook example of how a large part of a trait's heritability can be hidden in infrequent genetic polymorphisms. The attempt to transfer these results to lung function furthermore suggests that effects of common variants in this genetic region in ever-smokers may also be explained by rarer variants, but only in individuals with hampered pulmonary health.
Published: 2013

36. Development and Application of Genomic Control Methods for Genome-Wide Association Studies Using Non-Additive Models

Author: Konstantin Strauch, Janina S. Ried, Cornelia M. van Duijn, Yurii S. Aulchenko, Yakov A. Tsepilov, Harald Grallert, Tatiana I. Axenovich, and Epidemiology
Subjects: Genotype, Population, lcsh:Medicine, Genome-wide association study, Computational biology, Biology, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Databases, Genetic, Test statistic, Humans, Computer Simulation, Allele, lcsh:Science, education, Additive model, Allele frequency, 030304 developmental biology, Statistical hypothesis testing, Genetics, 0303 health sciences, education.field_of_study, Multidisciplinary, Genome, Models, Genetic, lcsh:R, Genomics, lcsh:Q, 030217 neurology & neurosurgery, Type I and type II errors, Genome-Wide Association Study, Research Article
Abstract: Genome-wide association studies (GWAS) comprise a powerful tool for mapping genes of complex traits. However, an inflation of the test statistic can occur because of population substructure or cryptic relatedness, which could cause spurious associations. If information on a large number of genetic markers is available, adjusting the analysis results by using the method of genomic control (GC) is possible. GC was originally proposed to correct the Cochran-Armitage additive trend test. For non-additive models, correction has been shown to depend on allele frequencies. Therefore, usage of GC is limited to situations where allele frequencies of null markers and candidate markers are matched. In this work, we extended the capabilities of the GC method for non-additive models, which allows us to use null markers with arbitrary allele frequencies for GC. Analytical expressions for the inflation of a test statistic describing its dependency on allele frequency and several population parameters were obtained for recessive, dominant, and over-dominant models of inheritance. We proposed a method to estimate these required population parameters. Furthermore, we suggested a GC method based on approximation of the correction coefficient by a polynomial of allele frequency and described procedures to correct the genotypic (two degrees of freedom) test for cases when the model of inheritance is unknown. Statistical properties of the described methods were investigated using simulated and real data. We demonstrated that all considered methods were effective in controlling type 1 error in the presence of genetic substructure. The proposed GC methods can be applied to statistical tests for GWAS with various models of inheritance. All methods developed and tested in this work were implemented using R language as a part of the GenABEL package.
Published: 2013

37. Integrative genetic and metabolite profiling analysis suggests altered phosphatidylcholine metabolism in asthma

Author: Thomas Illig, Konstantin Strauch, Heinz Erich Wichmann, Ferdinand Stückler, Rui Wang-Sattler, Michael Kabesch, Janina S. Ried, Cornelia Prehn, Christian Gieger, Stephan Weidinger, Hans-Ulrich Schulz, Joachim Heinrich, Fabian J. Theis, Jan Krumsiek, Karsten Suhre, Hansjörg Baurecht, Jerzy Adamski, Annette Peters, and Elke Rodriguez
Subjects: Adult, Male, Genotype, Metabolite, Immunology, Population, Single-nucleotide polymorphism, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Asthma, Genetics, Lipids, Metabolomics, chemistry.chemical_compound, medicine, Odds Ratio, Immunology and Allergy, Humans, education, Alleles, Genetic association, Aged, Aged, 80 and over, education.field_of_study, Gene Expression Profiling, Middle Aged, medicine.disease, respiratory tract diseases, Targeted mass spectrometry, Cross-Sectional Studies, chemistry, Genetic Loci, Metabolome, Phosphatidylcholines, Female
Abstract: Background Genome-wide association studies (GWAS) have identified many risk loci for asthma, but effect sizes are small, and in most cases, the biological mechanisms are unclear. Targeted metabolite quantification that provides information about a whole range of pathways of intermediary metabolism can help to identify biomarkers and investigate disease mechanisms. Combining genetic and metabolic information can aid in characterizing genetic association signals with high resolution. This work aimed to investigate the interrelation of current asthma, candidate asthma risk alleles and a panel of metabolites. Methods We investigated 151 metabolites, quantified by targeted mass spectrometry, in fasting serum of asthmatic and nonasthmatic individuals from the population-based KORA F4 study (N = 2925). In addition, we analysed effects of single-nucleotide polymorphisms (SNPs) at 24 asthma risk loci on these metabolites. Results Increased levels of various phosphatidylcholines and decreased levels of various lyso-phosphatidylcholines were associated with asthma. Likewise, asthma risk alleles from the PDED3 and MED24 genes at the asthma susceptibility locus 17q21 were associated with increased concentrations of various phosphatidylcholines with consistent effect directions. Conclusions Our study demonstrated the potential of metabolomics to infer asthma-related biomarkers by the identification of potentially deregulated phospholipids that associate with asthma and asthma risk alleles.
Published: 2012

38. Evaluation of gene-obesity interaction effects on cholesterol levels: a genetic predisposition score on HDL-cholesterol is modified by obesity

Author: Annette Peters, Lukas Forer, Barbara Kollerits, Claudia Lamina, Florian Kronenberg, Christian Gieger, H.-Erich Wichmann, Sebastian Schönherr, and Janina S. Ried
Subjects: Male, Candidate gene, Waist, Population, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Risk Assessment, Body Mass Index, chemistry.chemical_compound, Sex Factors, Risk Factors, Germany, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, Obesity, Allele, education, Aged, Genetics, education.field_of_study, Models, Genetic, Cholesterol, Waist-Hip Ratio, Cholesterol, HDL, nutritional and metabolic diseases, Cholesterol, LDL, Middle Aged, medicine.disease, Phenotype, chemistry, Linear Models, lipids (amino acids, peptides, and proteins), Female, Gene-Environment Interaction, Waist Circumference, Cardiology and Cardiovascular Medicine, Biomarkers, Genome-Wide Association Study
Abstract: Effect modification by obesity or obesity-related phenotypes (e.g. physical activity and diet) was observed in some candidate gene studies on lipids. We aimed to evaluate gene-obesity interaction effects on HDL (HDL-C), LDL (LDL-C) and total cholesterol (TC) levels using genetic predisposition scores.We derived imputed genotypes for 104 SNPs in 84 lipid-associated loci in the population-based studies KORA F3 (n = 1406) and KORA F4 (n = 1515). We inferred specific unbiased weights for each SNP from linear regression estimates in KORA F4. Weighted genotypic predisposition SNP-scores were then calculated for each lipid trait in KORA F3. Interaction terms of SNP-scores with each of the obesity parameters (BMI, waist-hip-ratio, waist circumference) were included in age- and sex-adjusted linear regression models on HDL-C, LDL-C and TC.All three SNP-scores were shown to be highly associated with their respective lipid levels (p = 1.11 × 10(-47) for HDL-C, p = 3.25 × 10(-19) for LDL-C and 1.53 × 10(-13) for TC). BMI, WHR and waist circumference modified the effect of the weighted HDL-C SNP-score on HDL-C significantly (all interaction p-values0.0062). No interaction term was significant for LDL-C or TC. Accounting for gene-obesity interaction substantially increased the proportion of HDL-C variance explained by 3-3.5%.Our investigation revealed a significant interaction effect between obesity parameters and a SNP-score on HDL-C: the combined effect of HDL-C-increasing alleles on HDL-C is attenuated with increasing levels of obesity-relevant parameters. Future studies aiming to detect new genetic variants or to model genetic predictions of HDL-C levels should take obesity or obesity associated parameters into account.
Published: 2012

39. Seventy-five genetic loci influencing the human red blood cell

Author: Teresa Nutile, Anna-Liisa Hartikainen, Stavroula Kanoni, Johannes H. Smit, Harm-Jan Westra, Beben Benyamin, Gonneke Willemsen, Clara S. Tang, Maria Dimitriou, Peter Vollenweider, Olle Melander, Inga Prokopenko, W.H. Wilson Tang, John P. Kemp, Tim D. Spector, Evelin Mihailov, Paul F. O'Reilly, Eleonora Porcu, Marcus E. Kleber, Sheila Ulivi, George Dedoussis, Manuela Uda, Matthias Nauck, Brenda W.J.H. Penninx, Daniela Ruggiero, Xinzhong Li, Dirk S. Paul, Niek Verweij, Bernd Genser, Harold Snieder, Willem H. Ouwehand, Ido P. Kema, Miriam F. Moffatt, Carmel Moore, Hilma Holm, Nicola Pirastu, Adamo Pio D'Adamo, Michael Stumvoll, Rossella Sorice, Kay-Tee Khaw, Heather Lloyd-Jones, Federico Murgia, Stephen F. Garner, Jing Hua Zhao, Laura Portas, Abdel Abdellaoui, Ursula Puc, Andres Metspalu, Marleen H. M. de Moor, Isleifur Olafsson, Ruth J. F. Loos, Andres Salumets, François Bastardot, James Scott, Jian Yang, Braxton D. Mitchell, Debora Parracciani, Maria Novatchkova, Panos Deloukas, William O.C.M. Cookson, Lorna M. Lopez, Andrew A. Hicks, Aude Saint-Pierre, Daniel F. Gudbjartsson, Vinicius Tragante, Mario Pirastu, Jacques S. Beckmann, L. Joost van Pelt, Winfried Maerz, Hooman Allayee, Jouke-Jan Hottenga, Kari Stefansson, Debashish Das, Weihua Zhang, Anke Tönjes, Michela Traglia, Stuart Meacham, Antonio Piga, Cornelis A. Albers, Nicholas G. Martin, John C. Chambers, Christa Meisinger, Leo-Pekka Lyytikäinen, Nicole Soranzo, Mika Kähönen, Katrin Voss, Micha Hersch, Claudia Langenberg, Sian Tsung Tan, Sandosh Padmanabhan, Christian X. Weichenberger, J. Gustav Smith, Antony P. Attwood, Claire E. Hastie, Gunnar Engström, Janina S. Ried, Carsten Oliver Schmidt, Pall T. Onundarson, Kathy Miller, Francisco S. Domingues, Stefania Bandinelli, Ulrich Elling, Augusto Rendon, Paul Elliott, Quince Gibson, Tõnu Esko, Robert Sladek, Marina Ciullo, Gerald Wirnsberger, Franco Anni, Antonietta Robino, Serena Sanna, Hein Schepers, Jonathan Stephens, Joban Sehmi, Beverley Balkau, Jennifer G. Sambrook, Lucia Perseu, Ilja M. Nolte, Herman H W Silljé, John M. Starr, Cinzia Sala, Peter P. Pramstaller, David M. Evans, Renzo Galanello, Uwe Völker, Philippe Froguel, Dorret I. Boomsma, Vasiliki Lagou, Gerjan Navis, Christian Gieger, Susan M. Ring, Alexander Teumer, Angela Döring, Ale Algra, Toshiko Tanaka, Bo Hedblad, Anneli Pouta, Unnur Thorsteinsdottir, Bernhard R. Winkelmann, Liming Liang, John Danesh, Paolo Gasparini, Sarah E. Medland, Ian J. Deary, Martin Gögele, Pim van der Harst, Giorgia Girotto, Josef M. Penninger, Jaspal S. Kooner, Patrick Sulem, Thomas Illig, Yasin Memari, Sarah E. Harris, Wiek H. van Gilst, Francesco Cucca, Dirk J. van Veldhuisen, So-Youn Shin, Giorgio Pistis, Olli T. Raitakari, Lude Franke, Folkert W. Asselbergs, Abtehale Al-Hussani, Stanley L. Hazen, Manuel A. R. Ferreira, Aimo Ruokonen, Christian Dina, Aparna Radhakrishnan, Irene Mateo Leach, Nicholas J. Wareham, George Davey Smith, Eric E. Schadt, Alan R. Shuldiner, John Whitfield, Gudmundur I. Eyjolfsson, Eco J. C. de Geus, Grant W. Montgomery, Afshin Parsa, Terho Lehtimäki, Paolo Fortina, Luigi Ferrucci, Andreas Greinacher, Marjo-Riitta Järvelin, Krista Fischer, Fabrice Danjou, Rudolf A. de Boer, Paul I.W. de Bakker, Peter M. Visscher, Anna F. Dominiczak, Ramiro Ramirez-Solis, Jennifer Jolley, Bruce H. R. Wolffenbuttel, Jaana Hartiala, Daniela Toniolo, Bernhard O. Boehm, van der Harst, P, Zhang, W, Mateo Leach, I, Rendon, A, Verweij, N, Sehmi, J, Paul, D, Elling, U, Allayee, H, Li, X, Radhakrishnan, A, Tan, St, Voss, K, Weichenberger, Cx, Albers, Ca, Al Hussani, A, Asselbergs, Fw, Ciullo, M, Danjou, F, Dina, C, Esko, T, Evans, Dm, Franke, L, Gögele, M, Hartiala, J, Hersch, M, Holm, H, Hottenga, Jj, Kanoni, S, Kleber, Me, Lagou, V, Langenberg, C, Lopez, Lm, Lyytikäinen, Lp, Melander, O, Murgia, F, Nolte, Im, O'Reilly, Pf, Padmanabhan, S, Parsa, A, Pirastu, Nicola, Porcu, E, Portas, L, Prokopenko, I, Ried, J, Shin, Sy, Tang, C, Teumer, A, Traglia, Michela, Ulivi, S, Westra, Hj, Yang, J, Zhao, Jh, Anni, F, Abdellaoui, A, Attwood, A, Balkau, B, Bandinelli, S, Bastardot, F, Benyamin, B, Boehm, Bo, Cookson, Wo, Das, D, de Bakker, Pi, de Boer, Ra, de Geus, Ej, de Moor, Mh, Dimitriou, M, Domingues, F, Döring, A, Engström, G, Eyjolfsson, Gi, Ferrucci, L, Fischer, K, Galanello, R, Garner, Sf, Genser, B, Gibson, Qd, Girotto, Giorgia, Gudbjartsson, Df, Harris, Se, Hartikainen, Al, Hastie, Ce, Hedblad, B, Illig, T, Jolley, J, Kähönen, M, Kema, Ip, Kemp, Jp, Liang, L, Lloyd Jones, H, Loos, Rj, Meacham, S, Medland, Se, Meisinger, C, Memari, Y, Mihailov, E, Miller, K, Moffatt, Mf, Nauck, M, Novatchkova, M, Nutile, T, Olafsson, I, Onundarson, Pt, Parracciani, D, Penninx, Bw, Perseu, L, Piga, A, Pistis, G, Pouta, A, Puc, U, Raitakari, O, Ring, Sm, Robino, Antonietta, Ruggiero, D, Ruokonen, A, Saint Pierre, A, Sala, C, Salumets, A, Sambrook, J, Schepers, H, Schmidt, Co, Silljé, Hh, Sladek, R, Smit, Jh, Starr, Jm, Stephens, J, Sulem, P, Tanaka, T, Thorsteinsdottir, U, Tragante, V, van Gilst, Wh, van Pelt, Lj, van Veldhuisen, Dj, Völker, U, Whitfield, Jb, Willemsen, G, Winkelmann, Br, Wirnsberger, G, Algra, A, Cucca, F, D'Adamo, ADAMO PIO, Danesh, J, Deary, Ij, Dominiczak, Af, Elliott, P, Fortina, P, Froguel, P, Gasparini, Paolo, Greinacher, A, Hazen, Sl, Jarvelin, Mr, Khaw, Kt, Lehtimäki, T, Maerz, W, Martin, Ng, Metspalu, A, Mitchell, Bd, Montgomery, Gw, Moore, C, Navis, G, Pirastu, M, Pramstaller, Pp, Ramirez Solis, R, Schadt, E, Scott, J, Shuldiner, Ar, Smith, Gd, Smith, Jg, Snieder, H, Sorice, R, Spector, Td, Stefansson, K, Stumvoll, M, Tang, Wh, Toniolo, D, Tönjes, A, Visscher, Pm, Vollenweider, P, Wareham, Nj, Wolffenbuttel, Bh, Boomsma, Di, Beckmann, J, Dedoussis, Gv, Deloukas, P, Ferreira, Ma, Sanna, S, Uda, M, Hicks, Aa, Penninger, Jm, Gieger, C, Kooner, J, Ouwehand, Wh, Soranzo, N, Chambers, J. C., Psychiatry, EMGO - Mental health, NCA - Anxiety & Depression, Biological Psychology, Neuroscience Campus Amsterdam - Anxiety & Depression, EMGO+ - Mental Health, Van Der Harst, Pim, Zhang, Weihua, Mateo Leach, Irene, Rendon, Augusto, Benyamin, Beben, Chambers, John C, Cardiovascular Centre (CVC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Lifestyle Medicine (LM), Stem Cell Aging Leukemia and Lymphoma (SALL), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), and Center for Liver, Digestive and Metabolic Diseases (CLDM)
Subjects: Male, Netherlands Twin Register (NTR), Candidate gene, Erythrocytes, PROTEIN, Genome-wide association study, DISEASE, Hemoglobins, Mice, 0302 clinical medicine, Genetics, Genomics, blood, 0303 health sciences, Multidisciplinary, biology, Cell Cycle, COMMON VARIANTS, Genomics, Phenotype, anemia, 3. Good health, Haematopoiesis, DROSOPHILA, Drosophila melanogaster, medicine.anatomical_structure, HEMOGLOBIN LEVELS, Organ Specificity, 030220 oncology & carcinogenesis, Cytokines, Female, RNA Interference, TRAITS, Signal Transduction, EXPRESSION, Polymorphism, Single Nucleotide, Article, Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory [IGMD 3], 03 medical and health sciences, SDG 3 - Good Health and Well-being, Genetic, blood, medicine, Animals, Humans, GENOME-WIDE ASSOCIATION, 030304 developmental biology, RECEPTOR, CONSORTIUM, ta3121, hemoglobin, biology.organism_classification, Hematopoiesis, meta-analysis, Red blood cell, Gene Expression Regulation, Genetic Loci, Expression quantitative trait loci, genome-wide association studies, Genome-Wide Association Study
Abstract: Item does not contain fulltext Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10(-8), which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.
Published: 2012

40. Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile

Author: Peter Vollenweider, Ruth J. F. Loos, Sarah H. Wild, Unnur Styrkarsdottir, Talin Haritunians, Christian Gieger, Gudmar Thorleifsson, Mao Fu, Stephen O'Rahilly, Markku Laakso, Steve E. Humphries, Braxton D. Mitchell, Mika Kivimäki, John C. Chambers, Yanhua Zhou, Cornelia M. van Duijn, Samuli Ripatti, Robert Luben, Jing Hua Zhao, Veikko Salomaa, Tatjana Škarić-Jurić, José Manuel Fernández-Real, Vilmundur Gudnason, Jeffery R. O'Connell, Robert C. Kaplan, Emmi Tikkanen, Elizabeth K. Speliotes, Sailaja Vedantam, Leonie C. Jacobs, Caroline Hayward, Östen Ljunggren, Bo Isomaa, Albert Hofman, Unnur Thorsteinsdottir, Tuomas O. Kilpeläinen, Nicole L. Glazer, Ben A. Oostra, Vincent Mooser, Magnus Karlsson, Douglas P. Kiel, André G. Uitterlinden, Alan F. Wright, Gérard Waeber, Fernando Rivadeneira, H-Erich Wichmann, Angela Döring, Tamara B. Harris, Leif Groop, Gudny Eiriksdottir, Nicole Soranzo, Philippa J. Talmud, Claes Ohlsson, Erik Ingelsson, Nicholas J. Wareham, Kari Stefansson, Ci Song, Robert K. Semple, Bruce M. Psaty, David B. Savage, Harry Campbell, Meena Kumari, Norman Klopp, Alena Stančáková, Antti Jula, Alice M. Arnold, Najaf Amin, Bjarni V. Halldorsson, Laura Pascoe, Yongmei Liu, Karol Estrada, Mark Walker, Ann-Christine Syvänen, Jaspal S. Kooner, James F. Wilson, Belén Peral, Mary F. Feitosa, Johanna Kuusisto, Melissa Garcia, L. Adrienne Cupples, Albert V. Smith, Tim D. Spector, John-Olov Jansson, Candace Guiducci, Joel N. Hirschhorn, Alan R. Shuldiner, Inês Barroso, Francis M. Finucane, Deborah J. Clegg, Ingrid B. Borecki, Weihua Zhang, Kathryn Davis, Massimo Mangino, Caroline S. Fox, So-Youn Shin, Leena Peltonen, Lauren J. Kim, Eric E. Schadt, Kijoung Song, José María Moreno, Mattias Lorentzon, Gunnar Sigurdsson, Kay-Tee Khaw, Claudia Langenberg, Markus Perola, Liesbeth Vandenput, Jacques S. Beckmann, Barbara McKnight, Satu Männistö, Antonio Vidal-Puig, Igor Rudan, Brigitte Kühnel, Jian'an Luan, Yurii S. Aulchenko, Dan Mellström, M. Carola Zillikens, Janina S. Ried, David Karasik, Internal Medicine, Epidemiology, Clinical Genetics, and Dermatology
Subjects: Male, medicine.medical_specialty, Adiponectin/blood, Adiposity/genetics, Alleles, Body Fat Distribution, Body Mass Index, Body Weight, Female, Genetic Variation/genetics, Genome-Wide Association Study, Humans, Insulin Receptor Substrate Proteins/genetics, Intracellular Signaling Peptides and Proteins/genetics, Meta-Analysis as Topic, Metabolome/genetics, Obesity/genetics, Polymorphism, Single Nucleotide/genetics, Subcutaneous Fat, IRS1, 030209 endocrinology & metabolism, Biology, Polymorphism, Single Nucleotide, FTO gene, Body fat percentage, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Insulin resistance, SDG 3 - Good Health and Well-being, Adipocyte, Internal medicine, Genetics, medicine, Obesity, Genetic variation, 10. No inequality, Adiposity, 030304 developmental biology, 2. Zero hunger, 0303 health sciences, Adiponectin, Intracellular Signaling Peptides and Proteins, Membrane Proteins, genome-wide association study, meta-analysis, fat distribution, adiposity, dyslipidemia, insulin resistance, medicine.disease, 3. Good health, Endocrinology, chemistry, Insulin Receptor Substrate Proteins, Metabolome, Body mass index, Dyslipidemia
Abstract: El pdf del artículo es el manuscrito de autor: PMC3262230.-- et al., Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between ~2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10−6) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 × 10−26) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 × 10−11) and one near SPRY2 (P = 3 × 10−8). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat–decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance., Funding was provided by Academy of Finland (10404, 124243, 129680, 129494, 141005 and 213506); Agency for Health Care Policy Research (HS06516); Althingi (the Icelandic Parliament); American Heart Association (10SDG269004); AstraZeneca; Baltimore Geriatric Research Education and Clinical Centers; Biocentrum Helsinki Foundation; Biotechnology and Biological Sciences Research Council (G20234); British Heart Foundation (PG/07/133/24260, RG/08/008, SP/04/002, SP/07/007/23671); CamStrad; Cancer Research UK; Cedars-Sinai Board of Governors’ Chair in Medical Genetics; Centre for Medical Systems Biology (The Netherlands); Centre Hospitalier Universitaire Vaudois (Lausanne); Croatian Ministry of Science, Education and Sport (196-1962766-2747, 216-1080315-0302 and 309-0061194-2023); Department of Health (UK); Department of Veterans Affairs (USA); Emil and Vera Cornell Foundation; Erasmus Medical Center (Rotterdam); Erasmus University (Rotterdam); European Commission (DG XII, FP7/2007-2013, FP7-KBBE-2010-4-266408, HEALTH-F2-2007-201681, HEALTH-F2-2008-201865-GEFOS, HEALTH-F4-2007-201413, HEALTH-F4-2007-201550, LSHG-CT-2006-018947, LSHG-CT-2006-01947, LSHM-CT-2003-503041, LSHM-CT-2004-512013, QLG1-CT-2001-01252 and QLG2-CT-2002-01254), Finnish Diabetes Foundation; Finnish Diabetes Research Foundation; Finnish Foundation for Cardiovascular Research; Finnish Heart Foundation; Finnish Medical Society; Folkhälsan Research Foundation; Food Standards Agency (UK); Foundation for Life and Health in Finland; German Bündesministerium für Forschung und Technology (01AK803A-H and 01IG07015G); German Federal Ministry of Education and Research; German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823); Giorgi-Cavaglieri Foundation; GlaxoSmithKline; Göteborg Medical Society; Gyllenberg Foundation; Health and Safety Executive (UK); Health Care Centers in Vasa, Närpes and Korsholm; Hjartavernd (the Icelandic Heart Association); John D. and Catherine T. MacArthur Foundation; Knut and Alice Wallenberg Foundation; Leenaards Foundation; Ludwig-Maximilians Universität München; Lundberg Foundation; Medical Research Council (UK); Men’s Associates of Hebrew SeniorLife; Ministerio de Ciencia e Innovación (Spain) (SAF-2009 and SAF-2008-02073); Ministry for Health, Welfare and Sports (The Netherlands); Ministry of Education (Finland); Ministry of Education, Culture and Science (The Netherlands); Municipal Health Care Center and Hospital in Jakobstad; Municipality of Rotterdam; Närpes Health Care Foundation; National Institute for Health Research (UK); US National Institutes of Health (USA) (AG13196, DK063491, K23-DK080145, M01-RR00425, N01-AG12100, N01-AG62101, N01-AG62103, N01-AG62106, N01-HC15103, N01-HC25195, N01-HC35129, N01-HC45133, N01-HC55222, N01-HC75150, N01- HC85079 through N01-HC85086, P30-DK072488, R01-AG031890-01, R01-AG18728, R01-AG032098-01A1, R01-AR/AG41398, R01-AR046838, R01-DK06833603, R01-DK075787, R01-DK07568102, R01-HL036310-20A2, R01-HL087652, R01-HL08770003, R01-HL088119, U01-HL080295, U01-HL72515 and U01-HL84756); Netherlands Genomics Initiative/Netherlands Consortium for Healthy Aging (050-060-810); Netherlands Organisation for Scientific Research (175.010.2005.011 and 911-03-012); Netherlands Organization for the Health Research and Development; Nordic Center of Excellence in Disease Genetics; Novo Nordisk Foundation; Ollqvist Foundation; Paavo Nurmi Foundation; Perklén Foundation; Petrus and Augusta Hedlunds Foundation; Research Institute for Diseases in the Elderly (014-93-015; RIDE2); Robert Dawson Evans Endowment; Royal Society (UK); Sahlgrenska Center for Cardiovascular and Metabolic Research (A305:188); Sahlgrenska University Hospital Foundation (ALF/LUA); Science Funding programme (UK); Scottish Executive Health Department; Sigrid Juselius Foundation; State of Bavaria; Stroke Association (UK); Swedish Cultural Foundation in Finland; Swedish Foundation for Strategic Research; Swedish Research Council (K2010-54X-09894-19-3, K2010-52X-20229-05-3 and 2006-3832); Swedish Strategic Foundation; Swiss Institute of Bioinformatics; Swiss National Science Foundation (3100AO-116323/1, 310000-112552 and 33CSCO-122661); TEKES (1510/31/06); Torsten and Ragnar Söderberg’s Foundation; United Kingdom NIHR Cambridge Biomedical Research Centre; University of Lausanne; University of Maryland General Clinical Research Center (M01 RR 16500); Uppsala University; Västra Götaland Foundation; and Wellcome Trust (077016/Z/05/Z, 084723/Z/08/Z and 091746/Z/10/Z).
Published: 2011

41. Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus

Author: Stephen W. Scherer, Mònica Gratacòs, Kari Stefansson, Muriel Holder, Unnur Thorsteinsdottir, Lukas Forer, Katharina M. Roetzer, Josette Lucas, Claudia Schurmann, Satu Kaksonen, Armand Valsesia, Carina Wallgren-Pettersson, Barbara Leube, Alexandra I. F. Blakemore, Alexandre Moerman, Marco Belfiore, Anne Faudet, Dominique Gaillard, Roberto Ravazzolo, Dominique Bonneau, Marjo-Riitta Järvelin, Yongguo Yu, Louis Vallée, Bénédicte Demeer, Sophie Visvikis-Siest, Frédérique Béna, Brigitte H. W. Faas, Benoit Arveiler, Georg Homuth, Charles Coutton, Bénédicte de Fréminville, Giorgio Gimelli, Xavier Estivill, Richard I. Fisher, Stefania Gimelli, Wendy Roberts, Jacques S. Beckmann, Emilie Landais, Orah S. Platt, Robin G. Walters, Gudmar Thorleifsson, Alexandre Reymond, Anna-Liisa Hartikainen, Solenn Legallic, James F. Gusella, Peter Vollenweider, Gian Paolo Ramelli, Tõnu Esko, Boris Keren, Nine V A M Knoers, Fanny Morice-Picard, Dominique Campion, Odile Boute, Evica Rajcan-Separovic, Rolph Pfundt, Nathalie Bednarek, Martine Doco-Fenzy, Suzanne M E Lewis, Gérard Didelot, Mylène Beri, Engilbert Sigurdsson, Véronique Satre, Audrey Labalme, Carola Tengstrom, Florian Kronenberg, Florence Petit, Simon Zwolinksi, Philippe Froguel, Paul Elliott, Dorothée Cailley, Christian R. Marshall, Bruno Leheup, Klaus Dieterich, Janina S. Ried, Sylvie Jaillard, Armand Bottani, Stylianos E. Antonarakis, Elisabetta Lapi, Jean-Christophe Cuvellier, Robert M. Witwicki, Gérard Waeber, Christèle Dubourg, Marion Gérard, Lachlan J. M. Coin, Magalie Barth, Anita Kloss-Brandstätter, Vincent Mooser, Cristóbal Richart, Giuseppe Merla, Bénédicte Duban-Bedu, Yiping Shen, Ants Kurg, Audrey Guilmatre, Juliane Hoyer, Susana Jiménez-Murcia, Mafalda Mucciolo, Bai-Lin Wu, Alessandra Ferrarini, Séverine Drunat, Yves Alembik, Páll Magnússon, Han G. Brunner, Maria Antonietta Mencarelli, Dominique Descamps, R. Frank Kooy, Azzedine Aboura, Valérie Layet, Sven Bergmann, Thomas Meitinger, Peter M. Kroisel, Nathalie Van der Aa, Olivier Guillin, Michèle Mathieu-Dramard, Zoltán Kutalik, Elisabeth Flori, Laurent Pasquier, André Reis, Noam D. Beckmann, Bertrand Isidor, Delphine Héron, Philippe Jonveaux, Sergi Villatoro Gomez, Ann Nordgren, José Manuel Fernández-Real, Florence Fellmann, Fernando Fernández-Aranda, Laurence Faivre, Dimitri J. Stavropoulos, Katrin Männik, Christian Gieger, Evald Saemundsen, Agnès Guichet, Jean-Marie Cuisset, R. Touraine, Laura Bernardini, Marie-Ange Delrue, Alessandra Renieri, Omar Gustafsson, Flore Zufferey, David A. Koolen, Massimiliano Rossi, Jacqueline Chrast, Ghislaine Plessis, Faida Walha, Joris Andrieux, Ellen van Binsbergen, Albert David, Catherine Vincent-Delorme, Cédric Le Caignec, Jean Chiesa, Ndeye Coumba Ndiaye, Geraldine Joly Helas, Damien Sanlaville, Anita Rauch, Louise Harewood, Mark I. McCarthy, Bridget A. Fernandez, Sébastien Jacquemont, Hreinn Stefansson, Anneke T. Vulto-van Silfhout, Zdenek Jaros, Matthias Nauck, Hans J. Grabe, Sonia Bouquillon, Mieke M. van Haelst, Andres Metspalu, Loyse Hippolyte, Patrick Callier, Bert B.A. de Vries, Francisco J. Tinahones, Nicole de Leeuw, Julia S. El-Sayed Moustafa, Claudine Rieubland, Kay D. MacDermot, Vittoria Disciglio, Henry Völzke, Caroline Rooryck, Bettina Blaumeiser, Danielle Martinet, Marie-Claude Addor, Bruno Delobel, Jacquemont, S, Reymond, A, Zufferey, F, Harewood, L, Walters, Rg, Kutalik, Z, Martinet, D, Shen, Y, Valsesia, A, Beckmann, Nd, Thorleifsson, G, Belfiore, M, Bouquillon, S, Campion, D, de Leeuw, N, de Vries, Bb, Esko, T, Fernandez, Ba, Fernández-Aranda, F, Fernández-Real, Jm, Gratacòs, M, Guilmatre, A, Hoyer, J, Jarvelin, Mr, Kooy, Rf, Kurg, A, Le Caignec, C, Männik, K, Platt, O, Sanlaville, D, Van Haelst, Mm, Villatoro Gomez, S, Walha, F, Wu, Bl, Yu, Y, Aboura, A, Addor, Mc, Alembik, Y, Antonarakis, Se, Arveiler, B, Barth, M, Bednarek, N, Béna, F, Bergmann, S, Beri, M, Bernardini, L, Blaumeiser, B, Bonneau, D, Bottani, A, Boute, O, Brunner, Hg, Cailley, D, Callier, P, Chiesa, J, Chrast, J, Coin, L, Coutton, C, Cuisset, Jm, Cuvellier, Jc, David, A, de Freminville, B, Delobel, B, Delrue, Ma, Demeer, B, Descamps, D, Didelot, G, Dieterich, K, Disciglio, V, Doco-Fenzy, M, Drunat, S, Duban-Bedu, B, Dubourg, C, El-Sayed Moustafa, J, Elliott, P, Faas, Bh, Faivre, L, Faudet, A, Fellmann, F, Ferrarini, A, Fisher, R, Flori, E, Forer, L, Gaillard, D, Gerard, M, Gieger, C, Gimelli, S, Gimelli, G, Grabe, Hj, Guichet, A, Guillin, O, Hartikainen, Al, Heron, D, Hippolyte, L, Holder, M, Homuth, G, Isidor, B, Jaillard, S, Jaros, Z, Jiménez-Murcia, S, Helas, Gj, Jonveaux, P, Kaksonen, S, Keren, B, Kloss-Brandstätter, A, Knoers, Nv, Koolen, Da, Kroisel, Pm, Kronenberg, F, Labalme, A, Landais, E, Lapi, E, Layet, V, Legallic, S, Leheup, B, Leube, B, Lewis, S, Lucas, J, Macdermot, Kd, Magnusson, P, Marshall, C, Mathieu-Dramard, M, Mccarthy, Mi, Meitinger, T, Mencarelli, Ma, Merla, G, Moerman, A, Mooser, V, Morice-Picard, F, Mucciolo, M, Nauck, M, Ndiaye, Nc, Nordgren, A, Pasquier, L, Petit, F, Pfundt, R, Plessis, G, Rajcan-Separovic, E, Ramelli, Gp, Rauch, A, Ravazzolo, R, Reis, A, Renieri, A, Richart, C, Ried, J, Rieubland, C, Roberts, W, Roetzer, Km, Rooryck, C, Rossi, M, Saemundsen, E, Satre, V, Schurmann, C, Sigurdsson, E, Stavropoulos, Dj, Stefansson, H, Tengström, C, Thorsteinsdóttir, U, Tinahones, Fj, Touraine, R, Vallée, L, van Binsbergen, E, Van der Aa, N, Vincent-Delorme, C, Visvikis-Siest, S, Vollenweider, P, Völzke, H, Vulto-van Silfhout, At, Waeber, G, Wallgren-Pettersson, C, Witwicki, Rm, Zwolinksi, S, Andrieux, J, Estivill, X, Gusella, Jf, Gustafsson, O, Metspalu, A, Scherer, Sw, Stefansson, K, Blakemore, Ai, Beckmann, J, Froguel, P, Faculteit Medische Wetenschappen/UMCG, Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), Department of Genomics of Common Disease, Imperial College London, Department of Medical Genetics, Université de Lausanne = University of Lausanne (UNIL), Laboratory Medicine, Boston Children's Hospital, Center for Human Genetic Research, Massachusetts General Hospital [Boston], Ludwig Institute for Cancer Research, deCODE Genetics, deCODE genetics [Reykjavik], Laboratoire de Génétique Médicale, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Estonian Genome and Medicine, University of Tartu, Department of human genetics, Radboud University Medical Center [Nijmegen]-Nijmegen Centre for Molecular Life Sciences-Institute for Genetic and Metabolic Disorders, Institute of Molecular and Cell Biology, Disciplines of Genetics and Medicine, Memorial University of Newfoundland = Université Memorial de Terre-Neuve [St. John's, Canada] (MUN), Department of Psychiatry (IDIBELL), CIBERobn Fisiopatología de la Obesidad y Nutrición-University Hospital of Bellvitge, Section of Diabetes, Endocrinology and Nutrition, University Hospital of Girona-Biomedical Research Institute 'Dr Josep Trueta'-CIBERobn Fisiopatología de la Obesidad y Nutrición, Center for Genomic Regulation (CRG-UPF), CIBER de Epidemiología y Salud Pública (CIBERESP), Institute of Human Genetics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Department of child and adolescent health, University of Oulu-Institute of Health Sciences and Biocenter Oulu-National Institute for Health and Welfare [Helsinki], Antwerp University Hospital [Edegem] (UZA), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, University Medical Center [Utrecht], Institutes of Biomedical Science, Fudan University [Shanghai]-Children's Hospital, Shanghai Children's Medical Center, Département de génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service de cytogénétique, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Génétique médicale, Hôpitaux Universitaires de Genève (HUG), Maladies Rares - Génétique et Métabolisme (MRGM), Université Bordeaux Segalen - Bordeaux 2-Hôpital Pellegrin-Service de Génétique Médicale du CHU de Bordeaux, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Université de Reims Champagne-Ardenne (URCA), Department of Molecular Genetics, Weizmann Institute of Science [Rehovot, Israël], Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Mendel Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), Service de Génétique clinique, Laboratoire de cytogénétique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire de Cytogénétique, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-faculté de médecine-pharmacie, AGeing and IMagery (AGIM), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biochimie et génétique moléculaire, CHU Grenoble, Service de Neuropédiatrie, Hôpital Roger Salengro [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de génétique, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre de Génétique Chromosomique, Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), CHU Amiens-Picardie, Centre Hospitalier de Béthune (CH Béthune), GHT de l'Artois, Service de Génétique Clinique, Department of Biotechnology, Università degli Studi di Siena = University of Siena (UNISI)-Medical Genetics, Service de Génétique, Centre Hospitalier Universitaire de Reims (CHU Reims)-Hôpital Maison Blanche-IFR 53, Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Department of Epidemiology and Public Health, Department of Human Genetics [Nijmegen], Radboud University Medical Center [Nijmegen], Department of Experimental Cardiology, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA)-Heart Failure Research Center (HFRC), CHU Pitié-Salpêtrière [AP-HP], Institute of human genetics, International Centre for Life, Division of genetic epidemiology, HMNC Brain Health-Molecular and Clinical Pharmacology-Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Institute of Experimental Medicine, Czech Academy of Sciences [Prague] (CAS), Department of Obstetrics and Gynecology, University of Oulu-Institute of Clinical Medicine, Laboratorio di citogenetica, G. Gaslini Institute, Department of Psychiatry and Psychotherapy, Universität Greifswald - University of Greifswald, Interfaculty Institute for Genetics and Functional Genomics, Abteilung für Kinder und Jugendheilkunde, Landesklinikum Waldviertel Zwettl, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), The Habilitation Unit of Folkhalsan, Medical University Graz, Medical Genetics Unit, Children's Hospital Anna Meyer, Unité de Cytogénétique et Génétique Médicale, Groupe Hospitalier du Havre-Hôpital Gustave Flaubert, Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], Institute of Human Genetics and Anthropology, Heinrich-Heine University Hospital Duesseldorf, Child and Family Research Institute-University of British Columbia (UBC), North West Thames Regional Genetics Service, Northwick Park & St Marks Hospital, Child and Adolescent Psychiatry, Landspitali University Hospital, Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, The Wellcome Trust Centre for Human Genetics [Oxford], Institute of Human Genetics, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz Zentrum München = German Research Center for Environmental Health, Genetics, GlaxoSmithKline R&D, GlaxoSmithKline, Institute of Clinical Chemistry and Laboratory Medicine, Génétique cardiovasculaire (GC), Université Henri Poincaré - Nancy 1 (UHP), Molecular Medicine and Surgery department, Karolinska Institutet [Stockholm], Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Department of Pathology, Division of pediatrics, Ospedale San Giovanni, Institute of Medical Genetics, Universität Zürich [Zürich] = University of Zurich (UZH), Department of pediatrics and CEBR, Università degli studi di Genova = University of Genoa (UniGe)-G. Gaslini Institute, Department of Internal Medicine, Universitat Rovira i Virgili-University Hospital Juan XXIII-Instituto Salud Carlos III-Ciber Fisiopatologia Obesidad y Nutricion (CIBEROBN), Division of Human Genetics, Department of Paediatrics, Inselspital-University of Bern, Autism Research Unit, The Hospital for sick children [Toronto] (SickKids)-University of Toronto, State Diagnostic, Counseling Center, University of Iceland [Reykjavik], Department of Pediatric Laboratory Medicine, Hospital for Sick Children, Genetic Services, Rinnekoti Research Foundation, Department of Endocrinology and Nutrition, Instituto Salud Carlos III-Clinic Hospital of Virgen de la Victoria-Ciber Fisiopatologia y Nutricion (CIBEROBN), Centre de Maladies Rares, Anomalies du Développement Nord de France-CH Arras - CHRU Lille, Institute for Community Medicine, Department of Medical and Clinical Genetics [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, The Centre for Applied Genomics, Toronto, The Hospital for sick children [Toronto] (SickKids)-University of Toronto-Department of Molecular Genetics-McLaughlin Centre, Institut de biologie de Lille - UMS 3702 (IBL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Leenaards Foundation Prize (SJ, DM and AR), the Jérôme Lejeune Foundation (AR), the Telethon Action Suisse Foundation (AR), the Swiss National Science Foundation (AR, JSB, SB and SEA), a SNSF Sinergia grant (SJ, DM, SB, JSB and AR), the European Commission anEUploidy Integrated Project grant 037627 (AR, SB, XE, HGB and SEA), the Ludwig Institute for Cancer Research (AV), the Swiss Institute of Bioinformatics (SB, ZK), an Imperial College Dept of Medicine PhD studentship (JSe-SM), the Comprehensive Biomedical Research Centre, Imperial College Healthcare NHS Trust, and the National Institute for Health Research (PE), the Wellcome Trust and the Medical Research Council (AIFB and PF), the Instituto de Salud Carlos III (ISCIII)-FIS, the German Mental Retardation Network funded through a grant of the German Federal Ministry of Education and Research (NGFNplus 01GS08160) to A Reis and European Union-FEDER (PI081714, PS09/01778), SAF2008-02278 (XE, MG, FFA), the Belgian National Fund for Scientific Research - Flanders (NVA, RFK), the Dutch Organisation for Health Research and Development (ZONMW grant 917-86-319) and Hersenstichting Nederland (BBAdV), grant 81000346 from the Chinese National Natural Science Foundation (YGY), the Simons Foundation Autism Research Initiative, Autism Speaks and NIH grant GM061354 (JFG), and the OENB grant 13059 (AK-B). YS holds a Young Investigator Award from the Children's Tumor Foundation and Catalyst Award from Harvard Medical School, and BLW, a Fudan Scholar Research Award from Fudan University, a grant from Chinese National '973' project on Population and Health (2010CB529601) and a grant from Science and Technology Council of Shanghai (09JC1402400). ERS and SL, recipients of the Michael Smith Foundation for Health Research Scholar award, acknowledge the CIHR MOP 74502 operational grant. EGCUT received support from the EU Centre of Excellence in Genomics and FP7 grants #201413 and #245536, from Estonian Government SF0180142s08, SF0180026s09 and SF0180027s10 (AM, KM, AK). The Helmholtz Zentrum Munich and the State of Bavaria financed KORA, also supported by the German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823), the German Federal Ministry of Education and Research (BMBF), and the Munich Center of Health Sciences (MC Health, LMUinnovativ). CIBEROBN and CIBERESP are initiatives of ISCIII (Spain). SWS holds the GlaxoSmithKline-Canadian Institutes of Health (CIHR) Chair in Genetics, Genomics at the University of Toronto and the Hospital for Sick Children and is supported by Genome Canada and the McLaughlin Centre. deCODE was funded in part by NIH grant MH071425 (KS), EU grant HEALTH-2007-2.2.1-10-223423 (Project PsychCNV) and EU grant IMI-JU-NewMeds., Centre de génomique intégrative, Université de Lausanne (UNIL), Swiss Institute of Bioinformatics (SIB), Swiss Institute of Bioinformatics, Memorial University of Newfoundland [St. John's], Friedrich Alexander University [Erlangen-Nürnberg], Service d'ORL et de Chirurgie Cervicofaciale, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Weizmann Institute of Science, IRCCS Casa Sollievo della Sofferenza Hospital, Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE)-Centre National de la Recherche Scientifique (CNRS), Hôpital Roger Salengro-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Saint-Etienne-Hôpital nord, Hôpital Saint Vincent de Paul-GHICL, Centre hospitalier de Béthune, Università degli Studi di Siena (UNISI)-Medical Genetics, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140-Centre National de la Recherche Scientifique (CNRS), Department of Human Genetics, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Innsbruck Medical University [Austria] (IMU)-HMNC Brain Health-Molecular and Clinical Pharmacology, Czech Academy of Sciences [Prague] (ASCR), University of Oxford [Oxford], Technische Universität München [München] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, University of Zürich [Zürich] (UZH), Universita degli studi di Genova -G. Gaslini Institute, University of Toronto-The Hospital for Sick Children, University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, University of Toronto-The Hospital for Sick Children-Department of Molecular Genetics-McLaughlin Centre, Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), De Villemeur, Hervé, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE), Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland., Other departments, Reymond, Alexandre, Antonarakis, Stylianos, Sloan Bena, Frédérique, Bottani, Armand, Callier, Patrick, Gimelli, Stefania, Merla, Giuseppe, Vollenweider, Peter, Université de Lausanne (UNIL)-Université de Lausanne (UNIL), Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Joseph Fourier - Grenoble 1 (UJF)-Université Pierre Mendès France - Grenoble 2 (UPMF), Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), University of Toronto-The Hospital for sick children [Toronto] (SickKids)-Department of Molecular Genetics-McLaughlin Centre, Université de Lille-Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Aging, Transcription, Genetic, Adolescent, Adult, Aged, Body Height, Body Mass Index, Case-Control Studies, Child, Child, Preschool, Chromosomes, Human, Pair 16, Cohort Studies, Comparative Genomic Hybridization, Developmental Disabilities, Energy Metabolism, Europe, Female, Gene Dosage, Gene Duplication, Gene Expression Profiling, Genetic Predisposition to Disease, Genome-Wide Association Study, Head, Heterozygote, Humans, Infant, Infant, Newborn, Mental Disorders, Middle Aged, Mutation, North America, Obesity, Phenotype, RNA, Messenger, Sequence Deletion, Thinness, Young Adult, Physiology, RNA, Messenger/analysis/genetics, Genome-wide association study, HIDDEN-MARKOV MODEL, 0302 clinical medicine, Sequence Deletion/genetics, ddc:576.5, 0303 health sciences, education.field_of_study, Body Height/genetics, Genetic Predisposition to Disease/genetics, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, population characteristics, Chromosomes, Human, Pair 16/genetics, Human, Locus (genetics), Gene Duplication/genetics, Article, 03 medical and health sciences, Genetic, education, SNP GENOTYPING DATA, Thinness/genetics, [SDV.GEN]Life Sciences [q-bio]/Genetics, Pair 16, Case-control study, nutritional and metabolic diseases, social sciences, medicine.disease, DEPENDENT PROBE AMPLIFICATION, Human medicine, Body mass index, 030217 neurology & neurosurgery, Messenger, Obesity/genetics, FAILURE-TO-THRIVE, [SDV.GEN] Life Sciences [q-bio]/Genetics, Head/anatomy & histology, METABOLIC SYNDROME, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 2. Zero hunger, Genetics, Multidisciplinary, TIME QUANTITATIVE PCR, Failure to thrive, medicine.symptom, Underweight, Transcription, geographic locations, Mutation/genetics, Population, Biology, Chromosomes, 150 000 MR Techniques in Brain Function, medicine, Preschool, 030304 developmental biology, COPY NUMBER VARIATION, Mental Disorders/genetics, Energy Metabolism/genetics, RELATIVE QUANTIFICATION, Gene Dosage/genetics, Newborn, BODY-MASS INDEX, CIRCULAR BINARY SEGMENTATION, RNA, Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6], human activities, Developmental Disabilities/genetics
Abstract: To access publisher full text version of this article. Please click on the hyperlink in Additional Links field. Both obesity and being underweight have been associated with increased mortality. Underweight, defined as a body mass index (BMI) ≤ 18.5 kg per m(2) in adults and ≤ -2 standard deviations from the mean in children, is the main sign of a series of heterogeneous clinical conditions including failure to thrive, feeding and eating disorder and/or anorexia nervosa. In contrast to obesity, few genetic variants underlying these clinical conditions have been reported. We previously showed that hemizygosity of a ∼600-kilobase (kb) region on the short arm of chromosome 16 causes a highly penetrant form of obesity that is often associated with hyperphagia and intellectual disabilities. Here we show that the corresponding reciprocal duplication is associated with being underweight. We identified 138 duplication carriers (including 132 novel cases and 108 unrelated carriers) from individuals clinically referred for developmental or intellectual disabilities (DD/ID) or psychiatric disorders, or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight and BMI. Half of the boys younger than five years are underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers have an 8.3-fold increased risk of being clinically underweight. We observe a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive eating behaviours and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlate with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiologies, possibly through contrasting effects on energy balance. Leenaards Foundation Jerome Lejeune Foundation Telethon Action Suisse Foundation Swiss National Science Foundation European Commission 037627 QLG1-CT-2000-01643 Ludwig Institute for Cancer Research Swiss Institute of Bioinformatics Imperial College Department of Medicine Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust National Institute for Health Research Wellcome Trust Medical Research Council Instituto de Salud Carlos III (ISCIII)-FIS German Mental Retardation Network German Federal Ministry of Education and Research NGFNplus 01GS08160 European Union PI081714 PS09/01778 201413 245536 info:eu-repo/grantAgreement/EC/FP7/223423 Belgian National Fund for Scientific Research, Flanders Dutch Organisation for Health Research and Development (ZON-MW) 917-86-319 Hersenstichting Nederland (B.B.A.d.V.) Chinese National Natural Science Foundation 81000346 Simons Foundation Autism Research Initiative Autism Speaks NIH GM061354 MH071425 Oesterreichische Nationalbank (OENB) 13059 Children's Tumor Foundation Harvard Medical School Fudan University Chinese National '973' project on Population and Health 2010CB529601 Science and Technology Council of Shanghai 09JC1402400 Michael Smith Foundation for Health CIHR MOP 74502 Estonian Government SF0180142s08 SF0180026s09 SF0180027s10 Helmholtz Zentrum Munich State of Bavaria German National Genome Research Network 01GS0823 German Federal Ministry of Education and Research (BMBF) Munich Center of Health Sciences (MC Health, LMUinnovativ) Genome Canada McLaughlin Centre Academy of Finland 104781 120315 129269 1114194 University Hospital Oulu Biocenter University of Oulu, Finland 75617 NHLBI 5R01HL087679-02 1RL1MH083268-01 NIH/NIMH 5R01MH63706:02 ENGAGE project Medical Research Council, UK G0500539 G0600705 Academy of Finland Biocentrum Helsinki SAF2008-02278 HEALTH-F4-2007-201413
Published: 2011

42. Genome-Wide Association Study Identifies Two Novel Regions at 11p15.5-p13 and 1p31 with Major Impact on Acute-Phase Serum Amyloid A

Author: H.-Erich Wichmann, Marcus E. Kleber, Janina S. Ried, Peter Kovacs, Wolfgang Koenig, Pirro G. Hysi, Katharina Heim, Bernhard O. Boehm, Massimo Mangino, Barbara Thorand, Hannah Blackburn, Thomas Illig, Vasiliki Lagou, Carola Marzi, Melanie Waldenberger, Anke Tönjes, Christopher J Hammond, Ludwig Geistlinger, Nicole Soranzo, Christian Gieger, Annette Peters, Eva Albrecht, Michael Stumvoll, Tim D. Spector, Bernhard R. Winkelmann, Winfried März, Inga Prokopenko, Harald Grallert, and Holger Prokisch
Subjects: Male, Cancer Research, medicine.medical_specialty, lcsh:QH426-470, Lactate dehydrogenase A, Population, 030204 cardiovascular system & hematology, Biology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Meta-Analysis as Topic, Internal medicine, Lactate dehydrogenase, Genetics, medicine, Humans, Genetic Predisposition to Disease, Serum amyloid A, education, Molecular Biology, Genetics (clinical), Ecology, Evolution, Behavior and Systematics, Serum Amyloid A Protein, 030304 developmental biology, 0303 health sciences, education.field_of_study, 0604 Genetics, Leptin receptor, Amyloidosis, Chromosomes, Human, Pair 11, Serum amyloid A1, medicine.disease, 3. Good health, lcsh:Genetics, Endocrinology, chemistry, Chromosomes, Human, Pair 1, Genetics and Genomics/Gene Discovery, Genetics and Genomics/Genetics of the Immune System, Female, Developmental Biology, Research Article, Genome-Wide Association Study
Abstract: Elevated levels of acute-phase serum amyloid A (A-SAA) cause amyloidosis and are a risk factor for atherosclerosis and its clinical complications, type 2 diabetes, as well as various malignancies. To investigate the genetic basis of A-SAA levels, we conducted the first genome-wide association study on baseline A-SAA concentrations in three population-based studies (KORA, TwinsUK, Sorbs) and one prospective case cohort study (LURIC), including a total of 4,212 participants of European descent, and identified two novel genetic susceptibility regions at 11p15.5-p13 and 1p31. The region at 11p15.5-p13 (rs4150642; p = 3.20×10−111) contains serum amyloid A1 (SAA1) and the adjacent general transcription factor 2 H1 (GTF2H1), Hermansky-Pudlak Syndrome 5 (HPS5), lactate dehydrogenase A (LDHA), and lactate dehydrogenase C (LDHC). This region explains 10.84% of the total variation of A-SAA levels in our data, which makes up 18.37% of the total estimated heritability. The second region encloses the leptin receptor (LEPR) gene at 1p31 (rs12753193; p = 1.22×10−11) and has been found to be associated with CRP and fibrinogen in previous studies. Our findings demonstrate a key role of the 11p15.5-p13 region in the regulation of baseline A-SAA levels and provide confirmative evidence of the importance of the 1p31 region for inflammatory processes and the close interplay between A-SAA, leptin, and other acute-phase proteins., Author Summary An elevated level of acute-phase serum amyloid A (A-SAA), a sensitive marker of the acute inflammatory state with high heritability estimates, causes amyloidosis and is a risk factor for atherosclerosis and its clinical complications, type 2 diabetes, as well as various malignancies. This study describes the first genome-wide association study on baseline A-SAA concentrations. In a meta-analysis of four genome-wide scans totalling 4,212 participants of European descent, we identified two novel genetic susceptibility regions on chromosomes 11 and 1 to be associated with baseline A-SAA concentrations. The chromosome 11 region contains the serum amyloid A1 gene and the adjacent genes and explains a high percentage of the total estimated heritability. The chromosome 1 region is a known genetic susceptibility region for inflammation. Taken together, we identified one region, which seems to be of key importance in the regulation of A-SAA levels and represents a novel potential target for the investigation of related clinical entities. In addition, our findings indicate a close interplay between A-SAA and other inflammatory proteins, as well as a larger role of a known genetic susceptibility region for inflammatory processes as it has been assumed in the past.
Published: 2010

43. Discovery of sexual dimorphisms in metabolic and genetic biomarkers

Author: Werner Roemisch-Margl, Karsten Suhre, Cornelia Prehn, Fabian J. Theis, Jerzy Adamski, Thomas Meitinger, Jan Krumsiek, Florian Kronenberg, Alexey Polonikov, Heinz Erich Wichmann, Annette Peters, Thomas Illig, Christian Gieger, Zhonghao Yu, Janina S. Ried, Stephan Weidinger, Kirstin Mittelstrass, and Rui Wang-Sattler
Subjects: Adult, Genetic Markers, Male, Cancer Research, lcsh:QH426-470, Metabolite, Glycine, Genome-wide association study, Single-nucleotide polymorphism, Biology, Bioinformatics, Polymorphism, Single Nucleotide, no keywords, chemistry.chemical_compound, Carnitine, Genetic variation, Genetics, Metabolome, Humans, Amino Acids, Molecular Biology, Genetics (clinical), Ecology, Evolution, Behavior and Systematics, Genetic association, Aged, Aged, 80 and over, Sex Characteristics, Middle Aged, Lipids, Sexual dimorphism, lcsh:Genetics, chemistry, Genetic marker, Female, Genome-Wide Association Study
Abstract: Metabolomic profiling and the integration of whole-genome genetic association data has proven to be a powerful tool to comprehensively explore gene regulatory networks and to investigate the effects of genetic variation at the molecular level. Serum metabolite concentrations allow a direct readout of biological processes, and association of specific metabolomic signatures with complex diseases such as Alzheimer's disease and cardiovascular and metabolic disorders has been shown. There are well-known correlations between sex and the incidence, prevalence, age of onset, symptoms, and severity of a disease, as well as the reaction to drugs. However, most of the studies published so far did not consider the role of sexual dimorphism and did not analyse their data stratified by gender. This study investigated sex-specific differences of serum metabolite concentrations and their underlying genetic determination. For discovery and replication we used more than 3,300 independent individuals from KORA F3 and F4 with metabolite measurements of 131 metabolites, including amino acids, phosphatidylcholines, sphingomyelins, acylcarnitines, and C6-sugars. A linear regression approach revealed significant concentration differences between males and females for 102 out of 131 metabolites (p-values
Published: 2010

44. Genome-wide association studies of serum magnesium, potassium, and sodium concentrations identify six Loci influencing serum magnesium levels

Author: Aravinda Chakravarti, Albert Hofman, Thomas Meitinger, Frank J. A. van Rooij, Ronit Katz, Georg Homuth, Mark J. Sarnak, Thomas Kocher, Yii-Der Ida Chen, David S. Siscovick, Tamara B. Harris, Vilmundur Gudnason, Qiong Yang, Anna Köttgen, Albert V. Smith, Bruce M. Psaty, Shih-Jen Hwang, Jacqueline C. M. Witteman, Eric Boerwinkle, Janina S. Ried, Hanna Prucha, Caroline S. Fox, Nicole L. Glazer, Cornelia M. van Duijn, André G. Uitterlinden, Arne Pfeufer, Christian Gieger, Abbas Dehghan, Josef Coresh, Georg Ehret, Janine F. Felix, Rainer Rettig, Thor Aspelund, W. H. Linda Kao, Tamra E. Meyer, Tennille S. Leak, Germaine C. Verwoert, Internal Medicine, and Epidemiology
Subjects: Adult, Male, Cancer Research, medicine.medical_specialty, lcsh:QH426-470, Cardiovascular Disorders, Magnesium transporter, Sodium, Potassium, Public Health and Epidemiology, Blood sugar, chemistry.chemical_element, Single-nucleotide polymorphism, Genome-wide association study, 030204 cardiovascular system & hematology, Biology, Polymorphism, Single Nucleotide, White People, Hypomagnesemia, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Genetics, medicine, Humans, Magnesium, Genetics and Genomics/Genomics, Molecular Biology, Genetics (clinical), Ecology, Evolution, Behavior and Systematics, Aged, 030304 developmental biology, 0303 health sciences, Physiology/Genomics, Middle Aged, medicine.disease, lcsh:Genetics, Endocrinology, Biochemistry, chemistry, Physiology/Renal, Fluid, and Electrolyte Physiology, Female, Research Article, Genome-Wide Association Study
Abstract: Magnesium, potassium, and sodium, cations commonly measured in serum, are involved in many physiological processes including energy metabolism, nerve and muscle function, signal transduction, and fluid and blood pressure regulation. To evaluate the contribution of common genetic variation to normal physiologic variation in serum concentrations of these cations, we conducted genome-wide association studies of serum magnesium, potassium, and sodium concentrations using ∼2.5 million genotyped and imputed common single nucleotide polymorphisms (SNPs) in 15,366 participants of European descent from the international CHARGE Consortium. Study-specific results were combined using fixed-effects inverse-variance weighted meta-analysis. SNPs demonstrating genome-wide significant (p, Author Summary Magnesium, potassium, and sodium are involved in important physiological processes. To better understand how common genetic variation may contribute to inter-individual differences in serum concentrations of these electrolytes, we evaluated single nucleotide polymorphisms (SNPs) across the genome in association with serum magnesium, potassium, and sodium levels in 15,366 participants of European descent from the CHARGE Consortium. We then verified the associations in an additional 8,463 study participants. Six different genomic regions contain variants that are reproducibly associated with serum magnesium levels, and only one of the regions had been previously known to influence serum magnesium concentrations in humans. The identified SNPs also show association with clinically defined hypomagnesemia, and some of them with traits that have been linked to serum magnesium levels, including kidney function, fasting glucose, and bone mineral density. We further provide evidence for a physiological role of magnesium transporters in humans which have previously only been studied in model systems. None of the SNPs evaluated in our study are significantly associated with serum levels of sodium or potassium. Additional studies are needed to investigate the underlying molecular mechanisms in order to help us understand the contribution of these newly identified regions to magnesium homeostasis.
Published: 2010

45. Common Genetic Variants Associate with Serum Phosphorus Concentration

Author: Anna Köttgen, Bryan Kestenbaum, Eric Boerwinkle, Harry Campbell, Josef Coresh, Yii-Der Ida Chen, Shih-Jen Hwang, Caroline S. Fox, H.-Erich Wichmann, Dorothy B. Hausman, Qiong Yang, Christian Gieger, Yongmei Liu, Frank J.A. van Rooij, Janine F. Felix, Michael G. Shlipak, Kurt Lohman, Albert Hofman, Jacqueline C.M. Witteman, Caroline Hayward, David S. Siscovick, Tim Matthias Strom, Thomas Meitinger, Kenneth Rice, Cornelia M. van Duijn, Abbas Dehghan, Daniel Levy, Fernando Rivadeneira, Janina S. Ried, Man Li, Nicole L. Glazer, Ian H. de Boer, Ann Kristin Petersen, AndréG Uitterlinden, D.E. Arking, W. H. Linda Kao, Stephen B. Kritchevsky, Bruce M. Psaty, Igor Rudan, Epidemiology, Erasmus MC other, and Internal Medicine
Subjects: Adult, Male, medicine.medical_specialty, Population, chemistry.chemical_element, Single-nucleotide polymorphism, Genome-wide association study, Biology, Kidney, Sodium-Phosphate Cotransporter Proteins, Type IIa, Polymorphism, Single Nucleotide, White People, Phosphorus metabolism, Sex Factors, Gene Frequency, Clinical Research, Internal medicine, Genetic variation, medicine, Humans, Allele, education, Aged, Genetics, education.field_of_study, Phosphorus, Genetic Variation, General Medicine, Middle Aged, Minor allele frequency, Fibroblast Growth Factors, Fibroblast Growth Factor-23, Endocrinology, chemistry, Nephrology, Genetic Loci, Female, Receptors, Calcium-Sensing, Genome-Wide Association Study
Abstract: Phosphorus is an essential mineral that maintains cellular energy and mineralizes the skeleton. Because complex actions of ion transporters and regulatory hormones regulate serum phosphorus concentrations, genetic variation may determine interindividual variation in phosphorus metabolism. Here, we report a comprehensive genome-wide association study of serum phosphorus concentration. We evaluated 16,264 participants of European ancestry from the Cardiovascular Heath Study, Atherosclerosis Risk in Communities Study, Framingham Offspring Study, and the Rotterdam Study. We excluded participants with an estimated GFR
Published: 2010

46. Correction: Corrigendum: Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis

Author: Toshiko Tanaka, Clara Camaschella, Niek Verweij, Denise Anderson, Peter Vollenweider, Nicholas G. Martin, Stefania Bandinelli, Andres Metspalu, Peter P. Pramstaller, Dorine W. Swinkels, Maristella Steri, Ayse Demirkan, Serena Sanna, Jennifer Jolley, Irene Pichler, Pamela A. F. Madden, Gérard Waeber, Lambertus A. Kiemeney, Clara Podmore, Daniela Toniolo, Jennie Hui, Tõnu Esko, Thomas Meitinger, Jennifer G. Sambrook, Jiaåan Luan, Andrew A. Hicks, Joachim Thiery, Claudia Langenberg, Andrew Heath, Robert A. Scott, Aaron Isaacs, Peter van der Meer, Cornelia M. van Duijn, Juliane Winkelmann, Fudi Wang, Peter M. Visscher, Fred C.G.J. Sweep, Zoltán Kutalik, Annette Peters, Michela Traglia, Cinzia Sala, Manuela Uda, Augusto Rendon, Melanie Waldenberger, Christian Gieger, Lili Milani, John Beilby, Margaret J. Wright, Konrad Oexle, Christine Schwienbacher, Linda Broer, Grant W. Montgomery, Najaf Amin, Dale R. Nyholt, Martin Gögele, Pim van der Harst, Dena G. Hernandez, Janina S. Ried, Aparna Radhakrishnan, Nicholas J. Wareham, Sita H. Vermeulen, John Whitfield, Harm-Jan Westra, Beben Benyamin, Joseph E. Powell, Evelin Mihailov, Lude Franke, Jonas Hälldin, Willem H. Ouwehand, Benyamin, B, Esko, T, Ried, J, Radhakrishnan, A, Vermeulen, Sh, Traglia, M, Gögele, M, Anderson, D, Broer, L, Podmore, C, Luan, J, Kutalik, Z, Sanna, S, VAN DER MEER, P, Tanaka, T, Wang, F, Westra, Hj, Franke, L, Mihailov, E, Milani, L, Hälldin, J, Winkelmann, J, Meitinger, T, Thiery, J, Peters, A, Waldenberger, M, Rendon, A, Jolley, J, Sambrook, J, Kiemeney, La, Sweep, Fc, Sala, Cf, Schwienbacher, C, Pichler, I, Hui, J, Demirkan, A, Isaacs, A, Amin, N, Steri, M, Waeber, G, Verweij, N, Powell, Je, Nyholt, Dr, Heath, Ac, Madden, Pa, Visscher, Pm, Wright, Mj, Montgomery, Gw, Martin, Ng, Hernandez, D, Bandinelli, S, VAN DER HARST, P, Uda, M, Vollenweider, P, Scott, Ra, Langenberg, C, Wareham, Nj, VAN DUIJN, C, Beilby, J, Pramstaller, Pp, Hicks, Aa, Ouwehand, Wh, Oexle, K, Gieger, C, Metspalu, A, Camaschella, Clara, Toniolo, D, Swinkels, Dw, and Whitfield, Jb
Subjects: Genetics, Multidisciplinary, General Physics and Astronomy, General Chemistry, Biology, medicine.disease, General Biochemistry, Genetics and Molecular Biology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Iron homeostasis, 030220 oncology & carcinogenesis, medicine, 030217 neurology & neurosurgery, Hemochromatosis
Abstract: Corrigendum: Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis
Published: 2015

47. A Genome-Wide Screen for Interactions Reveals a New Locus on 4p15 Modifying the Effect of Waist-to-Hip Ratio on Total Cholesterol

Author: Nancy L. Pedersen, Antti J. Kangas, James F. Wilson, Anke Toenjes, Ben A. Oostra, Janina S. Ried, Theodore Papamarkou, Angela Doering, Zoltán Kutalik, André G. Uitterlinden, Nicholas G. Martin, Antti Jula, Tõnu Esko, Bruce H. R. Wolffenbuttel, Lennart C. Karssen, Pirkka-Pekka Laurila, Åsa Johansson, Gerjan Navis, Aarno Palotie, Christian Gieger, Cisca Wijmenga, Peter P. Pramstaller, Aaron Isaacs, Inga Prokopenko, Jouke-Jan Hottenga, Massimo Mangino, Antti-Pekka Sarin, Ida Surakka, Veikko Salomaa, Taina Rantanen, Ulf Gyllensten, Nicole Soranzo, Jacqueline C.M. Witteman, Cornelia M. van Duijn, Samuli Ripatti, Albert Hofman, Nicholas W.J. Wainwright, Pasi Soininen, Leena Peltonen, Rita P. S. Middelberg, Pim van der Harst, Kirsten Ohm Kyvik, Dorret I. Boomsma, Harry Campbell, John Whitfield, Ann-Kristin Petersen, Vasiliki Lagou, Tim D. Spector, Wilmar Igl, Markus Perola, Florian Kronenberg, Maksim Struchalin, Nelson B. Freimer, Mika Kähönen, Jaakko Kaprio, Irene Mateo Leach, Fernando Rivadeneira, Mark I. McCarthy, Mika Ala-Korpela, Jorma Viikari, Andres Metspalu, Johan G. Eriksson, Eco J. C. de Geus, H.-Erich Wichmann, Grant W. Montgomery, M. S. Sandhu, Olli T. Raitakari, Michael Stumvoll, Terho Lehtimäki, Marja-Riitta Taskinen, Gonneke Willemsen, Andrew C. Heath, Igor Rudan, Yurii S. Aulchenko, Marjo-Riitta Jaervelin, Emmi Tikkanen, Claudia Lamina, Dawn M. Waterworth, Taskinen M.R., ENGAGE Consortium, Gibson, Greg, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Cardiovascular Centre (CVC), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Center for Liver, Digestive and Metabolic Diseases (CLDM), Biological Psychology, EMGO+ - Mental Health, Epidemiology, Internal Medicine, Clinical Genetics, Institute for Molecular Medicine Finland, Department of Medical and Clinical Genetics, Department of Medicine, Hjelt Institute (-2014), Department of Public Health, Department of General Practice and Primary Health Care, Biostatistics Helsinki, Complex Disease Genetics, Genomics of Neurological and Neuropsychiatric Disorders, Genetic Epidemiology, and Medical Research Council (MRC)
Subjects: Netherlands Twin Register (NTR), Adipose Tissue/metabolism, Body Fat Distribution, Cadherins/genetics, Cholesterol/blood, Cholesterol/genetics, Chromosome Mapping, Chromosomes, Human, Pair 4/genetics, European Continental Ancestry Group/genetics, Genome-Wide Association Study, Genotype, Humans, Lipids/blood, Lipids/genetics, Lipoproteins/blood, Lipoproteins/genetics, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci/genetics, Risk Factors, Triglycerides/blood, Triglycerides/genetics, Waist-Hip Ratio, Genome-wide association study, 0302 clinical medicine, Genetics(clinical), Aetiology, 0303 health sciences, education.field_of_study, ta3141, ta3142, ASSOCIATION, Cadherins, Lipids, 3. Good health, Cholesterol, Adipose Tissue, DENSITY-LIPOPROTEIN CHOLESTEROL, TRIGLYCERIDE, Chromosomes, Human, Pair 4, SMOKING, Human, Lipoproteins, education, European Continental Ancestry Group, Quantitative Trait Loci, Locus (genetics), White People, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Clinical Research, Genome-Wide Association Studies, Genetics, Polymorphism, Biology, Molecular Biology, POLYMORPHISMS, Ecology, Evolution, Behavior and Systematics, 0604 Genetics, HDL CHOLESTEROL, Science & Technology, Density-lipoprotein cholesterol, HDL chloesterol, Association, Gene, Smoking, Plasma, Triglyeride, Obesity, Polymorphisms, Developmental Biology, Cancer Research, 030204 cardiovascular system & hematology, Waist–hip ratio, 2.1 Biological and endogenous factors, GENETICS & HEREDITY, Genetics (clinical), PLASMA, Single Nucleotide, ENGAGE Consortium, Pair 4/genetics, Pair 4, OBESITY, Life Sciences & Biomedicine, Research Article, LIPIDS, lcsh:QH426-470, Population, Quantitative trait locus, Chromosomes, gene, waist-to-hip ratio, cholesterol, Allele, Triglycerides, 030304 developmental biology, Whites, Human Genome, Human Genetics, Heritability, GENE, Protocadherins, lcsh:Genetics, 3111 Biomedicine
Abstract: Recent genome-wide association (GWA) studies described 95 loci controlling serum lipid levels. These common variants explain ∼25% of the heritability of the phenotypes. To date, no unbiased screen for gene–environment interactions for circulating lipids has been reported. We screened for variants that modify the relationship between known epidemiological risk factors and circulating lipid levels in a meta-analysis of genome-wide association (GWA) data from 18 population-based cohorts with European ancestry (maximum N = 32,225). We collected 8 further cohorts (N = 17,102) for replication, and rs6448771 on 4p15 demonstrated genome-wide significant interaction with waist-to-hip-ratio (WHR) on total cholesterol (TC) with a combined P-value of 4.79×10−9. There were two potential candidate genes in the region, PCDH7 and CCKAR, with differential expression levels for rs6448771 genotypes in adipose tissue. The effect of WHR on TC was strongest for individuals carrying two copies of G allele, for whom a one standard deviation (sd) difference in WHR corresponds to 0.19 sd difference in TC concentration, while for A allele homozygous the difference was 0.12 sd. Our findings may open up possibilities for targeted intervention strategies for people characterized by specific genomic profiles. However, more refined measures of both body-fat distribution and metabolic measures are needed to understand how their joint dynamics are modified by the newly found locus., Author Summary Circulating serum lipids contribute greatly to the global health by affecting the risk for cardiovascular diseases. Serum lipid levels are partly inherited, and already 95 loci affecting high- and low-density lipoprotein cholesterol, total cholesterol, and triglycerides have been found. Serum lipids are also known to be affected by multiple epidemiological risk factors like body composition, lifestyle, and sex. It has been hypothesized that there are loci modifying the effects between risk factors and serum lipids, but to date only candidate gene studies for interactions have been reported. We conducted a genome-wide screen with meta-analysis approach to identify loci having interactions with epidemiological risk factors on serum lipids with over 30,000 population-based samples. When combining results from our initial datasets and 8 additional replication cohorts (maximum N = 17,102), we found a genome-wide significant locus in chromosome 4p15 with a joint P-value of 4.79×10−9 modifying the effect of waist-to-hip ratio on total cholesterol. In the area surrounding this genetic variant, there were two genes having association between the genotypes and the gene expression in adipose tissue, and we also found enrichment of association in genes belonging to lipid metabolism related functions.
Published: 2011

48. Maps of open chromatin highlight cell type-restricted patterns of regulatory sequence variation at hematological trait loci

Author: Paul, Ds, Albers, Ca, Rendon, A, Voss, K, Stephens, J, Akkerman, Jan Willem N., Albers, Cornelis A., Ale, Algra, Abtehale Al Hussani, Hooman, Allayee, Franco, Anni, Asselbergs, Folkert W., Antony, Attwood, Beverley, Balkau, Stefania, Bandinelli, François, Bastardot, Saonli, Basu, Baumeister, Sebastian E., Jacques, Beckmann, Beben, Benyamin, Ginevra, Biino, Bis, Joshua C., Lorenzo, Bomba, Amélie, Bonnefond, Boomsma, Dorret I., Bradley, John R., François, Cambien, Chambers, John C., Marina, Ciullo, Cookson, William O., Francesco, Cucca, Ana, Cvejic, D'Adamo, ADAMO PIO, John, Danesh, Fabrice, Danjou, Debashish, Das, Gail, Davies, Paul IW de Bakker, de Boer, Rudolf A., Eco JC de Geus, Deary, Ian J., Dedoussis, George V., Panos, Deloukas, Maria, Dimitriou, Christian, Dina, Angela, Döring, Ulrich, Elling, David, Ellinghaus, Paul, Elliott, Gunnar, Engström, Jeanette, Erdmann, Tõnu, Esko, Evans, David M., Eyjolfsson, Gudmundur I., Mario, Falchi, Wei, Feng, Ferreira, Manuel A., Luigi, Ferrucci, Krista, Fischer, Folsom, Aaron R., Paolo, Fortina, Andre, Franke, Lude, Franke, Frazer, Ian H., Philippe, Froguel, Renzo, Galanello, Ganesh, Santhi K., Garner, Stephen F., Gasparini, Paolo, Bernd, Genser, Gibson, Quince D., Christian, Gieger, Girotto, Giorgia, Glazer, Nicole L., Martin, Gögele, Goodall, Alison H., Andreas, Greinacher, Gudbjartsson, Daniel F., Chris, Hammond, Harris, Sarah E., Jaana, Hartiala, Anna Liisa Hartikainen, Hazen, Stanley L., Heckbert, Susan R., Hedblad, Bo, Christian, Hengstenberg, Micha, Hersch, Hicks, Andrew A., Hilma, Holm, Jouke Jan Hottenga, Thomas, Illig, Marjo Riitta Jarvelin, Jennifer, Jolley, Steve, Jupe, Mika, Kähönen, Naoyuki, Kamatani, Stavroula, Kanoni, Kema, Ido P., Kemp, John P., Jyoti, Khadake, Kay Tee Khaw, Kleber, Marcus E., Kooner, Jaspal S., Peter, Kovacs, Brigitte, Kühnel, Marie Christine Kyrtsonis, Yann, Labrune, Vasiliki, Lagou, Claudia, Langenberg, Terho, Lehtimäki, Xinzhong, Li, Liming, Liang, Lifelines Cohort Study, Heather Lloyd Jones, Ruth JF Loos, Lopez, Lorna M., Thomas, Lumley, Leo Pekka Lyytikäinen, Winfried, Maerz, Reedik, Mägi, Massimo, Mangino, Martin, Nicholas G., Andrea, Maschio, Irene Mateo Leach, Barbara, Mcknight, Stuart, Meacham, Medland, Sarah E., Christa, Meisinger, Olle, Melander, Yasin, Memari, Andres, Metspalu, Kathy, Miller, Mitchell, Braxton D., Moffatt, Miriam F., Montgomery, Grant W., Carmel, Moore, Federico, Murgia, Yusuke, Nakamura, Matthias, Nauck, Gerjan, Navis, Nolte, Ilja M., Ute, Nöthlings, Teresa, Nutile, Yukinori, Okada, Isleifur, Olafsson, Onundarson, Pall T., O’Reilly, Paul F., Ouwehand, Willem H., Debora, Parracciani, Afshin, Parsa, Paul, Dirk S., Penninger, Josef M., Penninx, Brenda W., Mario, Pirastu, Pirastu, Nicola, Giorgio, Pistis, Eleonora, Porcu, Laura, Portas, David, Porteous, Anneli, Pouta, Pramstaller, Peter P., Inga, Prokopenko, Psaty, Bruce M., Janne, Pullat, Aparna, Radhakrishnan, Olli, Raitakari, Ramiro Ramirez Solis, Augusto, Rendon, Ried, Janina S., Ring, Susan M., Robino, Antonietta, Rotter, Jerome I., Daniela, Ruggiero, Aimo, Ruokonen, Cinzia, Sala, Andres, Saluments, Samani, Nilesh J., Jennifer, Sambrook, Serena, Sanna, David, Schlessinger, Schmidt, Carsten O., Stefan, Schreiber, Heribert, Schunkert, James, Scott, Joban, Sehmi, Jovana Serbanovic Canic, So Youn Shin, Shuldiner, Alan R., Rob, Sladek, Smit, Johannes H., George Davey Smith, Gustav Smith, J., Smith, Nicholas L., Harold, Snieder, Nicole, Soranzo, Rossella, Sorice, Spector, Timothy D., Starr, John M., Kari, Stefansson, Derek, Stemple, Jonathan, Stephens, Michael, Stumvoll, Patrick, Sulem, Atsushi, Takahashi, Sian Tsung Tan, Toshiko, Tanaka, Clara, Tang, Weihong, Tang, WH Wilson Tang, Kent, Taylor, Albert, Tenesa, Alexander, Teumer, Swee Lay Thein, Unnur, Thorsteinsdottir, Daniela, Toniolo, Anke, Tönjes, Traglia, Michela, Manuela, Uda, Sheila, Ulivi, Pim van der Harst, Ellen van der Schoot, C., van Gilst, Wiek H., Joost van Pelt, L., van Veldhuisen, Dirk J., Niek, Verweij, Visscher, Peter M., Uwe, Völker, Peter, Vollenweider, Katrin, Voss, Wareham, Nicholas J., Lorenz, Wernisch, Harm Jan Westra, Whitfield, John B., Herich, Wichmann, Wiggins, Kerri L., Gonneke, Willemsen, Winkelmann, Bernhard R., Gerald, Wirnsberger, Bruce HR Wolffenbuttel, Jian, Yang, Tsun Po Yang, Weihua, Zhang, Jing Hua Zhao, Paavo, Zitting, Jaap Jan Zwaginga, van der Harst, P, Chambers, Jc, Soranzo, N, Ouwehand, Wh, Deloukas, P., Paul, D, Albers, Ca, Rendon, A, Voss, K, Stephens, J, Jan Willem N., Akkerman, Cornelis A., Alber, Ale, Algra, Abtehale Al, Hussani, Hooman, Allayee, Franco, Anni, Folkert W., Asselberg, Antony, Attwood, Beverley, Balkau, Stefania, Bandinelli, François, Bastardot, Saonli, Basu, Sebastian E., Baumeister, Jacques, Beckmann, Beben, Benyamin, Ginevra, Biino, Joshua C., Bi, Lorenzo, Bomba, Amélie, Bonnefond, Dorret I., Boomsma, John R., Bradley, François, Cambien, John C., Chamber, Marina, Ciullo, William O., Cookson, Francesco, Cucca, Ana, Cvejic, D'Adamo, ADAMO PIO, John, Danesh, Fabrice, Danjou, Debashish, Da, Gail, Davie, Paul IW de, Bakker, Rudolf A., de Boer, Eco JC de, Geu, Ian J., Deary, George V., Dedoussi, Panos, Delouka, Maria, Dimitriou, Christian, Dina, Angela, Döring, Ulrich, Elling, David, Ellinghau, Paul, Elliott, Gunnar, Engström, Jeanette, Erdmann, Tõnu, Esko, David M., Evan, Gudmundur I., Eyjolfsson, Mario, Falchi, Wei, Feng, Manuel A., Ferreira, Luigi, Ferrucci, Krista, Fischer, Aaron R., Folsom, Paolo, Fortina, Andre, Franke, Lude, Franke, Ian H., Frazer, Philippe, Froguel, Renzo, Galanello, Santhi K., Ganesh, Stephen F., Garner, Gasparini, Paolo, Bernd, Genser, Quince D., Gibson, Christian, Gieger, Girotto, Giorgia, Nicole L., Glazer, Martin, Gögele, Alison H., Goodall, Andreas, Greinacher, Daniel F., Gudbjartsson, Chris, Hammond, Sarah E., Harri, Jaana, Hartiala, Anna Liisa, Hartikainen, Stanley L., Hazen, Susan R., Heckbert, Bo, Hedblad, Christian, Hengstenberg, Micha, Hersch, Andrew A., Hick, Hilma, Holm, Jouke Jan, Hottenga, Thomas, Illig, Marjo Riitta, Jarvelin, Jennifer, Jolley, Steve, Jupe, Mika, Kähönen, Naoyuki, Kamatani, Stavroula, Kanoni, Ido P., Kema, John P., Kemp, Jyoti, Khadake, Kay Tee, Khaw, Marcus E., Kleber, Jaspal S., Kooner, Peter, Kovac, Brigitte, Kühnel, Marie Christine, Kyrtsoni, Yann, Labrune, Vasiliki, Lagou, Claudia, Langenberg, Terho, Lehtimäki, Xinzhong, Li, Liming, Liang, Lifelines Cohort, Study, Heather Lloyd, Jone, Ruth JF, Loo, Lorna M., Lopez, Thomas, Lumley, Leo Pekka, Lyytikäinen, Winfried, Maerz, Reedik, Mägi, Massimo, Mangino, Nicholas G., Martin, Andrea, Maschio, Irene Mateo, Leach, Barbara, Mcknight, Stuart, Meacham, Sarah E., Medland, Christa, Meisinger, Olle, Melander, Yasin, Memari, Andres, Metspalu, Kathy, Miller, Braxton D., Mitchell, Miriam F., Moffatt, Grant W., Montgomery, Carmel, Moore, Federico, Murgia, Yusuke, Nakamura, Matthias, Nauck, Gerjan, Navi, Ilja M., Nolte, Ute, Nöthling, Teresa, Nutile, Yukinori, Okada, Isleifur, Olafsson, Pall T., Onundarson, Paul F., O’Reilly, Willem H., Ouwehand, Debora, Parracciani, Afshin, Parsa, Dirk S., Paul, Josef M., Penninger, Brenda W., Penninx, Mario, Pirastu, Pirastu, Nicola, Giorgio, Pisti, Eleonora, Porcu, Laura, Porta, David, Porteou, Anneli, Pouta, Peter P., Pramstaller, Inga, Prokopenko, Bruce M., Psaty, Janne, Pullat, Aparna, Radhakrishnan, Olli, Raitakari, Ramiro Ramirez, Soli, Augusto, Rendon, Janina S., Ried, Susan M., Ring, Robino, Antonietta, Jerome I., Rotter, Daniela, Ruggiero, Aimo, Ruokonen, Cinzia, Sala, Andres, Salument, Nilesh J., Samani, Jennifer, Sambrook, Serena, Sanna, David, Schlessinger, Carsten O., Schmidt, Stefan, Schreiber, Heribert, Schunkert, James, Scott, Joban, Sehmi, Jovana Serbanovic, Canic, So Youn, Shin, Alan R., Shuldiner, Rob, Sladek, Johannes H., Smit, George Davey, Smith, J., Gustav Smith, Nicholas L., Smith, Harold, Snieder, Nicole, Soranzo, Rossella, Sorice, Timothy D., Spector, John M., Starr, Kari, Stefansson, Derek, Stemple, Jonathan, Stephen, Michael, Stumvoll, Patrick, Sulem, Atsushi, Takahashi, Sian Tsung, Tan, Toshiko, Tanaka, Clara, Tang, Weihong, Tang, WH Wilson, Tang, Kent, Taylor, Albert, Tenesa, Alexander, Teumer, Swee Lay, Thein, Unnur, Thorsteinsdottir, Daniela, Toniolo, Anke, Tönje, Traglia, Michela, Manuela, Uda, Sheila, Ulivi, Pim van der, Harst, C., Ellen van der Schoot, Wiek H., van Gilst, L., Joost van Pelt, Dirk J., van Veldhuisen, Niek, Verweij, Peter M., Visscher, Uwe, Völker, Peter, Vollenweider, Katrin, Vo, Nicholas J., Wareham, Lorenz, Wernisch, Harm Jan, Westra, John B., Whitfield, Herich, Wichmann, Kerri L., Wiggin, Gonneke, Willemsen, Bernhard R., Winkelmann, Gerald, Wirnsberger, Bruce HR, Wolffenbuttel, Jian, Yang, Tsun Po, Yang, Weihua, Zhang, Jing Hua, Zhao, Paavo, Zitting, Jaap Jan, Zwaginga, van der Harst, P, Chambers, Jc, Soranzo, N, Ouwehand, Wh, Deloukas, P., Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Mental Health, Neuroscience Campus Amsterdam - Brain Imaging Technology, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England, UCL, UCL Canc Inst, London WC1E 6BT, England, Univ Cambridge, Dept Haematol, Cambridge CB2 0PT, England, Natl Hlth Serv NHS Blood & Transplant, Cambridge CB2 0PT, England, Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6500 HB Nijmegen, Netherlands, Inst Publ Hlth, MRC Biostat Unit, Cambridge CB2 0SR, England, NIHR Biomed Res Ctr, Cambridge CB2 0PT, England, Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9713 GZ Groningen, Netherlands, Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9713 GZ Groningen, Netherlands, Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London W2 1NY, England, Hammersmith Hosp, Imperial Coll Healthcare NHS Trust, London W12 0HS, England, Royal Brompton & Harefield Hosp NHS Trust, London SW3 6NP, England, Ealing Hosp NHS Trust, Southall UB1 3HW, Middx, England, Psychiatry, Epidemiology and Data Science, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Mental health, NCA - Brain imaging technology, and Cardiovascular Centre (CVC)
Subjects: Netherlands Twin Register (NTR), Erythrocytes, Genome-wide association study, UNCERTAINTY, Regulatory Sequences, Nucleic Acid, VARIANTS, ANNOTATION, COLORECTAL-CANCER, Histones, 0302 clinical medicine, BINDING, Cluster Analysis, Myeloid Cells, Genetics (clinical), Genetics, hematological trait, 0303 health sciences, Chromosome Mapping, MRP4 ABCC4, Chromatin, Nucleosomes, Phenotype, Organ Specificity, 030220 oncology & carcinogenesis, Blood Platelets, Quantitative Trait Loci, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, DYNAMIN 3, 03 medical and health sciences, Quantitative Trait, Heritable, MEGAKARYOCYTES, Humans, Cell Lineage, ddc:610, GENOME-WIDE ASSOCIATION, Enhancer, Transcription factor, Gene, ChIA-PET, 030304 developmental biology, Research, Genetic Variation, DNA, Chromatin Assembly and Disassembly, Genetic architecture, Gene Expression Regulation, Genome-Wide Association Study
Abstract: To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. Nearly three-quarters of the 143 genetic signals associated with platelet and erythrocyte phenotypes identified by meta-analyses of genome-wide association (GWA) studies are located at non-protein-coding regions. Here, we assessed the role of candidate regulatory variants associated with cell type-restricted, closely related hematological quantitative traits in biologically relevant hematopoietic cell types. We used formaldehyde-assisted isolation of regulatory elements followed by next-generation sequencing (FAIRE-seq) to map regions of open chromatin in three primary human blood cells of the myeloid lineage. In the precursors of platelets and erythrocytes, as well as in monocytes, we found that open chromatin signatures reflect the corresponding hematopoietic lineages of the studied cell types and associate with the cell type-specific gene expression patterns. Dependent on their signal strength, open chromatin regions showed correlation with promoter and enhancer histone marks, distance to the transcription start site, and ontology classes of nearby genes. Cell type-restricted regions of open chromatin were enriched in sequence variants associated with hematological indices. The majority (63.6%) of such candidate functional variants at platelet quantitative trait loci (QTLs) coincided with binding sites of five transcription factors key in regulating megakaryopoiesis. We experimentally tested 13 candidate regulatory variants at 10 platelet QTLs and found that 10 (76.9%) affected protein binding, suggesting that this is a frequent mechanism by which regulatory variants influence quantitative trait levels. Our findings demonstrate that combining large-scale GWA data with open chromatin profiles of relevant cell types can be a powerful means of dissecting the genetic architecture of closely related quantitative traits. Marie-Curie Initial Training Network NETSIM British Heart Foundation RG/09/12/28096 National Institutes for Health RP-PG-0310-1002 Wellcome Trust 098051 info:eu-repo/grantAgreement/EC/FP7/282510
Published: 2013

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