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1. The genetic architecture of the human cerebral cortex

Author

Grasby, Katrina L, Jahanshad, Neda, Painter, Jodie N, Colodro-Conde, Lucía, Bralten, Janita, Hibar, Derrek P, Lind, Penelope A, Pizzagalli, Fabrizio, Ching, Christopher RK, McMahon, Mary Agnes B, Shatokhina, Natalia, Zsembik, Leo CP, Thomopoulos, Sophia I, Zhu, Alyssa H, Strike, Lachlan T, Agartz, Ingrid, Alhusaini, Saud, Almeida, Marcio AA, Alnæs, Dag, Amlien, Inge K, Andersson, Micael, Ard, Tyler, Armstrong, Nicola J, Ashley-Koch, Allison, Atkins, Joshua R, Bernard, Manon, Brouwer, Rachel M, Buimer, Elizabeth EL, Bülow, Robin, Bürger, Christian, Cannon, Dara M, Chakravarty, Mallar, Chen, Qiang, Cheung, Joshua W, Couvy-Duchesne, Baptiste, Dale, Anders M, Dalvie, Shareefa, de Araujo, Tânia K, de Zubicaray, Greig I, de Zwarte, Sonja MC, Braber, Anouk den, Doan, Nhat Trung, Dohm, Katharina, Ehrlich, Stefan, Engelbrecht, Hannah-Ruth, Erk, Susanne, Fan, Chun Chieh, Fedko, Iryna O, Foley, Sonya F, Ford, Judith M, Fukunaga, Masaki, Garrett, Melanie E, Ge, Tian, Giddaluru, Sudheer, Goldman, Aaron L, Green, Melissa J, Groenewold, Nynke A, Grotegerd, Dominik, Gurholt, Tiril P, Gutman, Boris A, Hansell, Narelle K, Harris, Mathew A, Harrison, Marc B, Haswell, Courtney C, Hauser, Michael, Herms, Stefan, Heslenfeld, Dirk J, Ho, New Fei, Hoehn, David, Hoffmann, Per, Holleran, Laurena, Hoogman, Martine, Hottenga, Jouke-Jan, Ikeda, Masashi, Janowitz, Deborah, Jansen, Iris E, Jia, Tianye, Jockwitz, Christiane, Kanai, Ryota, Karama, Sherif, Kasperaviciute, Dalia, Kaufmann, Tobias, Kelly, Sinead, Kikuchi, Masataka, Klein, Marieke, Knapp, Michael, Knodt, Annchen R, Krämer, Bernd, Lam, Max, Lancaster, Thomas M, Lee, Phil H, Lett, Tristram A, Lewis, Lindsay B, Lopes-Cendes, Iscia, Luciano, Michelle, Macciardi, Fabio, Marquand, Andre F, Mathias, Samuel R, Melzer, Tracy R, and Milaneschi, Yuri

Subjects
Biological Sciences, Genetics, Neurosciences, Mental Health, Brain Disorders, Stem Cell Research, 2.1 Biological and endogenous factors, Aetiology, Neurological, Attention Deficit Disorder with Hyperactivity, Brain Mapping, Cerebral Cortex, Cognition, Genetic Loci, Genetic Variation, Genome-Wide Association Study, Humans, Magnetic Resonance Imaging, Organ Size, Parkinson Disease, Alzheimer’s Disease Neuroimaging Initiative, CHARGE Consortium, EPIGEN Consortium, IMAGEN Consortium, SYS Consortium, Parkinson’s Progression Markers Initiative, Enhancing NeuroImaging Genetics through Meta-Analysis Consortium (ENIGMA)—Genetics working group, General Science & Technology
Abstract

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.

Published
2020

2. Genome‐Wide Interactions with Dairy Intake for Body Mass Index in Adults of European Descent

Author

Smith, Caren E, Follis, Jack L, Dashti, Hassan S, Tanaka, Toshiko, Graff, Mariaelisa, Fretts, Amanda M, Kilpeläinen, Tuomas O, Wojczynski, Mary K, Richardson, Kris, Nalls, Mike A, Schulz, Christina‐Alexandra, Liu, Yongmei, Frazier‐Wood, Alexis C, van Eekelen, Esther, Wang, Carol, de Vries, Paul S, Mikkilä, Vera, Rohde, Rebecca, Psaty, Bruce M, Hansen, Torben, Feitosa, Mary F, Lai, Chao‐Qiang, Houston, Denise K, Ferruci, Luigi, Ericson, Ulrika, Wang, Zhe, de Mutsert, Renée, Oddy, Wendy H, de Jonge, Ester AL, Seppälä, Ilkka, Justice, Anne E, Lemaitre, Rozenn N, Sørensen, Thorkild IA, Province, Michael A, Parnell, Laurence D, Garcia, Melissa E, Bandinelli, Stefania, Orho‐Melander, Marju, Rich, Stephen S, Rosendaal, Frits R, Pennell, Craig E, Jong, Jessica C Kiefte‐de, Kähönen, Mika, Young, Kristin L, Pedersen, Oluf, Aslibekyan, Stella, Rotter, Jerome I, Mook‐Kanamori, Dennis O, Zillikens, M Carola, Raitakari, Olli T, North, Kari E, Overvad, Kim, Arnett, Donna K, Hofman, Albert, Lehtimäki, Terho, Tjønneland, Anne, Uitterlinden, André G, Rivadeneira, Fernando, Franco, Oscar H, German, J Bruce, Siscovick, David S, Cupples, L Adrienne, and Ordovás, José M

Subjects
Biomedical and Clinical Sciences, Nutrition and Dietetics, Genetics, Prevention, Nutrition, Obesity, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Cancer, Metabolic and endocrine, Actins, Adult, Aged, Body Mass Index, Cohort Studies, Cross-Sectional Studies, Dairy Products, Female, Gene Frequency, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Myosin-Light-Chain Phosphatase, Polymorphism, Single Nucleotide, White People, body mass index, CHARGE consortium, dairy intake, genome-wide interaction study, meta-analysis, Food Sciences, Public Health and Health Services, Food Science, Nutrition & Dietetics, Food sciences, Nutrition and dietetics
Abstract

ScopeBody weight responds variably to the intake of dairy foods. Genetic variation may contribute to inter-individual variability in associations between body weight and dairy consumption.Methods and resultsA genome-wide interaction study to discover genetic variants that account for variation in BMI in the context of low-fat, high-fat and total dairy intake in cross-sectional analysis was conducted. Data from nine discovery studies (up to 25 513 European descent individuals) were meta-analyzed. Twenty-six genetic variants reached the selected significance threshold (p-interaction

Published
2018

3. Genome-wide physical activity interactions in adiposity - A meta-analysis of 200,452 adults.

Author

Graff, Mariaelisa, Scott, Robert A, Justice, Anne E, Young, Kristin L, Feitosa, Mary F, Barata, Llilda, Winkler, Thomas W, Chu, Audrey Y, Mahajan, Anubha, Hadley, David, Xue, Luting, Workalemahu, Tsegaselassie, Heard-Costa, Nancy L, den Hoed, Marcel, Ahluwalia, Tarunveer S, Qi, Qibin, Ngwa, Julius S, Renström, Frida, Quaye, Lydia, Eicher, John D, Hayes, James E, Cornelis, Marilyn, Kutalik, Zoltan, Lim, Elise, Luan, Jian'an, Huffman, Jennifer E, Zhang, Weihua, Zhao, Wei, Griffin, Paula J, Haller, Toomas, Ahmad, Shafqat, Marques-Vidal, Pedro M, Bien, Stephanie, Yengo, Loic, Teumer, Alexander, Smith, Albert Vernon, Kumari, Meena, Harder, Marie Neergaard, Justesen, Johanne Marie, Kleber, Marcus E, Hollensted, Mette, Lohman, Kurt, Rivera, Natalia V, Whitfield, John B, Zhao, Jing Hua, Stringham, Heather M, Lyytikäinen, Leo-Pekka, Huppertz, Charlotte, Willemsen, Gonneke, Peyrot, Wouter J, Wu, Ying, Kristiansson, Kati, Demirkan, Ayse, Fornage, Myriam, Hassinen, Maija, Bielak, Lawrence F, Cadby, Gemma, Tanaka, Toshiko, Mägi, Reedik, van der Most, Peter J, Jackson, Anne U, Bragg-Gresham, Jennifer L, Vitart, Veronique, Marten, Jonathan, Navarro, Pau, Bellis, Claire, Pasko, Dorota, Johansson, Åsa, Snitker, Søren, Cheng, Yu-Ching, Eriksson, Joel, Lim, Unhee, Aadahl, Mette, Adair, Linda S, Amin, Najaf, Balkau, Beverley, Auvinen, Juha, Beilby, John, Bergman, Richard N, Bergmann, Sven, Bertoni, Alain G, Blangero, John, Bonnefond, Amélie, Bonnycastle, Lori L, Borja, Judith B, Brage, Søren, Busonero, Fabio, Buyske, Steve, Campbell, Harry, Chines, Peter S, Collins, Francis S, Corre, Tanguy, Smith, George Davey, Delgado, Graciela E, Dueker, Nicole, Dörr, Marcus, Ebeling, Tapani, Eiriksdottir, Gudny, Esko, Tõnu, and Faul, Jessica D

Subjects
CHARGE Consortium, EPIC-InterAct Consortium, PAGE Consortium, Humans, Obesity, Genetic Predisposition to Disease, Body Mass Index, Waist-Hip Ratio, Exercise, Genotype, Female, Male, Adiposity, Waist Circumference, Genome-Wide Association Study, Epigenomics, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Genetics, Developmental Biology
Abstract

Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.

Published
2017

4. Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis

Author

Natarajan, Pradeep, Bis, Joshua C, Bielak, Lawrence F, Cox, Amanda J, Dörr, Marcus, Feitosa, Mary F, Franceschini, Nora, Guo, Xiuqing, Hwang, Shih-Jen, Isaacs, Aaron, Jhun, Min A, Kavousi, Maryam, Li-Gao, Ruifang, Lyytikäinen, Leo-Pekka, Marioni, Riccardo E, Schminke, Ulf, Stitziel, Nathan O, Tada, Hayato, van Setten, Jessica, Smith, Albert V, Vojinovic, Dina, Yanek, Lisa R, Yao, Jie, Yerges-Armstrong, Laura M, Amin, Najaf, Baber, Usman, Borecki, Ingrid B, Carr, J Jeffrey, Chen, Yii-Der Ida, Cupples, L Adrienne, de Jong, Pim A, de Koning, Harry, de Vos, Bob D, Demirkan, Ayse, Fuster, Valentin, Franco, Oscar H, Goodarzi, Mark O, Harris, Tamara B, Heckbert, Susan R, Heiss, Gerardo, Hoffmann, Udo, Hofman, Albert, Išgum, Ivana, Jukema, J Wouter, Kähönen, Mika, Kardia, Sharon LR, Kral, Brian G, Launer, Lenore J, Massaro, Joe, Mehran, Roxana, Mitchell, Braxton D, Mosley, Thomas H, de Mutsert, Renée, Newman, Anne B, Nguyen, Khanh-Dung, North, Kari E, O'Connell, Jeffrey R, Oudkerk, Matthijs, Pankow, James S, Peloso, Gina M, Post, Wendy, Province, Michael A, Raffield, Laura M, Raitakari, Olli T, Reilly, Dermot F, Rivadeneira, Fernando, Rosendaal, Frits, Sartori, Samantha, Taylor, Kent D, Teumer, Alexander, Trompet, Stella, Turner, Stephen T, Uitterlinden, Andre G, Vaidya, Dhananjay, van der Lugt, Aad, Völker, Uwe, Wardlaw, Joanna M, Wassel, Christina L, Weiss, Stefan, Wojczynski, Mary K, Becker, Diane M, Becker, Lewis C, Boerwinkle, Eric, Bowden, Donald W, Deary, Ian J, Dehghan, Abbas, Felix, Stephan B, Gudnason, Vilmundur, Lehtimäki, Terho, Mathias, Rasika, Mook-Kanamori, Dennis O, Psaty, Bruce M, Rader, Daniel J, Rotter, Jerome I, Wilson, James G, van Duijn, Cornelia M, Völzke, Henry, Kathiresan, Sekar, Peyser, Patricia A, and O'Donnell, Christopher J

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Heart Disease - Coronary Heart Disease, Aging, Human Genome, Atherosclerosis, Cardiovascular, Heart Disease, Clinical Research, Genetics, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Apolipoprotein B-100, Apolipoprotein E2, Asymptomatic Diseases, Black People, Carotid Artery Diseases, Carotid Intima-Media Thickness, Cholesterol, LDL, Computed Tomography Angiography, Coronary Angiography, Coronary Artery Disease, Exome, Gene Frequency, Genetic Markers, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Odds Ratio, Oligonucleotide Array Sequence Analysis, Phenotype, Prognosis, Risk Assessment, Risk Factors, Vascular Calcification, White People, carotid intima-media thickness, coronary artery calcification, exome, genome-wide association study, genomics, CHARGE Consortium, carotid intima–media thickness, Medical Biotechnology, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology
Abstract

BackgroundThe burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease. We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent coronary heart disease.Methods and resultsWe studied a total of 25 109 European ancestry and African ancestry participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52 869 participants with common carotid intima-media thickness measured by ultrasonography within the CHARGE Consortium (Cohorts for Heart and Aging Research in Genomic Epidemiology). Participants were genotyped for 247 870 DNA sequence variants (231 539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and carotid intima-media thickness. APOB p.Arg3527Gln was associated with 4-fold excess CAC (P=3×10-10). The APOE ε2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC (P=1×10-12) and 1.4% reduced carotid intima-media thickness (P=4×10-14) in carriers compared with noncarriers. In secondary analyses conditioning on low-density lipoprotein cholesterol concentration, the ε2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ε2 was associated with reduced risk for coronary heart disease (odds ratio 0.77; P=1×10-11).ConclusionsExome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE ε2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities, as well as clinical coronary heart disease.

Published
2016

5. A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease

Author

Scott, Robert A, Freitag, Daniel F, Li, Li, Chu, Audrey Y, Surendran, Praveen, Young, Robin, Grarup, Niels, Stancáková, Alena, Chen, Yuning, Varga, Tibor V, Yaghootkar, Hanieh, Luan, Jian’an, Zhao, Jing Hua, Willems, Sara M, Wessel, Jennifer, Wang, Shuai, Maruthur, Nisa, Michailidou, Kyriaki, Pirie, Ailith, van der Lee, Sven J, Gillson, Christopher, Al Olama, Ali Amin, Amouyel, Philippe, Arriola, Larraitz, Arveiler, Dominique, Aviles-Olmos, Iciar, Balkau, Beverley, Barricarte, Aurelio, Barroso, Inês, Garcia, Sara Benlloch, Bis, Joshua C, Blankenberg, Stefan, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Borecki, Ingrid B, Bork-Jensen, Jette, Bowden, Sarah, Caldas, Carlos, Caslake, Muriel, consortium, The CVD50, Cupples, L Adrienne, Cruchaga, Carlos, Czajkowski, Jacek, Hoed, Marcel den, Dunn, Janet A, Earl, Helena M, Ehret, Georg B, Ferrannini, Ele, Ferrieres, Jean, Foltynie, Thomas, Ford, Ian, Forouhi, Nita G, Gianfagna, Francesco, Gonzalez, Carlos, Grioni, Sara, Hiller, Louise, Jansson, Jan-Håkan, Jørgensen, Marit E, Jukema, J Wouter, Kaaks, Rudolf, Kee, Frank, Kerrison, Nicola D, Key, Timothy J, Kontto, Jukka, Kote-Jarai, Zsofia, Kraja, Aldi T, Kuulasmaa, Kari, Kuusisto, Johanna, Linneberg, Allan, Liu, Chunyu, Marenne, Gaëlle, Mohlke, Karen L, Morris, Andrew P, Muir, Kenneth, Müller-Nurasyid, Martina, Munroe, Patricia B, Navarro, Carmen, Nielsen, Sune F, Nilsson, Peter M, Nordestgaard, Børge G, Packard, Chris J, Palli, Domenico, Panico, Salvatore, Peloso, Gina M, Perola, Markus, Peters, Annette, Poole, Christopher J, Quirós, J Ramón, Rolandsson, Olov, Sacerdote, Carlotta, Salomaa, Veikko, Sánchez, María-José, Sattar, Naveed, Sharp, Stephen J, Sims, Rebecca, Slimani, Nadia, Smith, Jennifer A, Thompson, Deborah J, and Trompet, Stella

Subjects
Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Clinical Research, Diabetes, Human Genome, Cardiovascular, Prevention, Obesity, Genetics, Heart Disease, Heart Disease - Coronary Heart Disease, Clinical Trials and Supportive Activities, Aetiology, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, 2.1 Biological and endogenous factors, Metabolic and endocrine, Good Health and Well Being, Alleles, Coronary Disease, Diabetes Mellitus, Type 2, Dipeptidyl Peptidase 4, Genotype, Glucagon-Like Peptide-1 Receptor, Humans, Receptor, Cannabinoid, CB2, Receptor, Serotonin, 5-HT2C, Receptors, Somatostatin, Sodium-Glucose Transporter 1, CVD50 consortium, GERAD_EC Consortium, Neurology Working Group of the Cohorts for Heart, Aging Research in Genomic Epidemiology, Alzheimer’s Disease Genetics Consortium, Pancreatic Cancer Cohort Consortium, European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease, EPIC-InterAct, CHARGE consortium, CHD Exome+ Consortium, CARDIOGRAM Exome Consortium, Biological Sciences, Medical and Health Sciences, Medical biotechnology, Biomedical engineering
Abstract

Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.

Published
2016

6. Association of Forced Vital Capacity with the Developmental Gene NCOR2

Author

Minelli, Cosetta, Dean, Charlotte H, Hind, Matthew, Alves, Alexessander Couto, Amaral, André FS, Siroux, Valerie, Huikari, Ville, Soler Artigas, María, Evans, David M, Loth, Daan W, Bossé, Yohan, Postma, Dirkje S, Sin, Don, Thompson, John, Demenais, Florence, Henderson, John, Bouzigon, Emmanuelle, Jarvis, Deborah, Järvelin, Marjo-Riitta, and Burney, Peter

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Epidemiology, Health Sciences, Lung, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Respiratory, Adult, Aged, Female, Forced Expiratory Volume, Gene Expression Profiling, Genes, Developmental, Genetic Association Studies, Genome-Wide Association Study, Humans, Male, Middle Aged, Nuclear Receptor Co-Repressor 2, Organogenesis, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Young Adult, SpiroMeta consortium, CHARGE consortium, General Science & Technology
Abstract

BackgroundForced Vital Capacity (FVC) is an important predictor of all-cause mortality in the absence of chronic respiratory conditions. Epidemiological evidence highlights the role of early life factors on adult FVC, pointing to environmental exposures and genes affecting lung development as risk factors for low FVC later in life. Although highly heritable, a small number of genes have been found associated with FVC, and we aimed at identifying further genetic variants by focusing on lung development genes.MethodsPer-allele effects of 24,728 SNPs in 403 genes involved in lung development were tested in 7,749 adults from three studies (NFBC1966, ECRHS, EGEA). The most significant SNP for the top 25 genes was followed-up in 46,103 adults (CHARGE and SpiroMeta consortia) and 5,062 children (ALSPAC). Associations were considered replicated if the replication p-value survived Bonferroni correction (p

Published
2016

7. Structural Brain MRI Trait Polygenic Score Prediction of Cognitive Abilities

Author

Luciano, Michelle, Marioni, Riccardo E, Hernández, Maria Valdés, Maniega, Susana Muñoz, Hamilton, Iona F, Royle, Natalie A, Chauhan, Ganesh, Bis, Joshua C, Debette, Stephanie, DeCarli, Charles, Fornage, Myriam, Schmidt, Reinhold, Ikram, M Arfan, Launer, Lenore J, Seshadri, Sudha, Bastin, Mark E, Porteous, David J, Wardlaw, Joanna, and Deary, Ian J

Subjects
Reproductive Medicine, Biomedical and Clinical Sciences, Clinical Sciences, Clinical Research, Biomedical Imaging, Brain Disorders, Neurosciences, Prevention, Basic Behavioral and Social Science, Behavioral and Social Science, Mental Health, Aging, Aetiology, 2.1 Biological and endogenous factors, Mental health, Neurological, Brain, Cognition, Female, Forecasting, Genome-Wide Association Study, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Multifactorial Inheritance, Neuropsychological Tests, polygenic prediction, white matter hyperintensities, brain infarct, intracranial volume, hippocampal volume, total brain volume, general cognitive ability, Generation Scotland, CHARGE Consortium, Paediatrics and Reproductive Medicine, Cognitive Sciences, Genetics & Heredity, Clinical sciences, Reproductive medicine
Abstract

Structural brain magnetic resonance imaging (MRI) traits share part of their genetic variance with cognitive traits. Here, we use genetic association results from large meta-analytic studies of genome-wide association (GWA) for brain infarcts (BI), white matter hyperintensities, intracranial, hippocampal, and total brain volumes to estimate polygenic scores for these traits in three Scottish samples: Generation Scotland: Scottish Family Health Study (GS:SFHS), and the Lothian Birth Cohorts of 1936 (LBC1936) and 1921 (LBC1921). These five brain MRI trait polygenic scores were then used to: (1) predict corresponding MRI traits in the LBC1936 (numbers ranged 573 to 630 across traits), and (2) predict cognitive traits in all three cohorts (in 8,115-8,250 persons). In the LBC1936, all MRI phenotypic traits were correlated with at least one cognitive measure, and polygenic prediction of MRI traits was observed for intracranial volume. Meta-analysis of the correlations between MRI polygenic scores and cognitive traits revealed a significant negative correlation (maximal r = 0.08) between the HV polygenic score and measures of global cognitive ability collected in childhood and in old age in the Lothian Birth Cohorts. The lack of association to a related general cognitive measure when including the GS:SFHS points to either type 1 error or the importance of using prediction samples that closely match the demographics of the GWA samples from which prediction is based. Ideally, these analyses should be repeated in larger samples with data on both MRI and cognition, and using MRI GWA results from even larger meta-analysis studies.

Published
2015

8. The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.

Author

Winkler, Thomas W, Justice, Anne E, Graff, Mariaelisa, Barata, Llilda, Feitosa, Mary F, Chu, Su, Czajkowski, Jacek, Esko, Tõnu, Fall, Tove, Kilpeläinen, Tuomas O, Lu, Yingchang, Mägi, Reedik, Mihailov, Evelin, Pers, Tune H, Rüeger, Sina, Teumer, Alexander, Ehret, Georg B, Ferreira, Teresa, Heard-Costa, Nancy L, Karjalainen, Juha, Lagou, Vasiliki, Mahajan, Anubha, Neinast, Michael D, Prokopenko, Inga, Simino, Jeannette, Teslovich, Tanya M, Jansen, Rick, Westra, Harm-Jan, White, Charles C, Absher, Devin, Ahluwalia, Tarunveer S, Ahmad, Shafqat, Albrecht, Eva, Alves, Alexessander Couto, Bragg-Gresham, Jennifer L, de Craen, Anton JM, Bis, Joshua C, Bonnefond, Amélie, Boucher, Gabrielle, Cadby, Gemma, Cheng, Yu-Ching, Chiang, Charleston WK, Delgado, Graciela, Demirkan, Ayse, Dueker, Nicole, Eklund, Niina, Eiriksdottir, Gudny, Eriksson, Joel, Feenstra, Bjarke, Fischer, Krista, Frau, Francesca, Galesloot, Tessel E, Geller, Frank, Goel, Anuj, Gorski, Mathias, Grammer, Tanja B, Gustafsson, Stefan, Haitjema, Saskia, Hottenga, Jouke-Jan, Huffman, Jennifer E, Jackson, Anne U, Jacobs, Kevin B, Johansson, Åsa, Kaakinen, Marika, Kleber, Marcus E, Lahti, Jari, Mateo Leach, Irene, Lehne, Benjamin, Liu, Youfang, Lo, Ken Sin, Lorentzon, Mattias, Luan, Jian'an, Madden, Pamela AF, Mangino, Massimo, McKnight, Barbara, Medina-Gomez, Carolina, Monda, Keri L, Montasser, May E, Müller, Gabriele, Müller-Nurasyid, Martina, Nolte, Ilja M, Panoutsopoulou, Kalliope, Pascoe, Laura, Paternoster, Lavinia, Rayner, Nigel W, Renström, Frida, Rizzi, Federica, Rose, Lynda M, Ryan, Kathy A, Salo, Perttu, Sanna, Serena, Scharnagl, Hubert, Shi, Jianxin, Smith, Albert Vernon, Southam, Lorraine, Stančáková, Alena, Steinthorsdottir, Valgerdur, Strawbridge, Rona J, Sung, Yun Ju, and Tachmazidou, Ioanna

Subjects
CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global-BPGen Consortium, ICBP Consortium, MAGIC Consortium, Humans, Genetic Predisposition to Disease, Body Mass Index, Body Size, Waist-Hip Ratio, Chromosome Mapping, Age Factors, Sex Characteristics, Polymorphism, Single Nucleotide, Adult, Aged, Middle Aged, European Continental Ancestry Group, Female, Male, Genome-Wide Association Study, Developmental Biology, Genetics
Abstract

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR

Published
2015

9. Common genetic variants influence human subcortical brain structures

Author

Hibar, Derrek P, Stein, Jason L, Renteria, Miguel E, Arias-Vasquez, Alejandro, Desrivières, Sylvane, Jahanshad, Neda, Toro, Roberto, Wittfeld, Katharina, Abramovic, Lucija, Andersson, Micael, Aribisala, Benjamin S, Armstrong, Nicola J, Bernard, Manon, Bohlken, Marc M, Boks, Marco P, Bralten, Janita, Brown, Andrew A, Mallar Chakravarty, M, Chen, Qiang, Ching, Christopher RK, Cuellar-Partida, Gabriel, den Braber, Anouk, Giddaluru, Sudheer, Goldman, Aaron L, Grimm, Oliver, Guadalupe, Tulio, Hass, Johanna, Woldehawariat, Girma, Holmes, Avram J, Hoogman, Martine, Janowitz, Deborah, Jia, Tianye, Kim, Sungeun, Klein, Marieke, Kraemer, Bernd, Lee, Phil H, Olde Loohuis, Loes M, Luciano, Michelle, Macare, Christine, Mather, Karen A, Mattheisen, Manuel, Milaneschi, Yuri, Nho, Kwangsik, Papmeyer, Martina, Ramasamy, Adaikalavan, Risacher, Shannon L, Roiz-Santiañez, Roberto, Rose, Emma J, Salami, Alireza, Sämann, Philipp G, Schmaal, Lianne, Schork, Andrew J, Shin, Jean, Strike, Lachlan T, Teumer, Alexander, van Donkelaar, Marjolein MJ, van Eijk, Kristel R, Walters, Raymond K, Westlye, Lars T, Whelan, Christopher D, Winkler, Anderson M, Zwiers, Marcel P, Alhusaini, Saud, Athanasiu, Lavinia, Ehrlich, Stefan, Hakobjan, Marina MH, Hartberg, Cecilie B, Haukvik, Unn K, Heister, Angelien JGAM, Hoehn, David, Kasperaviciute, Dalia, Liewald, David CM, Lopez, Lorna M, Makkinje, Remco RR, Matarin, Mar, Naber, Marlies AM, Reese McKay, D, Needham, Margaret, Nugent, Allison C, Pütz, Benno, Royle, Natalie A, Shen, Li, Sprooten, Emma, Trabzuni, Daniah, van der Marel, Saskia SL, van Hulzen, Kimm JE, Walton, Esther, Wolf, Christiane, Almasy, Laura, Ames, David, Arepalli, Sampath, Assareh, Amelia A, Bastin, Mark E, Brodaty, Henry, Bulayeva, Kazima B, Carless, Melanie A, Cichon, Sven, Corvin, Aiden, Curran, Joanne E, and Czisch, Michael

Subjects
Biological Psychology, Biological Sciences, Genetics, Psychology, Brain Disorders, Human Genome, Mental Health, Neurosciences, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Neurological, Mental health, Adolescent, Adult, Aged, Aged, 80 and over, Aging, Apoptosis, Brain, Caudate Nucleus, Child, Female, Gene Expression Regulation, Developmental, Genetic Loci, Genetic Variation, Genome-Wide Association Study, Hippocampus, Humans, Magnetic Resonance Imaging, Male, Membrane Proteins, Middle Aged, Organ Size, Putamen, Sex Characteristics, Skull, Young Adult, Alzheimer’s Disease Neuroimaging Initiative, CHARGE Consortium, EPIGEN, IMAGEN, SYS, General Science & Technology
Abstract

The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.

Published
2015

10. Sequencing of SCN5A Identifies Rare and Common Variants Associated With Cardiac Conduction

Author

Magnani, Jared W, Brody, Jennifer A, Prins, Bram P, Arking, Dan E, Lin, Honghuang, Yin, Xiaoyan, Liu, Ching-Ti, Morrison, Alanna C, Zhang, Feng, Spector, Tim D, Alonso, Alvaro, Bis, Joshua C, Heckbert, Susan R, Lumley, Thomas, Sitlani, Colleen M, Cupples, L Adrienne, Lubitz, Steven A, Soliman, Elsayed Z, Pulit, Sara L, Newton-Cheh, Christopher, O'Donnell, Christopher J, Ellinor, Patrick T, Benjamin, Emelia J, Muzny, Donna M, Gibbs, Richard A, Santibanez, Jireh, Taylor, Herman A, Rotter, Jerome I, Lange, Leslie A, Psaty, Bruce M, Jackson, Rebecca, Rich, Stephen S, Boerwinkle, Eric, Jamshidi, Yalda, and Sotoodehnia, Nona

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Human Genome, Heart Disease, Biotechnology, Genetics, Clinical Research, Cardiovascular, 2.1 Biological and endogenous factors, Aetiology, Adult, Aged, Aged, 80 and over, Aging, Cohort Studies, Female, Genetic Variation, Genome-Wide Association Study, Genomics, Heart Conduction System, Heart Diseases, Humans, Male, Middle Aged, NAV1.5 Voltage-Gated Sodium Channel, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, electrocardiography, genomics, CHARGE Consortium, NHLBI Exome Sequencing Project, UK10K, Medical Biotechnology, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology
Abstract

BackgroundThe cardiac sodium channel SCN5A regulates atrioventricular and ventricular conduction. Genetic variants in this gene are associated with PR and QRS intervals. We sought to characterize further the contribution of rare and common coding variation in SCN5A to cardiac conduction.Methods and resultsIn Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study, we performed targeted exonic sequencing of SCN5A (n=3699, European ancestry individuals) and identified 4 common (minor allele frequency >1%) and 157 rare variants. Common and rare SCN5A coding variants were examined for association with PR and QRS intervals through meta-analysis of European ancestry participants from CHARGE, National Heart, Lung, and Blood Institute's Exome Sequencing Project (n=607), and the UK10K (n=1275) and by examining Exome Sequencing Project African ancestry participants (n=972). Rare coding SCN5A variants in aggregate were associated with PR interval in European and African ancestry participants (P=1.3×10(-3)). Three common variants were associated with PR and QRS interval duration among European ancestry participants and one among African ancestry participants. These included 2 well-known missense variants: rs1805124 (H558R) was associated with PR and QRS shortening in European ancestry participants (P=6.25×10(-4) and P=5.2×10(-3), respectively) and rs7626962 (S1102Y) was associated with PR shortening in those of African ancestry (P=2.82×10(-3)). Among European ancestry participants, 2 novel synonymous variants, rs1805126 and rs6599230, were associated with cardiac conduction. Our top signal, rs1805126 was associated with PR and QRS lengthening (P=3.35×10(-7) and P=2.69×10(-4), respectively) and rs6599230 was associated with PR shortening (P=2.67×10(-5)).ConclusionsBy sequencing SCN5A, we identified novel common and rare coding variants associated with cardiac conduction.

Published
2014

11. Genome-wide association analysis of red blood cell traits in African Americans: the COGENT Network

Author

Chen, Zhao, Tang, Hua, Qayyum, Rehan, Schick, Ursula M, Nalls, Michael A, Handsaker, Robert, Li, Jin, Lu, Yingchang, Yanek, Lisa R, Keating, Brendan, Meng, Yan, van Rooij, Frank JA, Okada, Yukinori, Kubo, Michiaki, Rasmussen-Torvik, Laura, Keller, Margaux F, Lange, Leslie, Evans, Michele, Bottinger, Erwin P, Linderman, Michael D, Ruderfer, Douglas M, Hakonarson, Hakon, Papanicolaou, George, Zonderman, Alan B, Gottesman, Omri, Project, CHARGE Consortium BioBank Japan, Thomson, Cynthia, Ziv, Elad, Singleton, Andrew B, Loos, Ruth JF, Sleiman, Patrick MA, Ganesh, Santhi, McCarroll, Steven, Becker, Diane M, Wilson, James G, Lettre, Guillaume, and Reiner, Alexander P

Subjects
Biological Sciences, Genetics, Human Genome, Clinical Research, Hematology, Aetiology, 2.1 Biological and endogenous factors, Blood, Adolescent, Adult, Black or African American, Child, Chromosomes, Human, Pair 16, Cohort Studies, Erythrocyte Count, Erythrocyte Indices, Erythrocytes, Female, Genome-Wide Association Study, Hemoglobins, Humans, Male, Polymorphism, Single Nucleotide, White People, Young Adult, alpha-Globins, BioBank Japan Project, CHARGE Consortium, Medical and Health Sciences, Genetics & Heredity
Abstract

Laboratory red blood cell (RBC) measurements are clinically important, heritable and differ among ethnic groups. To identify genetic variants that contribute to RBC phenotypes in African Americans (AAs), we conducted a genome-wide association study in up to ~16 500 AAs. The alpha-globin locus on chromosome 16pter [lead SNP rs13335629 in ITFG3 gene; P < 1E-13 for hemoglobin (Hgb), RBC count, mean corpuscular volume (MCV), MCH and MCHC] and the G6PD locus on Xq28 [lead SNP rs1050828; P < 1E - 13 for Hgb, hematocrit (Hct), MCV, RBC count and red cell distribution width (RDW)] were each associated with multiple RBC traits. At the alpha-globin region, both the common African 3.7 kb deletion and common single nucleotide polymorphisms (SNPs) appear to contribute independently to RBC phenotypes among AAs. In the 2p21 region, we identified a novel variant of PRKCE distinctly associated with Hct in AAs. In a genome-wide admixture mapping scan, local European ancestry at the 6p22 region containing HFE and LRRC16A was associated with higher Hgb. LRRC16A has been previously associated with the platelet count and mean platelet volume in AAs, but not with Hgb. Finally, we extended to AAs the findings of association of erythrocyte traits with several loci previously reported in Europeans and/or Asians, including CD164 and HBS1L-MYB. In summary, this large-scale genome-wide analysis in AAs has extended the importance of several RBC-associated genetic loci to AAs and identified allelic heterogeneity and pleiotropy at several previously known genetic loci associated with blood cell traits in AAs.

Published
2013

12. A Genome-Wide Association Study of Depressive Symptoms

Author

Hek, Karin, Demirkan, Ayse, Lahti, Jari, Terracciano, Antonio, Teumer, Alexander, Cornelis, Marilyn C, Amin, Najaf, Bakshis, Erin, Baumert, Jens, Ding, Jingzhong, Liu, Yongmei, Marciante, Kristin, Meirelles, Osorio, Nalls, Michael A, Sun, Yan V, Vogelzangs, Nicole, Yu, Lei, Bandinelli, Stefania, Benjamin, Emelia J, Bennett, David A, Boomsma, Dorret, Cannas, Alessandra, Coker, Laura H, de Geus, Eco, De Jager, Philip L, Diez-Roux, Ana V, Purcell, Shaun, Hu, Frank B, Rimm, Eric B, Hunter, David J, Jensen, Majken K, Curhan, Gary, Rice, Kenneth, Penman, Alan D, Rotter, Jerome I, Sotoodehnia, Nona, Emeny, Rebecca, Eriksson, Johan G, Evans, Denis A, Ferrucci, Luigi, Fornage, Myriam, Gudnason, Vilmundur, Hofman, Albert, Illig, Thomas, Kardia, Sharon, Kelly-Hayes, Margaret, Koenen, Karestan, Kraft, Peter, Kuningas, Maris, Massaro, Joseph M, Melzer, David, Mulas, Antonella, Mulder, Cornelis L, Murray, Anna, Oostra, Ben A, Palotie, Aarno, Penninx, Brenda, Petersmann, Astrid, Pilling, Luke C, Psaty, Bruce, Rawal, Rajesh, Reiman, Eric M, Schulz, Andrea, Shulman, Joshua M, Singleton, Andrew B, Smith, Albert V, Sutin, Angelina R, Uitterlinden, André G, Völzke, Henry, Widen, Elisabeth, Yaffe, Kristine, Zonderman, Alan B, Cucca, Francesco, Harris, Tamara, Ladwig, Karl-Heinz, Llewellyn, David J, Räikkönen, Katri, Tanaka, Toshiko, van Duijn, Cornelia M, Grabe, Hans J, Launer, Lenore J, Lunetta, Kathryn L, Mosley, Thomas H, Newman, Anne B, Tiemeier, Henning, and Murabito, Joanne

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Mental Illness, Clinical Research, Brain Disorders, Depression, Human Genome, Mental Health, 2.1 Biological and endogenous factors, Aged, Aged, 80 and over, Chromosomes, Human, Pair 5, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Center for Epidemiologic Studies Depression Scale, CHARGE consortium, depression, depressive symptoms, genetics, genome-wide association study, meta-analysis, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Biological sciences, Biomedical and clinical sciences, Psychology
Abstract

BackgroundDepression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms.MethodsIn this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p

Published
2013

13. Genome-Wide Interaction Analysis with DASH Diet Score Identified Novel Loci for Systolic Blood Pressure.

Author

Guirette M, Lan J, McKeown N, Brown MR, Chen H, DE Vries PS, Kim H, Rebholz CM, Morrison AC, Bartz TM, Fretts AM, Guo X, Lemaitre RN, Liu CT, Noordam R, DE Mutsert R, Rosendaal FR, Wang CA, Beilin L, Mori TA, Oddy WH, Pennell CE, Chai JF, Whitton C, VAN Dam RM, Liu J, Tai ES, Sim X, Neuhouser ML, Kooperberg C, Tinker L, Franceschini N, Huan T, Winkler TW, Bentley AR, Gauderman WJ, Heerkens L, Tanaka T, van Rooij J, Munroe PB, Warren HR, Voortman T, Chen H, Rao DC, Levy D, and Ma J

Abstract

Objective: We examined interactions between genotype and a Dietary Approaches to Stop Hypertension (DASH) diet score in relation to systolic blood pressure (SBP)., Methods: We analyzed up to 9,420,585 biallelic imputed single nucleotide polymorphisms (SNPs) in up to 127,282 individuals of six population groups (91% of European population) from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (CHARGE; n=35,660) and UK Biobank (n=91,622) and performed European population-specific and cross-population meta-analyses., Results: We identified three loci in European-specific analyses and an additional four loci in cross-population analyses at P for interaction < 5e-8. We observed a consistent interaction between rs117878928 at 15q25.1 (minor allele frequency = 0.03) and the DASH diet score (P for interaction = 4e-8; P for heterogeneity = 0.35) in European population, where the interaction effect size was 0.42±0.09 mm Hg (P for interaction = 9.4e-7) and 0.20±0.06 mm Hg (P for interaction = 0.001) in CHARGE and the UK Biobank, respectively. The 1 Mb region surrounding rs117878928 was enriched with cis -expression quantitative trait loci (eQTL) variants (P = 4e-273) and cis -DNA methylation quantitative trait loci (mQTL) variants (P = 1e-300). While the closest gene for rs117878928 is MTHFS , the highest narrow sense heritability accounted by SNPs potentially interacting with the DASH diet score in this locus was for gene ST20 at 15q25.1., Conclusion: We demonstrated gene-DASH diet score interaction effects on SBP in several loci. Studies with larger diverse populations are needed to validate our findings.

Published
2023
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14. An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype.

Author

Direk, Nese, Williams, Stephanie, Smith, Jennifer A., Ripke, Stephan, Air, Tracy, Amare, Azmeraw T., Amin, Najaf, Baune, Bernhard T., Bennett, David A., Blackwood, Douglas H.R., Boomsma, Dorret, Breen, Gerome, Buttenschøn, Henriette N., Byrne, Enda M., Børglum, Anders D., Castelao, Enrique, Cichon, Sven, Clarke, Toni-Kim, Cornelis, Marilyn C., and Dannlowski, Udo

Subjects
*MENTAL depression, *AFFECTIVE disorders, *SINGLE nucleotide polymorphisms, *GENETIC polymorphisms, *HELPLESSNESS (Psychology), *ANTIDEPRESSANTS
Abstract

Background The genetics of depression has been explored in genome-wide association studies that focused on either major depressive disorder or depressive symptoms with mostly negative findings. A broad depression phenotype including both phenotypes has not been tested previously using a genome-wide association approach. We aimed to identify genetic polymorphisms significantly associated with a broad phenotype from depressive symptoms to major depressive disorder. Methods We analyzed two prior studies of 70,017 participants of European ancestry from general and clinical populations in the discovery stage. We performed a replication meta-analysis of 28,328 participants. Single nucleotide polymorphism (SNP)-based heritability and genetic correlations were calculated using linkage disequilibrium score regression. Discovery and replication analyses were performed using a p -value-based meta-analysis. Lifetime major depressive disorder and depressive symptom scores were used as the outcome measures. Results The SNP-based heritability of major depressive disorder was 0.21 (SE = 0.02), the SNP-based heritability of depressive symptoms was 0.04 (SE = 0.01), and their genetic correlation was 1.001 (SE = 0.2). We found one genome-wide significant locus related to the broad depression phenotype (rs9825823, chromosome 3: 61,082,153, p = 8.2 × 10 –9 ) located in an intron of the FHIT gene. We replicated this SNP in independent samples ( p = .02) and the overall meta-analysis of the discovery and replication cohorts (1.0 × 10 –9 ). Conclusions This large study identified a new locus for depression. Our results support a continuum between depressive symptoms and major depressive disorder. A phenotypically more inclusive approach may help to achieve the large sample sizes needed to detect susceptibility loci for depression. [ABSTRACT FROM AUTHOR]

Published
2017
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15. Gene-based analysis in HRC imputed genome wide association data identifies three novel genes for Alzheimer’s disease

Author

Sudha Seshadri, John Hardy, Wolfgang Maier, Janet C Harwood, Emily Baker, Carol Brayne, Julie Williams, Lesley Jones, Gerard D. Schellenberg, Reinhard Heun, Frank Jessen, Valentina Escott-Price, Matthew Hill, Oliver Peters, John Powell, Dobril Ivanov, Peter Passmore, Martin Dichgans, Lutz Frölich, Alfredo Ramirez, Aura Frizzati, Alison Goate, Kevin Morgan, Paul Morgan, Carlos Cruchaga, Ganna Leonenko, Gianfranco Spalletta, Paola Bossù, Michael Gill, Clive Holmes, Simon Mead, Detelina Grozeva, Peter Holmans, Philippe Amouyel, Rebecca Sims, Nicholas D. Allen, Baker, Emily [0000-0001-5691-597X], Grozeva, Detelina [0000-0003-3239-8415], Brayne, Carol [0000-0001-5307-663X], Mead, Simon [0000-0002-4326-1468], Ramirez, Alfredo [0000-0003-4991-763X], Ivanov, Dobril [0000-0001-6271-6301], Hill, Matthew [0000-0001-6776-8709], Holmans, Peter [0000-0003-0870-9412], Schellenberg, Gerard D [0000-0003-1115-2475], Apollo - University of Cambridge Repository, van Duijn, Cornelia [0000-0002-2374-9204], and Williams, Julie [0000-0002-4069-0259]

Subjects
0301 basic medicine, Male, DNA Repair, Gene Expression, Social Sciences, genetics [Alzheimer Disease], genetics [Cholesterol], Genome-wide association study, Alzheimer's Disease, Biochemistry, IGAP consortia, pathology [Centrosome], pathology [Alzheimer Disease], 0302 clinical medicine, Sociology, metabolism [Centrosome], Consortia, Medicine and Health Sciences, genetics [Amyloid beta-Peptides], Genetics, Regulation of gene expression, metabolism [Inflammation], Multidisciplinary, biology, metabolism [Proteins], Neurodegenerative Diseases, Nuclear Receptor Subfamily 1, Group F, Member 1, Genomics, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Circadian Rhythm, Circadian Rhythms, Cholesterol, Neurology, Medicine, Female, metabolism [Alzheimer Disease], Research Article, medicine.medical_specialty, genetics [Circadian Rhythm], Amyloid beta, Science, Lipoproteins, metabolism [Amyloid beta-Peptides], Single-nucleotide polymorphism, genetics [Energy Metabolism], Polymorphism, Single Nucleotide, GERAD Consortium, Apolipoprotein Genes, Molecular Genetics, genetics [Inflammation], 03 medical and health sciences, Alzheimer Disease, genetics [Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha], Molecular genetics, Mental Health and Psychiatry, medicine, Genome-Wide Association Studies, GERAD/PERADES, Dementia, Humans, genetics [DNA Damage], Gene Regulation, ddc:610, genetics [DNA Repair], Gene, Molecular Biology, EADI Consortium, pathology [Inflammation], Centrosome, Inflammation, Amyloid beta-Peptides, Genome, Human, Biology and Life Sciences, Proteins, Computational Biology, Human Genetics, metabolism [Cholesterol], medicine.disease, Genome Analysis, ADGC Consortium, genetics [Proteins], 030104 developmental biology, metabolism [Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha], CHARGE Consortium, biology.protein, Energy Metabolism, Chronobiology, 030217 neurology & neurosurgery, genetics [Nuclear Receptor Subfamily 1, Group F, Member 1], metabolism [Nuclear Receptor Subfamily 1, Group F, Member 1], DNA Damage, Genome-Wide Association Study
Abstract

A novel POLARIS gene-based analysis approach was employed to compute gene-based polygenic risk score (PRS) for all individuals in the latest HRC imputed GERAD (N cases=3,332 and N controls=9,832) data using the International Genomics of Alzheimer’s Project summary statistics (N cases=13,676 and N controls=27,322, excluding GERAD subjects) to identify the SNPs and weight their risk alleles for the PRS score. SNPs were assigned to known, protein coding genes using GENCODE (v19). SNPs are assigned using both 1) no window around the gene and 2) a window of 35kb upstream and 10kb downstream to include transcriptional regulatory elements. The overall association of a gene is determined using a logistic regression model, adjusting for population covariates. Three novel gene-wide significant genes were determined from the POLARIS gene-based analysis using a gene window; PPARGC1A, RORA and ZNF423 . The ZNF423 gene resides in an Alzheimer’s disease (AD)-specific protein network which also includes other AD-related genes. The PPARGC1A gene has been linked to energy metabolism and the generation of amyloid beta plaques and the RORA has strong links with genes which are differentially expressed in the hippocampus. We also demonstrate no enrichment for genes in either loss of function intolerant or conserved noncoding sequence regions.

Published
2019

16. Cystatin C and Cardiovascular Disease A Mendelian Randomization Study

Subjects
CHRONIC KIDNEY-DISEASE, RISK, SUSCEPTIBILITY LOCI, INCIDENT HEART-FAILURE, heart failure, COMMON VARIANTS, CHARGE CONSORTIUM, BODY-MASS INDEX, ISCHEMIC-STROKE, ischemic stroke, CORONARY-ARTERY-DISEASE, genetics, coronary heart disease, GENOME-WIDE ASSOCIATION
Abstract

BACKGROUND Epidemiological studies show that high circulating cystatin C is associated with risk of cardiovascular disease (CVD), independent of creatinine-based renal function measurements. It is unclear whether this relationship is causal, arises from residual confounding, and/or is a consequence of reverse causation.OBJECTIVES The aim of this study was to use Mendelian randomization to investigate whether cystatin C is causally related to CVD in the general population.METHODS We incorporated participant data from 16 prospective cohorts (n = 76,481) with 37,126 measures of cystatin C and added genetic data from 43 studies (n = 252,216) with 63,292 CVD events. We used the common variant rs911119 in CST3 as an instrumental variable to investigate the causal role of cystatin C in CVD, including coronary heart disease, ischemic stroke, and heart failure.RESULTS Cystatin C concentrations were associated with CVD risk after adjusting for age, sex, and traditional risk factors (relative risk: 1.82 per doubling of cystatin C; 95% confidence interval [CI]: 1.56 to 2.13; p = 2.12 x 10(-14)). The minor allele of rs911119 was associated with decreased serum cystatin C (6.13% per allele; 95% CI: 5.75 to 6.50; p = 5.95 x 10(-211)), explaining 2.8% of the observed variation in cystatin C. Mendelian randomization analysis did not provide evidence fora causal role of cystatin C, with a causal relative risk for CVD of 1.00 per doubling cystatin C (95% CI: 0.82 to 1.22; p = 0,994), which was statistically different from the observational estimate (p = 1.6 x 10(-5)). A causal effect of cystatin C was not detected for any individual component of CVD.CONCLUSIONS Mendelian randomization analyses did not support a causal role of cystatin C in the etiology of CVD. As such, therapeutics targeted at lowering circulating cystatin C are unlikely to be effective in preventing CVD. (C) 2016 The Authors. Published by Elsevier Inc. on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license.

Published
2016

17. Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis

Author

Nora Franceschini, Lawrence F. Bielak, Anne B. Newman, Maryam Kavousi, Dennis O. Mook-Kanamori, Usman Baber, Shih-Jen Hwang, Lisa R. Yanek, Dermot F. Reilly, Amanda J. Cox, Sharon L.R. Kardia, Gerardo Heiss, Bob D. de Vos, Mika Kähönen, Pradeep Natarajan, Sekar Kathiresan, Mark O. Goodarzi, James G. Wilson, Joanna M. Wardlaw, Thomas H. Mosley, Donald W. Bowden, Dhananjay Vaidya, Nathan O. Stitziel, Michael A. Province, Bruce M. Psaty, Wendy Post, Gina M. Peloso, Jeffrey R. O'Connell, Laura M. Raffield, Stephen Turner, Patricia A. Peyser, Yii-Der Ida Chen, Hayato Tada, Joshua C. Bis, Kari E. North, Renée de Mutsert, Abbas Dehghan, Albert Hofman, Aaron Isaacs, Tamara B. Harris, Udo Hoffmann, Daniel J. Rader, Laura M. Yerges-Armstrong, Jessica van Setten, Kent D. Taylor, Matthijs Oudkerk, Braxton D. Mitchell, Xiuqing Guo, Aad van der Lugt, Harry J. de Koning, Vilmundur Gudnason, Riccardo E. Marioni, Cornelia M. van Duijn, Ingrid B. Borecki, Jerome I. Rotter, Oscar H. Franco, Roxana Mehran, Ivana Išgum, Pim A. de Jong, L. Adrienne Cupples, J. Wouter Jukema, Ruifang Li-Gao, Valentin Fuster, Fernando Rivadeneira, Ulf Schminke, Eric Boerwinkle, Alexander Teumer, Henry Völzke, Frits R. Rosendaal, Stefan Weiss, Leo-Pekka Lyytikäinen, Susan R. Heckbert, Jie Yao, Uwe Völker, James S. Pankow, Ian J. Deary, Stella Trompet, J. Jeffrey Carr, Mary K. Wojczynski, Christopher J. O'Donnell, Albert V. Smith, Mary F. Feitosa, Samantha Sartori, Stephan B. Felix, Ayse Demirkan, Olli T. Raitakari, Diane M. Becker, Terho Lehtimäki, Marcus Dörr, Khanh-Dung H. Nguyen, Brian G. Kral, Min A. Jhun, Rasika A. Mathias, André G. Uitterlinden, Dina Vojinovic, Lewis C. Becker, Najaf Amin, Lenore J. Launer, Joseph M. Massaro, Christina L. Wassel, Academic Medical Center, Epidemiology, Public Health, Internal Medicine, Radiology & Nuclear Medicine, Erasmus MC other, Biochemie, RS: FHML MaCSBio, and RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases

Subjects
0301 basic medicine, Apolipoprotein E, Carotid Artery Diseases, Aging, Apolipoprotein B, Apolipoprotein E2, Computed Tomography Angiography, Medical Biotechnology, Genome-wide association study, Coronary Artery Disease, Cardiorespiratory Medicine and Haematology, 030204 cardiovascular system & hematology, Cardiovascular, Coronary Angiography, INTIMA-MEDIA THICKNESS, 0302 clinical medicine, Gene Frequency, Risk Factors, Odds Ratio, 2.1 Biological and endogenous factors, Exome, Myocardial infarction, Aetiology, DEFECTIVE APOLIPOPROTEIN B-100, Genetics (clinical), Oligonucleotide Array Sequence Analysis, III HYPERLIPOPROTEINEMIA, biology, CARDIOVASCULAR RISK, Prognosis, Cholesterol, Heart Disease, Phenotype, Apolipoprotein B-100, Cardiology, medicine.symptom, Cardiology and Cardiovascular Medicine, Genetic Markers, CORONARY-ARTERY CALCIFICATION, BEAM COMPUTED-TOMOGRAPHY, medicine.medical_specialty, carotid intima-media thickness, Black People, Asymptomatic, Risk Assessment, Article, White People, LDL, 03 medical and health sciences, Clinical Research, Internal medicine, Genetics, medicine, Journal Article, genomics, Humans, Genetic Predisposition to Disease, cardiovascular diseases, Vascular Calcification, Heart Disease - Coronary Heart Disease, carotid intima–media thickness, Genetic association, genome-wide association study, business.industry, ta1184, Human Genome, Cholesterol, LDL, ta3121, Atherosclerosis, medicine.disease, coronary artery calcification, HEART-DISEASE RISK, AORTIC CALCIFICATION, Good Health and Well Being, 030104 developmental biology, Cardiovascular System & Hematology, Intima-media thickness, MYOCARDIAL-INFARCTION, OLD ORDER AMISH, Asymptomatic Diseases, CHARGE Consortium, biology.protein, business, exome
Abstract

Background— The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease. We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent coronary heart disease. Methods and Results— We studied a total of 25 109 European ancestry and African ancestry participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52 869 participants with common carotid intima–media thickness measured by ultrasonography within the CHARGE Consortium (Cohorts for Heart and Aging Research in Genomic Epidemiology). Participants were genotyped for 247 870 DNA sequence variants (231 539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and carotid intima–media thickness. APOB p.Arg3527Gln was associated with 4-fold excess CAC ( P =3×10 − 10 ). The APOE ε2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC ( P =1×10 − 12 ) and 1.4% reduced carotid intima–media thickness ( P =4×10 − 14 ) in carriers compared with noncarriers. In secondary analyses conditioning on low-density lipoprotein cholesterol concentration, the ε2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ε2 was associated with reduced risk for coronary heart disease (odds ratio 0.77; P =1×10 − 11 ). Conclusions— Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE ε2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities, as well as clinical coronary heart disease.

Published
2016

18. An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype

Author

Katri Räikkönen, Myriam Fornage, Jianxin Shi, Najaf Amin, Dale R. Nyholt, Jordan W. Smoller, Tõnu Esko, Wei Zhao, Carsten Horn, Andres Metspalu, Harold Snieder, Enrique Castelao, Luigi Ferrucci, Catharina A. Hartman, Thomas G. Schulze, Stanley I. Shyn, Joanne M. Murabito, James B. Potash, Cathryn M. Lewis, Karestan C. Koenen, Azmeraw T. Amare, Jari Lahti, Stephan Ripke, Michele L. Pergadia, Cornelia M. van Duijn, Michael Conlon O'Donovan, Markus M. Nöthen, Grant C.B. Sinnamon, Rudolf Uher, Roy H. Perlis, Qingqin S. Li, Hans-Jörgen Grabe, Johannes H. Smit, Bernhard T. Baune, Donald J. MacIntyre, Erin C. Dunn, Alexander Teumer, Gonneke Willemsen, Nicholas G. Martin, Udo Dannlowski, Karin Hek, Shaun Purcell, Toni-Kim Clarke, Toshiko Tanaka, Jorge A. Quiroz, Myrna M. Weissman, Andrew M. McIntosh, Kathryn L. Lunetta, Scott D. Gordon, David R. Weir, Daniel Umbricht, Marcella Rietschel, Zoltán Kutalik, Stephanie Williams, Michael Gill, Albert Hofman, Enrico Domenici, Margarita Rivera, Pamela A. F. Madden, Jingyun Yang, John P. Rice, Sandra Van der Auwera, Steven P. Hamilton, Georg Homuth, David A. Bennett, Stefan Kloiber, Sharon L.R. Kardia, Anders D. Børglum, Sven Cichon, Nese Direk, Jessica D. Faul, Susanne Lucae, Dorret I. Boomsma, Douglas Blackwood, Jouke-Jan Hottenga, Marilyn C. Cornelis, Erin B. Ware, Enda M. Byrne, Andrew C. Heath, Philip L. De Jager, Ole Mors, Karl-Heinz Ladwig, Bertram Müller-Myhsok, Thomas H. Mosley, Jennifer A. Smith, Tracy Air, Yuri Milaneschi, Glyn Lewis, Brenda W.J.H. Penninx, David J. Llewellyn, Gerard van Grootheest, Eco J. C. de Geus, Henning Tiemeier, Grant W. Montgomery, Martin Preisig, Katherine E. Tansey, Patrick F. Sullivan, Douglas F. Levinson, Henriette N. Buttenschøn, Gerome Breen, Johan G. Eriksson, Ayse Demirkan, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, APH - Mental Health, APH - Methodology, APH - Digital Health, Epidemiology, Child and Adolescent Psychiatry / Psychology, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Biological Psychology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Clinicum, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Medicum, Department of Psychology and Logopedics, and Developmental Psychology Research Group

Subjects
DISORDER, Netherlands Twin Register (NTR), Linkage disequilibrium, SYMPTOMS, STRESS, CHARGE consortium, genetics [Depressive Disorder], Genome-wide association study, 3124 Neurology and psychiatry, 0302 clinical medicine, Neoplasm Proteins/genetics, MINOR DEPRESSION, European Continental Ancestry Group/genetics, POPULATION, RISK, Genetics, education.field_of_study, HERITABILITY, Depression, Depressive symptoms, Depression/genetics, Acid Anhydride Hydrolases, Neoplasm Proteins, 3. Good health, genetics [European Continental Ancestry Group], Phenotype, fragile histidine triad protein, Major depressive disorder, genetics [Depression], Psychology, 515 Psychology, Population, genetics [White People], Single-nucleotide polymorphism, Locus (genetics), White People, Psychiatric Genomics Consortium, FHIT gene, 03 medical and health sciences, SDG 3 - Good Health and Well-being, ddc:570, Depressive Disorder/genetics, NATIONAL COMORBIDITY SURVEY, medicine, Journal Article, Humans, SNP, genetics [Acid Anhydride Hydrolases], Genetic Predisposition to Disease, ddc:610, education, Biological Psychiatry, Genetic association, Depressive Disorder, genetics [Neoplasm Proteins], major depressive disorder, 3112 Neurosciences, MAJOR DEPRESSION, medicine.disease, SUBTHRESHOLD DEPRESSION, 030227 psychiatry, Acid Anhydride Hydrolases/genetics, Genetic Loci, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

BACKGROUND: The genetics of depression has been explored in genome-wide association studies that focused on either major depressive disorder or depressive symptoms with mostly negative findings. A broad depression phenotype including both phenotypes has not been tested previously using a genome-wide association approach. We aimed to identify genetic polymorphisms significantly associated with a broad phenotype from depressive symptoms to major depressive disorder.METHODS: We analyzed two prior studies of 70,017 participants of European ancestry from general and clinical populations in the discovery stage. We performed a replication meta-analysis of 28,328 participants. Single nucleotide polymorphism (SNP)-based heritability and genetic correlations were calculated using linkage disequilibrium score regression. Discovery and replication analyses were performed using a p-value-based meta-analysis. Lifetime major depressive disorder and depressive symptom scores were used as the outcome measures.RESULTS: The SNP-based heritability of major depressive disorder was 0.21 (SE = 0.02), the SNP-based heritability of depressive symptoms was 0.04 (SE = 0.01), and their genetic correlation was 1.001 (SE = 0.2). We found one genome-wide significant locus related to the broad depression phenotype (rs9825823, chromosome 3: 61,082,153, p = 8.2 × 10(-9)) located in an intron of the FHIT gene. We replicated this SNP in independent samples (p = .02) and the overall meta-analysis of the discovery and replication cohorts (1.0 × 10(-9)).CONCLUSIONS: This large study identified a new locus for depression. Our results support a continuum between depressive symptoms and major depressive disorder. A phenotypically more inclusive approach may help to achieve the large sample sizes needed to detect susceptibility loci for depression.

Published
2017

19. Genome-wide physical activity interactions in adiposity ― a meta-analysis of 200,452 adults

Author

Mariaelisa Graff, Robert A Scott, Anne E Justice, Kristin L Young, Mary F Feitosa, Llilda Barata, Thomas W Winkler, Audrey Y Chu, Anubha Mahajan, David Hadley, Luting Xue, Tsegaselassie Workalemahu, Nancy L Heard-Costa, Marcel den Hoed, Tarunveer S Ahluwalia, Qibin Qi, Julius S Ngwa, Frida Renström, Lydia Quaye, John D Eicher, James E Hayes, Marilyn Cornelis, Zoltan Kutalik, Elise Lim, Jian'an Luan, Jennifer E Huffman, Weihua Zhang, Wei Zhao, Paula J Griffin, Toomas Haller, Shafqat Ahmad, Pedro M Marques-Vidal, Stephanie Bien, Loic Yengo, Alexander Teumer, Albert Vernon Smith, Meena Kumari, Marie Neergaard Harder, Johanne Marie Justesen, Marcus E Kleber, Mette Hollensted, Kurt Lohman, Natalia V Rivera, John B Whitfield, Jing Hua Zhao, Heather M Stringham, Leo-Pekka Lyytikäinen, Charlotte Huppertz, Gonneke Willemsen, Wouter J Peyrot, Ying Wu, Kati Kristiansson, Ayse Demirkan, Myriam Fornage, Maija Hassinen, Lawrence F Bielak, Gemma Cadby, Toshiko Tanaka, Reedik Mägi, Peter J van der Most, Anne U Jackson, Jennifer L Bragg-Gresham, Veronique Vitart, Jonathan Marten, Pau Navarro, Claire Bellis, Dorota Pasko, Åsa Johansson, Søren Snitker, Yu-Ching Cheng, Joel Eriksson, Unhee Lim, Mette Aadahl, Linda S Adair, Najaf Amin, Beverley Balkau, Juha Auvinen, John Beilby, Richard N Bergman, Sven Bergmann, Alain G Bertoni, John Blangero, Amélie Bonnefond, Lori L Bonnycastle, Judith B Borja, Søren Brage, Fabio Busonero, Steve Buyske, Harry Campbell, Peter S Chines, Francis S Collins, Tanguy Corre, George Davey Smith, Graciela E Delgado, Nicole Dueker, Marcus Dörr, Tapani Ebeling, Gudny Eiriksdottir, Tõnu Esko, Jessica D Faul, Mao Fu, Kristine Færch, Christian Gieger, Sven Gläser, Jian Gong, Penny Gordon-Larsen, Harald Grallert, Tanja B Grammer, Niels Grarup, Gerard van Grootheest, Kennet Harald, Nicholas D Hastie, Aki S Havulinna, Dena Hernandez, Lucia Hindorff, Lynne J Hocking, Oddgeir L Holmens, Christina Holzapfel, Jouke Jan Hottenga, Jie Huang, Tao Huang, Jennie Hui, Cornelia Huth, Nina Hutri-Kähönen, Alan L James, John-Olov Jansson, Min A Jhun, Markus Juonala, Leena Kinnunen, Heikki A Koistinen, Ivana Kolcic, Pirjo Komulainen, Johanna Kuusisto, Kirsti Kvaløy, Mika Kähönen, Timo A Lakka, Lenore J Launer, Benjamin Lehne, Cecilia M Lindgren, Mattias Lorentzon, Robert Luben, Michel Marre, Yuri Milaneschi, Keri L Monda, Grant W Montgomery, Marleen H M De Moor, Antonella Mulas, Martina Müller-Nurasyid, A W Musk, Reija Männikkö, Satu Männistö, Narisu Narisu, Matthias Nauck, Jennifer A Nettleton, Ilja M Nolte, Albertine J Oldehinkel, Matthias Olden, Ken K Ong, Sandosh Padmanabhan, Lavinia Paternoster, Jeremiah Perez, Markus Perola, Annette Peters, Ulrike Peters, Patricia A Peyser, Inga Prokopenko, Hannu Puolijoki, Olli T Raitakari, Tuomo Rankinen, Laura J Rasmussen-Torvik, Rajesh Rawal, Paul M Ridker, Lynda M Rose, Igor Rudan, Cinzia Sarti, Mark A Sarzynski, Kai Savonen, William R Scott, Serena Sanna, Alan R Shuldiner, Steve Sidney, Günther Silbernagel, Blair H Smith, Jennifer A Smith, Harold Snieder, Alena Stančáková, Barbara Sternfeld, Amy J Swift, Tuija Tammelin, Sian-Tsung Tan, Barbara Thorand, Dorothée Thuillier, Liesbeth Vandenput, Henrik Vestergaard, Jana V van Vliet-Ostaptchouk, Marie-Claude Vohl, Uwe Völker, Gérard Waeber, Mark Walker, Sarah Wild, Andrew Wong, Alan F Wright, M Carola Zillikens, Niha Zubair, Christopher A Haiman, Loic Lemarchand, Ulf Gyllensten, Claes Ohlsson, Albert Hofman, Fernando Rivadeneira, André G Uitterlinden, Louis Pérusse, James F Wilson, Caroline Hayward, Ozren Polasek, Francesco Cucca, Kristian Hveem, Catharina A Hartman, Anke Tönjes, Stefania Bandinelli, Lyle J Palmer, Sharon L R Kardia, Rainer Rauramaa, Thorkild I A Sørensen, Jaakko Tuomilehto, Veikko Salomaa, Brenda W J H Penninx, Eco J C de Geus, Dorret I Boomsma, Terho Lehtimäki, Massimo Mangino, Markku Laakso, Claude Bouchard, Nicholas G Martin, Diana Kuh, Yongmei Liu, Allan Linneberg, Winfried März, Konstantin Strauch, Mika Kivimäki, Tamara B Harris, Vilmundur Gudnason, Henry Völzke, Lu Qi, Marjo-Riitta Järvelin, John C Chambers, Jaspal S Kooner, Philippe Froguel, Charles Kooperberg, Peter Vollenweider, Göran Hallmans, Torben Hansen, Oluf Pedersen, Andres Metspalu, Nicholas J Wareham, Claudia Langenberg, David R Weir, David J Porteous, Eric Boerwinkle, Daniel I Chasman, CHARGE Consortium, EPIC-InterAct Consortium, PAGE Consortium, Gonçalo R Abecasis, Inês Barroso, Mark I McCarthy, Timothy M Frayling, Jeffrey R O'Connell, Cornelia M van Duijn, Michael Boehnke, Iris M Heid, Karen L Mohlke, David P Strachan, Caroline S Fox, Ching-Ti Liu, Joel N Hirschhorn, Robert J Klein, Andrew D Johnson, Ingrid B Borecki, Paul W Franks, Kari E North, L Adrienne Cupples, Ruth J F Loos, Tuomas O Kilpeläinen, Molecular Genetics, Epidemiology, Radiology & Nuclear Medicine, Erasmus MC other, Internal Medicine, Erasmus School of Economics, and Department of Finance

Subjects
Epigenomics, Male, 0301 basic medicine, Cancer Research, Published Erratum, lcsh:QH426-470, Genotype, Physical activity, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Computational biology, Biology, Genome, Body Mass Index, PAGE Consortium, 03 medical and health sciences, Text mining, Genetics, Humans, Genetic Predisposition to Disease, Obesity, Exercise, Molecular Biology, Genetics (clinical), Ecology, Evolution, Behavior and Systematics, Adiposity, 0604 Genetics, Waist-Hip Ratio, business.industry, Correction, lcsh:Genetics, 030104 developmental biology, Meta-analysis, CHARGE Consortium, Female, EPIC-InterAct Consortium, Waist Circumference, business, Developmental Biology, Genome-Wide Association Study
Abstract

Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.

Published
2017

20. Association of Forced Vital Capacity with the Developmental Gene NCOR2

Author

Minelli, C. (Cosetta), Dean, C. H. (Charlotte H.), Hind, M. (Matthew), Alves, A. C. (Alexessander Couto), Amaral, A. F. (André F. S.), Siroux, V. (Valerie), Huikari, V. (Ville), Soler Artigas, M. (María), Evans, D. M. (David M.), Loth, D. W. (Daan W.), Bossé, Y. (Yohan), Postma, D. S. (Dirkje S.), Sin, D. (Don), Thompson, J. (John), Demenais, F. (Florence), Henderson, J. (John), S. c. (SpiroMeta consortium), C. c. (CHARGE consortium), Bouzigon, E. (Emmanuelle), Jarvis, D. (Deborah), Järvelin, M.-R. (Marjo-Riitta), Burney, P. (Peter), School of Medicine / Public Health, and Latzin, Philipp

Subjects
Adult, Male, General Science & Technology, CHARGE consortium, Organogenesis, Quantitative Trait Loci, lcsh:Medicine, Young Adult, Clinical Research, Forced Expiratory Volume, Genetics, 2.1 Biological and endogenous factors, Humans, SpiroMeta consortium, Developmental, Nuclear Receptor Co-Repressor 2, Aetiology, Polymorphism, lcsh:Science, Lung, Genetic Association Studies, Aged, Gene Expression Profiling, lcsh:R, Single Nucleotide, Middle Aged, Genes, Respiratory, lcsh:Q, Female, Genome-Wide Association Study
Abstract

Article, Background Forced Vital Capacity (FVC) is an important predictor of all-cause mortality in the absence of chronic respiratory conditions. Epidemiological evidence highlights the role of early life factors on adult FVC, pointing to environmental exposures and genes affecting lung development as risk factors for low FVC later in life. Although highly heritable, a small number of genes have been found associated with FVC, and we aimed at identifying further genetic variants by focusing on lung development genes. Methods Per-allele effects of 24,728 SNPs in 403 genes involved in lung development were tested in 7,749 adults from three studies (NFBC1966, ECRHS, EGEA). The most significant SNP for the top 25 genes was followed-up in 46,103 adults (CHARGE and SpiroMeta consortia) and 5,062 children (ALSPAC). Associations were considered replicated if the replication p-value survived Bonferroni correction (p, published version, peerReviewed

Published
2016

21. A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease

Author

Nicola D. Kerrison, Carlos González, Mark Walker, Adam S. Butterworth, Martina Müller-Nurasyid, Mark I. McCarthy, Jarmo Virtamo, Nilesh J. Samani, Daniel F. Freitag, Jennifer Wessel, Inês Barroso, Jette Bork-Jensen, Marit E. Jørgensen, Torben Hansen, Nita G. Forouhi, Jennifer A. Smith, Peter Vollenweider, Douglas F. Easton, Heiner Boeing, Helena M. Earl, Laufey T. Amundadottir, Annette Peters, Ingrid B. Borecki, L. Adrienne Cupples, Li Li, Josée Dupuis, Sara Benlloch Garcia, J. Wouter Jukema, Shuai Wang, Veikko Salomaa, Jukka Kontto, Timothy J. Key, Yuning Chen, Sune F. Nielsen, Robin Young, Jing Hua Zhao, Andrew P. Morris, Larraitz Arriola, Claudia Langenberg, Joshua C. Bis, Nisa M. Maruthur, Ele Ferrannini, Joanna M. M. Howson, Marcel den Hoed, Jeanette Erdmann, Rosalind A. Eeles, Daphne L. van der A, Panos Deloukas, Eric Boerwinkle, Sara M. Willems, Elio Riboli, Markku Laakso, Gina M. Peloso, Muriel J. Caslake, Nadia Slimani, Zsofia Kote-Jarai, Paul W. Franks, EPIC-InterAct, Dominique Arveiler, Sarah Bowden, Janet A. Dunn, Jan-Håkan Jansson, Carlos Cruchaga, Audrey Y. Chu, James S. Pankow, Rudolf Kaaks, Jerome I. Rotter, Jaspal S. Kooner, Ailith Pirie, Johanna Kuusisto, Hanieh Yaghootkar, Niels Grarup, Danish Saleheen, Thomas Foltynie, Jean Abraham, Stefan Blankenberg, Mark O. Goodarzi, Markus Perola, Olov Rolandsson, Chris J. Packard, Praveen Surendran, Allan Linneberg, Beverley Balkau, Christopher J. Poole, Frank Kee, Carmen Navarro, Nicholas J. Wareham, Oluf Pedersen, Heribert Schunkert, Domenico Palli, Patricia B. Munroe, Sven J. van der Lee, Chunyu Liu, Rebecca Sims, Georg Ehret, Michael Boehnke, Stephen J. Sharp, Peter M. Nilsson, Salvatore Panico, Børge G. Nordestgaard, Aldi T. Kraja, Sara Grioni, Sekar Kathiresan, Dawn M. Waterworth, Francesco Gianfagna, Jacek Czajkowski, Naveed Sattar, Margaret G. Ehm, Christopher J. Gillson, Karen L. Mohlke, Stella Trompet, John Danesh, Carlotta Sacerdote, Gaëlle Marenne, Jian'an Luan, Timothy M. Frayling, J. Ramón Quirós, Iciar Aviles-Olmos, Robert A. Scott, Yvonne T. van der Schouw, Jennifer L. Aponte, María José Sánchez, Deborah J. Thompson, Klaudia Walter, James B. Meigs, Tibor V. Varga, Kari Kuulasmaa, Torben Jørgensen, Rosario Tumino, Kyriaki Michailidou, Kenneth Muir, Philippe Amouyel, Ian Ford, Aurelio Barricarte, Stephen O'Rahilly, Ali Amin Al Olama, Louise Hiller, Alena Stančáková, Carlos Caldas, Jean Ferrières, Scott, Robert A, Freitag, Daniel F, Li, Li, Chu, Audrey Y, Surendran, Praveen, Young, Robin, Grarup, Niel, Stancáková, Alena, Chen, Yuning, Varga, Tibor V, Yaghootkar, Hanieh, Luan, Jian'An, Zhao, Jing Hua, Willems, Sara M, Wessel, Jennifer, Wang, Shuai, Maruthur, Nisa, Michailidou, Kyriaki, Pirie, Ailith, van der Lee, Sven J, Gillson, Christopher, Al Olama, Ali Amin, Amouyel, Philippe, Arriola, Larraitz, Arveiler, Dominique, Aviles Olmos, Iciar, Balkau, Beverley, Barricarte, Aurelio, Barroso, Inê, Garcia, Sara Benlloch, Bis, Joshua C, Blankenberg, Stefan, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Borecki, Ingrid B, Bork Jensen, Jette, Bowden, Sarah, Caldas, Carlo, Caslake, Muriel, Cupples, L. Adrienne, Cruchaga, Carlo, Czajkowski, Jacek, den Hoed, Marcel, Dunn, Janet A, Earl, Helena M, Ehret, Georg B, Ferrannini, Ele, Ferrieres, Jean, Foltynie, Thoma, Ford, Ian, Forouhi, Nita G, Gianfagna, Francesco, Gonzalez, Carlo, Grioni, Sara, Hiller, Louise, Jansson, Jan Håkan, Jørgensen, Marit E, Jukema, J. Wouter, Kaaks, Rudolf, Kee, Frank, Kerrison, Nicola D, Key, Timothy J, Kontto, Jukka, Kote Jarai, Zsofia, Kraja, Aldi T, Kuulasmaa, Kari, Kuusisto, Johanna, Linneberg, Allan, Liu, Chunyu, Marenne, Gaëlle, Mohlke, Karen L, Morris, Andrew P, Muir, Kenneth, Müller Nurasyid, Martina, Munroe, Patricia B, Navarro, Carmen, Nielsen, Sune F, Nilsson, Peter M, Nordestgaard, Børge G, Packard, Chris J, Palli, Domenico, Panico, Salvatore, Peloso, Gina M, Perola, Marku, Peters, Annette, Poole, Christopher J, Quirós, J. Ramón, Rolandsson, Olov, Sacerdote, Carlotta, Salomaa, Veikko, Sánchez, María José, Sattar, Naveed, Sharp, Stephen J, Sims, Rebecca, Slimani, Nadia, Smith, Jennifer A, Thompson, Deborah J, Trompet, Stella, Tumino, Rosario, van der A, Daphne L, van der Schouw, Yvonne T, Virtamo, Jarmo, Walker, Mark, Walter, Klaudia, Abraham, Jean E, Amundadottir, Laufey T, Aponte, Jennifer L, Butterworth, Adam S, Dupuis, Josée, Easton, Douglas F, Eeles, Rosalind A, Erdmann, Jeanette, Franks, Paul W, Frayling, Timothy M, Hansen, Torben, Howson, Joanna M. M, Jørgensen, Torben, Kooner, Jaspal, Laakso, Markku, Langenberg, Claudia, Mccarthy, Mark I, Pankow, James S, Pedersen, Oluf, Riboli, Elio, Rotter, Jerome I, Saleheen, Danish, Samani, Nilesh J, Schunkert, Heribert, Vollenweider, Peter, O'Rahilly, Stephen, Deloukas, Pano, Danesh, John, Goodarzi, Mark O, Kathiresan, Sekar, Meigs, James B, Ehm, Margaret G, Wareham, Nicholas J, Waterworth, Dawn M., Surgery, Epidemiology, Ehret, Georg Benedikt, Surendran, Praveen [0000-0002-4911-6077], Luan, Jian'an [0000-0003-3137-6337], Barroso, Ines [0000-0001-5800-4520], Caldas, Carlos [0000-0003-3547-1489], Earl, Helena [0000-0003-1549-8094], Forouhi, Nita [0000-0002-5041-248X], Sharp, Stephen [0000-0003-2375-1440], Thompson, Deborah [0000-0003-1465-5799], Abraham, Jean [0000-0003-0688-4807], Butterworth, Adam [0000-0002-6915-9015], Easton, Douglas [0000-0003-2444-3247], Howson, Joanna [0000-0001-7618-0050], Langenberg, Claudia [0000-0002-5017-7344], O'Rahilly, Stephen [0000-0003-2199-4449], Danesh, John [0000-0003-1158-6791], Wareham, Nicholas [0000-0003-1422-2993], and Apollo - University of Cambridge Repository

Subjects
Type 2/genetics, 0301 basic medicine, Somatostatin/genetics, Heart disease, Epidemiology, CHARGE consortium, Obesity/genetics, RECEPTOR AGONIST LIXISENATIDE, Coronary Disease, Type 2 diabetes, Research & Experimental Medicine, Bioinformatics, PLACEBO-CONTROLLED TRIAL, Receptor, Cannabinoid, CB2, DOUBLE-BLIND, Dipeptidyl Peptidase 4/genetics, 0302 clinical medicine, ONCE-DAILY LIXISENATIDE, Receptors, Receptor, Serotonin, 5-HT2C, Receptors, Somatostatin, Exome sequencing, GLUCAGON-LIKE PEPTIDE-1, CHD Exome+ Consortium, Neurology Working Group of the Cohorts for Heart, General Medicine, 11 Medical And Health Sciences, RANDOMIZED CONTROLLED-TRIAL, 3. Good health, Coronary Disease/genetics, 5-HT2C/genetics, CVD50 consortium, Drug development, Medicine, Research & Experimental, EPIC-InterAct, Public Health, Life Sciences & Biomedicine, INCRETIN-BASED THERAPIES, Receptor, Serotonin, RM, European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease (EPIC-CVD), Genotype, Dipeptidyl Peptidase 4, CB2/genetics, TYPE-2 DIABETES-MELLITUS, 030209 endocrinology & metabolism, Article, Glucagon-Like Peptide-1 Receptor, 03 medical and health sciences, Sodium-Glucose Transporter 1, BETA-CELL FUNCTION, Diabetes mellitus, Diabetes Mellitus, Journal Article, medicine, Humans, Sodium-Glucose Transporter 1/genetics, Obesity, Cannabinoid, Alleles, Science & Technology, business.industry, Alzheimer’s Disease Genetics Consortium, Glucagon-Like Peptide-1 Receptor/genetics, GERAD_EC Consortium, Cell Biology, 06 Biological Sciences, medicine.disease, R1, Human genetics, CARDIOGRAM Exome Consortium, Clinical trial, Minor allele frequency, BODY-MASS INDEX, 030104 developmental biology, Diabetes Mellitus, Type 2, Aging Research in Genomic Epidemiology (CHARGE), business, RC, Pancreatic Cancer Cohort Consortium
Abstract

Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11, 806 individuals by targeted exome sequencing and follow-up in 39, 979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process. Copyright 2016 by the American Association for the Advancement of Science; all rights reserved.

Published
2016

22. Cystatin C and cardiovascular disease: a Mendelian randomization study

Author

van der Laan, Sander W., Fall, Tove, Soumaré, Aicha, Teumer, Alexander, Sedaghat, Sanaz, Baumert, Jens, Zabaneh, Delilah, van Setten, Jessica, Isgum, Ivana, Galesloot, Tessel E., Arpegård, Johannes, Amouyel, Philippe, Trompet, Stella, Waldenberger, Melanie, Dörr, Marcus, Magnusson, Patrik K., Giedraitis, Vilmantas, Larsson, Anders, Morris, Andrew P., Felix, Janine F., Morrison, Alanna C., Franceschini, Nora, Bis, Joshua C, Kavousi, Maryam, O'Donnell, Christopher, Drenos, Fotios, Tragante, Vinicius, Munroe, Patricia B., Malik, Rainer, Dichgans, Martin, Worrall, Bradford B., Erdmann, Jeanette, Nelson, Christopher P., Samani, Nilesh J., Schunkert, Heribert, Marchini, Jonathan, Patel, Riyaz S., Hingorani, Aroon D., Lind, Lars, Pedersen, Nancy L., de Graaf, Jacqueline, Kiemeney, Lambertus A.L.M., Baumeister, Sebastian E., Franco, Oscar H., Hofman, Albert, Uitterlinden, André G., Koenig, Wolfgang, Meisinger, Christa, Peters, Annette, Thorand, Barbara, Jukema, J. Wouter, Eriksen, Bjørn Odvar, Toft, Ingrid, Wilsgaard, Tom, Onland-Moret, N. Charlotte, van der Schouw, Yvonne T., Debette, Stéphanie, Kumari, Meena, Svensson, Per, van der Harst, Pim, Kivimaki, Mika, Keating, Brendan J., Sattar, Naveed, Dehghan, Abbas, Reiner, Alex P., Ingelsson, Erik, den Ruijter, Hester M., de Bakker, Paul I.W., Pasterkamp, Gerard, Ärnlöv, Johan, Holmes, Michael V., Asselbergs, Folkert W., Academic Medical Center, Isotope Research, Cardiovascular Centre (CVC), Epidemiology, and Internal Medicine

Subjects
CHRONIC KIDNEY-DISEASE, Cardiac & Cardiovascular Systems, SUSCEPTIBILITY LOCI, Genotype, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], Coronary, heart failure, Heart disease, Global Health, urologic and male genital diseases, Polymorphism, Single Nucleotide, 1102 Cardiovascular Medicine And Haematology, SDG 3 - Good Health and Well-being, Risk Factors, Journal Article, ischemic stroke, Humans, Cardiac and Cardiovascular Systems, genetics, Prospective Studies, GENOME-WIDE ASSOCIATION, Cystatin C, coronary heart disease, Alleles, Aged, RISK, Kardiologi, Science & Technology, VDP::Medisinske Fag: 700::Helsefag: 800::Samfunnsmedisin, sosialmedisin: 801, INCIDENT HEART-FAILURE, Incidence, COMMON VARIANTS, Mendelian Randomization Analysis, Middle Aged, female genital diseases and pregnancy complications, CHARGE CONSORTIUM, Multicenter Study, BODY-MASS INDEX, ISCHEMIC-STROKE, 1117 Public Health And Health Services, Cardiovascular System & Hematology, Cardiovascular Diseases, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Cardiovascular System & Cardiology, CORONARY-ARTERY-DISEASE, VDP::Medical disciplines: 700::Health sciences: 800::Community medicine, Social medicine: 801, Life Sciences & Biomedicine
Abstract

Source: doi: 10.1016/j.jacc.2016.05.092 BACKGROUND Epidemiological studies show that high circulating cystatin C is associated with risk of cardiovascular disease (CVD), independent of creatinine-based renal function measurements. It is unclear whether this relationship is causal, arises from residual confounding, and/or is a consequence of reverse causation. OBJECTIVESThe aim of this study was to use Mendelian randomization to investigate whether cystatin C is causally related to CVD in the general population. METHODS We incorporated participant data from 16 prospective cohorts (n ¼ 76,481) with 37,126 measures of cystatin C and added genetic data from 43 studies (n ¼ 252,216) with 63,292 CVD events. We used the common variant rs911119 in CST3 as an instrumental variable to investigate the causal role of cystatin C in CVD, including coronary heart disease, ischemic stroke, and heart failure. RESULTS Cystatin C concentrations were associated with CVD risk after adjusting for age, sex, and traditional risk factors (relative risk: 1.82 per doubling of cystatin C; 95% confidence interval [CI]: 1.56 to 2.13; p ¼ 2.12 10 14). The minor allele of rs911119 was associated with decreased serum cystatin C (6.13% per allele; 95% CI: 5.75 to 6.50; p ¼ 5.95 10 211), explaining 2.8% of the observed variation in cystatin C. Mendelian randomization analysis did not provide evidence for a causal role of cystatin C, with a causal relative risk for CVD of 1.00 per doubling cystatin C (95% CI: 0.82 to 1.22; p ¼ 0.994), which was statistically different from the observational estimate (p ¼ 1.6 10 5). A causal effect of cystatin C was not detected for any individual component of CVD.CONCLUSIONS Mendelian randomization analyses did not support a causal role of cystatin C in the etiology of CVD. As such, therapeutics targeted at lowering circulating cystatin C are unlikely to be effective in preventing CVD. (J Am Coll Cardiol 2016;68:934–45) © 2016 The Authors. Published by Elsevier Inc. on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

Published
2016

23. The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study

Author

Winkler, Thomas W, Justice, Anne E, Graff, Mariaelisa, Barata, Llilda, Feitosa, Mary F, Chu, Su, Czajkowski, Jacek, Esko, Tõnu, Fall, Tove, Kilpeläinen, Tuomas O, Lu, Yingchang, Mägi, Reedik, Mihailov, Evelin, Pers, Tune H, Rüeger, Sina, Teumer, Alexander, Ehret, Georg B, Ferreira, Teresa, Heard-Costa, Nancy L, Karjalainen, Juha, Lagou, Vasiliki, Mahajan, Anubha, Neinast, Michael D, Prokopenko, Inga, Simino, Jeannette, Teslovich, Tanya M, Jansen, Rick, Westra, Harm-Jan, White, Charles C, Absher, Devin, Ahluwalia, Tarunveer S, Ahmad, Shafqat, Albrecht, Eva, Alves, Alexessander Couto, Bragg-Gresham, Jennifer L, de Craen, Anton JM, Bis, Joshua C, Bonnefond, Amélie, Boucher, Gabrielle, Cadby, Gemma, Cheng, Yu-Ching, Chiang, Charleston WK, Delgado, Graciela, Demirkan, Ayse, Dueker, Nicole, Eklund, Niina, Eiriksdottir, Gudny, Eriksson, Joel, Feenstra, Bjarke, Fischer, Krista, Frau, Francesca, Galesloot, Tessel E, Geller, Frank, Goel, Anuj, Gorski, Mathias, Grammer, Tanja B, Gustafsson, Stefan, Haitjema, Saskia, Hottenga, Jouke-Jan, Huffman, Jennifer E, Jackson, Anne U, Jacobs, Kevin B, Johansson, Åsa, Kaakinen, Marika, Kleber, Marcus E, Lahti, Jari, Mateo Leach, Irene, Lehne, Benjamin, Liu, Youfang, Lo, Ken Sin, Lorentzon, Mattias, Luan, Jian'an, Madden, Pamela AF, Mangino, Massimo, McKnight, Barbara, Medina-Gomez, Carolina, Monda, Keri L, Montasser, May E, Müller, Gabriele, Müller-Nurasyid, Martina, Nolte, Ilja M, Panoutsopoulou, Kalliope, Pascoe, Laura, Paternoster, Lavinia, Rayner, Nigel W, Renström, Frida, Rizzi, Federica, Rose, Lynda M, Ryan, Kathy A, Salo, Perttu, Sanna, Serena, Scharnagl, Hubert, Shi, Jianxin, Smith, Albert Vernon, Southam, Lorraine, Stančáková, Alena, Steinthorsdottir, Valgerdur, Strawbridge, Rona J, Sung, Yun Ju, Tachmazidou, Ioanna, Tanaka, Toshiko, Thorleifsson, Gudmar, Trompet, Stella, Pervjakova, Natalia, Tyrer, Jonathan P, Vandenput, Liesbeth, van der Laan, Sander W, van der Velde, Nathalie, van Setten, Jessica, van Vliet-Ostaptchouk, Jana V, Verweij, Niek, Vlachopoulou, Efthymia, Waite, Lindsay L, Wang, Sophie R, Wang, Zhaoming, Wild, Sarah H, Willenborg, Christina, Wilson, James F, Wong, Andrew, Yang, Jian, Yengo, Loïc, Yerges-Armstrong, Laura M, Yu, Lei, Zhang, Weihua, Zhao, Jing Hua, Andersson, Ehm A, Bakker, Stephan JL, Baldassarre, Damiano, Banasik, Karina, Barcella, Matteo, Barlassina, Cristina, Bellis, Claire, Benaglio, Paola, Blangero, John, Blüher, Matthias, Bonnet, Fabrice, Bonnycastle, Lori L, Boyd, Heather A, Bruinenberg, Marcel, Buchman, Aron S, Campbell, Harry, Chen, Yii-Der Ida, Chines, Peter S, Claudi-Boehm, Simone, Cole, John, Collins, Francis S, de Geus, Eco JC, de Groot, Lisette CPGM, Dimitriou, Maria, Duan, Jubao, Enroth, Stefan, Eury, Elodie, Farmaki, Aliki-Eleni, Forouhi, Nita G, Friedrich, Nele, Gejman, Pablo V, Gigante, Bruna, Glorioso, Nicola, Go, Alan S, Gottesman, Omri, Gräßler, Jürgen, Grallert, Harald, Grarup, Niels, Gu, Yu-Mei, Broer, Linda, Ham, Annelies C, Hansen, Torben, Harris, Tamara B, Hartman, Catharina A, Hassinen, Maija, Hastie, Nicholas, Hattersley, Andrew T, Heath, Andrew C, Henders, Anjali K, Hernandez, Dena, Hillege, Hans, Holmen, Oddgeir, Hovingh, Kees G, Hui, Jennie, Husemoen, Lise L, Hutri-Kähönen, Nina, Hysi, Pirro G, Illig, Thomas, De Jager, Philip L, Jalilzadeh, Shapour, Jørgensen, Torben, Jukema, J Wouter, Juonala, Markus, Kanoni, Stavroula, Karaleftheri, Maria, Khaw, Kay Tee, Kinnunen, Leena, Kittner, Steven J, Koenig, Wolfgang, Kolcic, Ivana, Kovacs, Peter, Krarup, Nikolaj T, Kratzer, Wolfgang, Krüger, Janine, Kuh, Diana, Kumari, Meena, Kyriakou, Theodosios, Langenberg, Claudia, Lannfelt, Lars, Lanzani, Chiara, Lotay, Vaneet, Launer, Lenore J, Leander, Karin, Lindström, Jaana, Linneberg, Allan, Liu, Yan-Ping, Lobbens, Stéphane, Luben, Robert, Lyssenko, Valeriya, Männistö, Satu, Magnusson, Patrik K, McArdle, Wendy L, Menni, Cristina, Merger, Sigrun, Milani, Lili, Montgomery, Grant W, Morris, Andrew P, Narisu, Narisu, Nelis, Mari, Ong, Ken K, Palotie, Aarno, Pérusse, Louis, Pichler, Irene, Pilia, Maria G, Pouta, Anneli, Rheinberger, Myriam, Ribel-Madsen, Rasmus, Richards, Marcus, Rice, Kenneth M, Rice, Treva K, Rivolta, Carlo, Salomaa, Veikko, Sanders, Alan R, Sarzynski, Mark A, Scholtens, Salome, Scott, Robert A, Scott, William R, Sebert, Sylvain, Sengupta, Sebanti, Sennblad, Bengt, Seufferlein, Thomas, Silveira, Angela, Slagboom, P Eline, Smit, Jan H, Sparsø, Thomas H, Stirrups, Kathleen, Stolk, Ronald P, Stringham, Heather M, Swertz, Morris A, Swift, Amy J, Syvänen, Ann-Christine, Tan, Sian-Tsung, Thorand, Barbara, Tönjes, Anke, Tremblay, Angelo, Tsafantakis, Emmanouil, van der Most, Peter J, Völker, Uwe, Vohl, Marie-Claude, Vonk, Judith M, Waldenberger, Melanie, Walker, Ryan W, Wennauer, Roman, Widén, Elisabeth, Willemsen, Gonneke, Wilsgaard, Tom, Wright, Alan F, Zillikens, M Carola, van Dijk, Suzanne C, van Schoor, Natasja M, Asselbergs, Folkert W, de Bakker, Paul IW, Beckmann, Jacques S, Beilby, John, Bennett, David A, Bergman, Richard N, Bergmann, Sven, Böger, Carsten A, Boehm, Bernhard O, Boerwinkle, Eric, Boomsma, Dorret I, Bornstein, Stefan R, Bottinger, Erwin P, Bouchard, Claude, Chambers, John C, Chanock, Stephen J, Chasman, Daniel I, Cucca, Francesco, Cusi, Daniele, Dedoussis, George, Erdmann, Jeanette, Eriksson, Johan G, Evans, Denis A, de Faire, Ulf, Farrall, Martin, Ferrucci, Luigi, Ford, Ian, Franke, Lude, Franks, Paul W, Froguel, Philippe, Gansevoort, Ron T, Gieger, Christian, Grönberg, Henrik, Gudnason, Vilmundur, Gyllensten, Ulf, Hall, Per, Hamsten, Anders, van der Harst, Pim, Hayward, Caroline, Heliövaara, Markku, Hengstenberg, Christian, Hicks, Andrew A, Hingorani, Aroon, Hofman, Albert, Hu, Frank, Huikuri, Heikki V, Hveem, Kristian, James, Alan L, Jordan, Joanne M, Jula, Antti, Kähönen, Mika, Kajantie, Eero, Kathiresan, Sekar, Kiemeney, Lambertus ALM, Kivimaki, Mika, Knekt, Paul B, Koistinen, Heikki A, Kooner, Jaspal S, Koskinen, Seppo, Kuusisto, Johanna, Maerz, Winfried, Martin, Nicholas G, Laakso, Markku, Lakka, Timo A, Lehtimäki, Terho, Lettre, Guillaume, Levinson, Douglas F, Lind, Lars, Lokki, Marja-Liisa, Mäntyselkä, Pekka, Melbye, Mads, Metspalu, Andres, Mitchell, Braxton D, Moll, Frans L, Murray, Jeffrey C, Musk, Arthur W, Nieminen, Markku S, Njølstad, Inger, Ohlsson, Claes, Oldehinkel, Albertine J, Oostra, Ben A, Palmer, Lyle J, Pankow, James S, Pasterkamp, Gerard, Pedersen, Nancy L, Pedersen, Oluf, Penninx, Brenda W, Perola, Markus, Peters, Annette, Polašek, Ozren, Pramstaller, Peter P, Psaty, Bruce M, Qi, Lu, Quertermous, Thomas, Raitakari, Olli T, Rankinen, Tuomo, Rauramaa, Rainer, Ridker, Paul M, Rioux, John D, Rivadeneira, Fernando, Rotter, Jerome I, Rudan, Igor, den Ruijter, Hester M, Saltevo, Juha, Sattar, Naveed, Schunkert, Heribert, Schwarz, Peter EH, Shuldiner, Alan R, Sinisalo, Juha, Snieder, Harold, Sørensen, Thorkild IA, Spector, Tim D, Staessen, Jan A, Stefania, Bandinelli, Thorsteinsdottir, Unnur, Stumvoll, Michael, Tardif, Jean-Claude, Tremoli, Elena, Tuomilehto, Jaakko, Uitterlinden, André G, Uusitupa, Matti, Verbeek, André LM, Vermeulen, Sita H, Viikari, Jorma S, Vitart, Veronique, Völzke, Henry, Vollenweider, Peter, Waeber, Gérard, Walker, Mark, Wallaschofski, Henri, Wareham, Nicholas J, Watkins, Hugh, Zeggini, Eleftheria, arcOGEN Consortium, CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global-BPGen Consortium, ICBP Consortium, MAGIC Consortium, Chakravarti, Aravinda, Clegg, Deborah J, Cupples, L Adrienne, Gordon-Larsen, Penny, Jaquish, Cashell E, Rao, DC, Abecasis, Goncalo R, Assimes, Themistocles L, Barroso, Inês, Berndt, Sonja I, Boehnke, Michael, Deloukas, Panos, Fox, Caroline S, Groop, Leif C, Hunter, David J, Ingelsson, Erik, Kaplan, Robert C, McCarthy, Mark I, Mohlke, Karen L, O'Connell, Jeffrey R, Schlessinger, David, Strachan, David P, Stefansson, Kari, van Duijn, Cornelia M, Hirschhorn, Joel N, Lindgren, Cecilia M, Heid, Iris M, North, Kari E, Borecki, Ingrid B, Kutalik, Zoltán, Loos, Ruth JF, Division of Statistical Genomics, Washington University School of Medicine, Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP), Estonian Genome and Medicine, University of Tartu, Institute of Molecular and Cell Biology, Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Institute of Metabolic Science, MRC, Brown University, Center for Biological Sequence Analysis [Lyngby], Technical University of Denmark [Lyngby] (DTU), King‘s College London, Groningen Bioinformatics Centre, GBB, University of Groningen [Groningen], University of Queensland [Brisbane], National Institut of Food Science and Technology, University of Agriculture, Department of Biostatistics and Center for Statistical Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Department of neurology, Leiden University Medical Center (LUMC), University of Washington [Seattle], Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Genetic Epidemiology Unit, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Deptartment of Medical Biochemistry and Microbiology, Uppsala University, Infectious diseases division, Department of internal medicine, Washington University in Saint Louis (WUSTL), Limnology, Ecology, Department of Ecology and Evolutionary Biology, University of California, Core Genotyping Facility, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Division of Cancer Epidemiology and Genetics, Institute of Health Sciences and Biocenter Oulu, University of Oulu, Department of Chemical Engineering Taiwan (DCET - NTHU), National Tsing Hua University [Hsinchu] (NTHU), University of Oxford [Oxford], Department of Epidemiology, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Human Genetics, The Wellcome Trust Sanger Institute [Cambridge], Departments of Epidemiology and Nutrition, Harvard School of Public Health, Department of Clinical Sciences, Lund University [Lund]-Lund University Diabetes Centre, Genetic Epidemiology and Clinical Research Group, Umea University Hospital, Department of Medicine, University of Eastern Finland-Kuopio University Hospital, Department of Medical Sciences, Department of Educational Psychology and Counseling, National Taiwan Normal University (NTNU), Laboratory for Cardiovascular Genomics and Informatics [Yokohama] (RIKEN IMS), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN)-RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), deCODE Genetics, deCODE genetics [Reykjavik], Interuniversity Cardiology Institute Netherlands, Molecular Genetics Section, University of Groningen [Groningen]-University Medical Centre Groningen, Kidney Center, University Medical Center Groningen [Groningen] (UMCG), The University of Texas Health Science Center at Houston (UTHealth), Texas Biomedical Research Institute [San Antonio, TX], Medical Department III, Universität Leipzig [Leipzig], Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Dept. of Epidemiology Research, Statens Serum Institut [Copenhagen], GNS Science, Blackett Laboratory, Imperial College London, Medstar Research Institute, University of Rochester [USA], MRC Epidemiology Unit, University of Cambridge [UK] (CAM)-Institute of Metabolic Science, Institute of Epidemiology [Neuherberg] (EPI), German Research Center for Environmental Health - Helmholtz Center München (GmbH), Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Dept Biochem & Mol Biol, Pennsylvania State University (Penn State), Penn State System-Penn State System, Genomic Research Laboratory, Service of Infectious Disease, Hôpitaux Universitaires de Genève (HUG), Epidemiology, University Medical Centre Groningen, Unit for Molecular Epidemiology, German Research Center for Environmental Health-Helmholtz-Zentrum München (HZM), Program in Translational NeuroPsychiatric Genomics, Brigham and Women's Hospital [Boston], Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Research Centre for Prevention and Health (RCPH), Department of Public Health [Copenhagen], University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)-Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)-Capital Region of Denmark, University of Copenhagen = Københavns Universitet (KU), Faculty of Medicine, Institute of Public Health, Aalborg University [Denmark] (AAU), Department of Nutrition-Dietetics, Harokopio University of Athens, Department of Medical Statistics, Epidemiology and Medical Informatics, University of Zagreb, MRC National Survey of Health and Development, MRC Unit for Lifelong Health and Ageing, Department of Epidemiology and Public Health, University College of London [London] (UCL), Department of Public health and Caring Sciences, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden, Research Center for Prevention and Health, Glostrup Hospital, Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Cambridge Institute of Public Health, University of Cambridge [UK] (CAM), Chronic Disease Epidemiology and Prevention Unit, National Institute for Health and Welfare [Helsinki], Queensland Institute of Medical Research, Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Head of Medical Sequencing, Department of Biostatistics, University of Washington, Department of Chronic Disease Prevention, Molecular Epidemiology, Department of Genetics, Université Laval [Québec] (ULaval), Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, Netherlands Genomics Initiative, Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), Department of Internal Medicine, Université de Lausanne (UNIL), Carl Gustav Carus University Hospital, Loughborough University, Genomics and Bioinformatics Platform, Fondazione Filarete, Department of Medicine, Surgery, and Dentistry, University of Milano, Medizinische Klinik II, Universität zu Lübeck [Lübeck], Department of Genomic Medicine, University of Manchester [Manchester], The Wellcome Trust Centre for Human Genetics [Oxford], National Institutes of Health [Bethesda] (NIH), Department of Nephrology, University Medical Center, University of Groningen, Helmholtz-Zentrum München (HZM), Icelandic Heart Association, Kopavogur, Iceland., Faculty of Medicine, University of Iceland [Reykjavik], Genetics and Pathology, Department of child and adolescent psychiatry, Universität Duisburg-Essen [Essen], Department of Internal Medicine II, Division of Respirology, University of Regensburg, Regensburg, Germany, Universität Regensburg (UR), Franz-Volhard-Centrum für Klinische Forschung, ECRC, Department of Clinical Physiology, University of Tampere [Finland]-Tampere University Hospital, Finnish Institute of Occupational Health of Helsinki, Department of Clinical Chemistry, Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Department of Oncology, University of Tampere Medical School, University of Tampere, Department of Physiology, University of Eastern Finland-Institute of Biomedicine, Department of Medicine, Montreal, Developmental Brain and Behaviour Unit, University of Southampton, Division of Gastroenterology and Hepatology, Department of Immunology, Mayo Clinic, Centre for Bone and Arthritis Research, Institute of Medicine-University of Gothenburg (GU), Interdisciplinary Center for Psychiatric Epidemiology, Experimental Cardiology Laboratory, University Medical Center [Utrecht], Peter MacCallum Cancer Center, Faculty of Health Sciences, Aarhus University [Aarhus], Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Department of Health Services, University of Washington, Group Health Research Institute, Group Health Cooperative, Department of Epidemiology, University of Washington, Department of Medicine, University of Washington, Cardiovascular Health Research Unit, University of Washington, The Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku University Hospital (TYKS), Erasmus Medical Centre, Cedars-Sinai Medical Center, Department of Pathological Biochemistry, Royal Infirmary, Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology, University Medical Center Groningen, Department of Pediatrics, Augusta University - Medical College of Georgia, University System of Georgia (USG)-University System of Georgia (USG), Institute of Preventive Medicine, Copenhagen University Hospital-Bispebjerg and Frederiksberg Hospitals, Maastricht University [Maastricht], Department of Public Health, South Ostrobothnia Central Hospital, Department of Clinical and Preventive Medicine, Danube-University Krems, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Department of Epidemiology & Biostatistics, Radboud University Medical Center [Nijmegen], Institute for Community Medicine, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), MRC epidemiology Unit, Framingham Heart Study, National Heart, Lung, and Blood Institute [Bethesda] (NHLBI)-Boston University [Boston] (BU), Metabolic Disease Group, University of Cambridge Metabolic Research Laboratories, Department of Genetics and Biotechnology, Wellcome Trust, Divisions of Genetics and Endocrinology and Program in Genomics, Boston Children's Hospital, Metabolism Initiative and Program in Medical and Population Genetics, Endocrinology and Metabolism, The Churchill Hospital-Oxford Centre for Diabetes, Department of Epidemiology and Preventive Medicine, Regensburg University Medical Center, University of North Carolina System (UNC)-University of North Carolina System (UNC)-UNC Gillings School of Global Public Health-Carolina Center for Genome Sciences, Department of Medical Genetics, Epidemiology Unit, Addenbrooke's Hospital-Medical Research Council (MRC), P30 AG010161/AG/NIA NIH HHS/United States, Psychiatry, Epidemiology and Data Science, NCA - Neurobiology of mental health, EMGO - Lifestyle, overweight and diabetes, APH - Amsterdam Public Health, AMS - Amsterdam Movement Sciences, Geriatrics, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Other departments, Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Lifestyle, Overweight and Diabetes, RS: CARIM - R3 - Vascular biology, MUMC+: DA BV AIOS Radiologie (9), Epidemiologie, Orthopedie, Institute for Molecular Medicine Finland, Helsinki Collegium for Advanced Studies, Behavioural Sciences, University of Helsinki, Transplantation Laboratory, Medicum, Research Programs Unit, Research Programme of Molecular Medicine, Aarno Palotie / Principal Investigator, Elisabeth Ingrid Maria Widen / Principal Investigator, Clinicum, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Children's Hospital, Lastentautien yksikkö, Marja-Liisa Lokki / Principal Investigator, Kardiologian yksikkö, Leif Groop Research Group, Quantitative Genetics, Developmental Psychology Research Group, Genomics of Neurological and Neuropsychiatric Disorders, Genomic Discoveries and Clinical Translation, Ehret, Georg Benedikt, Danmarks Tekniske Universitet = Technical University of Denmark (DTU), Universiteit Leiden-Universiteit Leiden, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), 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 National de la Recherche Scientifique (CNRS), University of California (UC), University of Oxford, Lund University [Lund], Universität Leipzig, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Helmholtz Zentrum München = German Research Center for Environmental Health, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH)-Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH)-Capital Region of Denmark, University of Copenhagen = Københavns Universitet (UCPH), Université de Lausanne = University of Lausanne (UNIL), Universität zu Lübeck = University of Lübeck [Lübeck], Universität Duisburg-Essen = University of Duisburg-Essen [Essen], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, University of Gothenburg (GU)-Institute of Medicine, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), Luan, Jian'an [0000-0003-3137-6337], Tyrer, Jonathan [0000-0003-3724-4757], Forouhi, Nita [0000-0002-5041-248X], Khaw, Kay-Tee [0000-0002-8802-2903], Langenberg, Claudia [0000-0002-5017-7344], Luben, Robert [0000-0002-5088-6343], Ong, Kenneth [0000-0003-4689-7530], Johnson, Kathleen [0000-0002-6823-3252], Wareham, Nicholas [0000-0003-1422-2993], Barroso, Ines [0000-0001-5800-4520], Apollo - University of Cambridge Repository, CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global-BPGen Consortium, ICBP Consortium, MAGIC Consortium, Biochemistry, Surgery, Internal Medicine, Public Health, Medical Oncology, Pathology, Erasmus MC other, Child and Adolescent Psychiatry / Psychology, and Clinical Genetics

Subjects
0301 basic medicine, Netherlands Twin Register (NTR), Male, Cancer Research, endocrine system diseases, Biological pathways, QH426-470, Genome, Body Mass Index, Body Size, Genetics (clinical), ddc:616, Genetics & Heredity, Sex Characteristics, Loci, MAGIC Consortium, Mass index, Age Factors, Chromosome Mapping, Middle Aged, Genealogy, Self-reported height, Peripheral-blood, Scale (social sciences), ICBP Consortium, Female, Life Sciences & Biomedicine, Medical Genetics, Research Article, arcOGEN Consortium, musculoskeletal diseases, Adult, European Continental Ancestry Group, Natural menopause, Aged, Body Size/genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Waist-Hip Ratio, Biology, Body size, DIAGRAM Consortium, Age and sex, White People, Fat distribution, GLGC Consortium, 03 medical and health sciences, Life-course, Genetics, Weight-gain, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Medicinsk genetik, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0604 Genetics, Science & Technology, nutritional and metabolic diseases, Correction, 030104 developmental biology, GWAS meta-analysis, Global-BPGen Consortium, Common SNPS, CHARGE Consortium, 3111 Biomedicine, Developmental Biology
Abstract

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR, Author Summary Adult body size and body shape differ substantially between men and women and change over time. More than 100 genetic variants that influence body mass index (measure of body size) or waist-to-hip ratio (measure of body shape) have been identified. While there is evidence that some genetic loci affect body shape differently in men than in women, little is known about whether genetic effects differ in older compared to younger adults, and whether such changes differ between men and women. Therefore, we conducted a systematic genome-wide search, including 114 studies (>320,000 individuals), to specifically identify genetic loci with age- and or sex-dependent effects on body size and shape. We identified 15 loci of which the effect on BMI was different in older compared to younger adults, whereas we found no evidence for loci with different effects in men compared to women. The opposite was seen for body shape as we identified 44 loci of which the effect on waist-to-hip ratio differed between men and women, but no difference between younger and older adults were observed. Our observations may provide new insights into the biology that underlies weight change with age or the sexual dimorphism of body shape.

Published
2014

24. Sequencing of SCN5A identifies rare and common variants associated with cardiac conduction: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium

Author

Magnani, Jared W, Brody, Jennifer A, Prins, Bram P, Arking, Dan E, Lin, Honghuang, Yin, Xiaoyan, Liu, Ching-Ti, Morrison, Alanna C, Zhang, Feng, Spector, Tim D, Alonso, Alvaro, Bis, Joshua C, Heckbert, Susan R, Lumley, Thomas, Sitlani, Colleen M, Cupples, L Adrienne, Lubitz, Steven A, Soliman, Elsayed Z, Pulit, Sara L, Newton-Cheh, Christopher, O'Donnell, Christopher J, Ellinor, Patrick T, Benjamin, Emelia J, Muzny, Donna M, Gibbs, Richard A, Santibanez, Jireh, Taylor, Herman A, Rotter, Jerome I, Lange, Leslie A, Psaty, Bruce M, Jackson, Rebecca, Rich, Stephen S, Boerwinkle, Eric, Jamshidi, Yalda, Sotoodehnia, Nona, CHARGE Consortium, NHLBI Exome Sequencing Project (ESP), and UK10K

Subjects
Adult, Male, Aging, Heart Diseases, electrocardiography, Medical Biotechnology, Cardiorespiratory Medicine and Haematology, Cardiovascular, NAV1.5 Voltage-Gated Sodium Channel, Cohort Studies, Heart Conduction System, Clinical Research, 80 and over, genomics, Genetics, Humans, 2.1 Biological and endogenous factors, NHLBI Exome Sequencing Project, Polymorphism, Aetiology, Aged, Human Genome, Genetic Variation, DNA, Genomics, Single Nucleotide, Middle Aged, Heart Disease, UK10K, Cardiovascular System & Hematology, CHARGE Consortium, Female, Sequence Analysis, Genome-Wide Association Study, Biotechnology
Abstract

BackgroundThe cardiac sodium channel SCN5A regulates atrioventricular and ventricular conduction. Genetic variants in this gene are associated with PR and QRS intervals. We sought to characterize further the contribution of rare and common coding variation in SCN5A to cardiac conduction.Methods and resultsIn Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study, we performed targeted exonic sequencing of SCN5A (n=3699, European ancestry individuals) and identified 4 common (minor allele frequency >1%) and 157 rare variants. Common and rare SCN5A coding variants were examined for association with PR and QRS intervals through meta-analysis of European ancestry participants from CHARGE, National Heart, Lung, and Blood Institute's Exome Sequencing Project (n=607), and the UK10K (n=1275) and by examining Exome Sequencing Project African ancestry participants (n=972). Rare coding SCN5A variants in aggregate were associated with PR interval in European and African ancestry participants (P=1.3×10(-3)). Three common variants were associated with PR and QRS interval duration among European ancestry participants and one among African ancestry participants. These included 2 well-known missense variants: rs1805124 (H558R) was associated with PR and QRS shortening in European ancestry participants (P=6.25×10(-4) and P=5.2×10(-3), respectively) and rs7626962 (S1102Y) was associated with PR shortening in those of African ancestry (P=2.82×10(-3)). Among European ancestry participants, 2 novel synonymous variants, rs1805126 and rs6599230, were associated with cardiac conduction. Our top signal, rs1805126 was associated with PR and QRS lengthening (P=3.35×10(-7) and P=2.69×10(-4), respectively) and rs6599230 was associated with PR shortening (P=2.67×10(-5)).ConclusionsBy sequencing SCN5A, we identified novel common and rare coding variants associated with cardiac conduction.

Published
2014

25. A Genome-Wide Association Study of Depressive Symptoms

Author

Jari Lahti, Anne B. Newman, Vilmundur Gudnason, Aarno Palotie, Elisabeth Widen, Alessandra Cannas, Eric B. Rimm, Alexander Teumer, Toshiko Tanaka, Alan D. Penman, Ben A. Oostra, Andrea Schulz, Joshua M. Shulman, Luigi Ferrucci, Eric M. Reiman, Majken K. Jensen, Jens Baumert, Karestan C. Koenen, Shaun Purcell, Karl-Heinz Ladwig, Antonio Terracciano, David J. Llewellyn, Eco J. C. de Geus, Albert V. Smith, Kathryn L. Lunetta, Marilyn C. Cornelis, Osorio Meirelles, Brenda W.J.H. Penninx, Henry Völzke, Henning Tiemeier, Kristin D. Marciante, Emelia J. Benjamin, Maris Kuningas, Luke C. Pilling, Rajesh Rawal, Cornelis L. Mulder, David A. Bennett, David J. Hunter, Ana V. Diez-Roux, Rebecca T. Emeny, Yan V. Sun, Peter Kraft, Sharon L.R. Kardia, André G. Uitterlinden, Nona Sotoodehnia, Katri Räikkönen, Jerome I. Rotter, Erin Bakshis, Kristine Yaffe, Cornelia M. van Duijn, Lei Yu, Bruce M. Psaty, Philip L. De Jager, Margaret Kelly-Hayes, Hans J. Grabe, Angelina R. Sutin, Antonella Mulas, Anna Murray, Astrid Petersmann, Denis A. Evans, Gary C. Curhan, David Melzer, Frank B. Hu, Mike A. Nalls, Thomas H. Mosley, Lenore J. Launer, Myriam Fornage, Joanne M. Murabito, Laura H. Coker, Najaf Amin, Joseph M. Massaro, Alan B. Zonderman, Thomas Illig, Johan G. Eriksson, Ayse Demirkan, Francesco Cucca, Dorret I. Boomsma, Tamara B. Harris, Nicole Vogelzangs, Yongmei Liu, Jingzhong Ding, Kenneth Rice, Stefania Bandinelli, Albert Hofman, Andrew B. Singleton, Karin Hek, Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Neuroscience Campus Amsterdam - Brain Imaging Technology, EMGO+ - Mental Health, Psychiatry, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Mental health, NCA - Brain imaging technology, Epidemiology, Immunology, Clinical Genetics, and Internal Medicine

Subjects
Male, Oncology, DISORDER, Netherlands Twin Register (NTR), CHARGE consortium, Genome-wide association study, Medical and Health Sciences, 0302 clinical medicine, depressive symptoms, Polymorphism (computer science), Epidemiology, 80 and over, 2.1 Biological and endogenous factors, genetics, Aetiology, Depression (differential diagnoses), POPULATION, Psychiatry, Aged, 80 and over, Genetics, 0303 health sciences, education.field_of_study, Depression, Single Nucleotide, Biological Sciences, Middle Aged, Center for Epidemiologic Studies Depression Scale, 3. Good health, Mental Health, Meta-analysis, depression, Chromosomes, Human, Pair 5, Female, Pair 5, Psychology, VITAL EXHAUSTION, Human, medicine.medical_specialty, CES-D, LIFE EVENTS, Population, Single-nucleotide polymorphism, ATHEROSCLEROSIS RISK, and over, Polymorphism, Single Nucleotide, Chromosomes, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, Behavioral and Social Science, medicine, LINKAGE, Humans, Genetic Predisposition to Disease, Polymorphism, education, Biological Psychiatry, METAANALYSIS, Aged, 030304 developmental biology, genome-wide association study, Human Genome, Psychology and Cognitive Sciences, MAJOR DEPRESSION, GENE, Brain Disorders, meta-analysis, 030217 neurology & neurosurgery
Abstract

Background: Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms.Methods: In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p Results: The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05 x 10(-7)). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, p = 9.19 x 10(-3)). This 5q21 region reached genome-wide significance (p = 4.78 x 10(-8)) in the overall meta-analysis combining discovery and replication studies (n = 51,258).Conclusions: The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms.

Published
2013

26. Genome-Wide Association Study Identifies Novel Loci Associated with Circulating Phospho- and Sphingolipid Concentrations

Author

Andrew A. Hicks, Irina V. Zorkoltseva, Christopher S. Franklin, Thomas Meitinger, Michael Preuss, Cristian Pattaro, Lennart C. Karssen, Veronique Vitart, Sarah H. Wild, Fernando Rivadeneira, Åsa Johansson, James F. Wilson, Anatoly V. Kirichenko, Ghazal Zaboli, Ozren Polasek, Wilmar Igl, Tatiana I. Axenovich, Christopher J. O'Donnell, Jacqueline C. M. Witteman, James A B Floyd, Linda Broer, Arne Pfeufer, Lude Franke, Igor Rudan, Zrinka Biloglav, Christopher P. Nelson, Nora Franceschini, Ivana Kolcic, Aaron Isaacs, Yurii S. Aulchenko, Harry Campbell, Nicholas D. Hastie, Cornelia M. van Duijn, Ritsert C. Jansen, Irene Pichler, Alan F. Wright, Caroline Hayward, Albert Hofman, Ben A. Oostra, Jennifer E. Huffman, Ulf Gyllensten, Gerd Schmitz, Carsten Gnewuch, Inger Jonasson, Francisco S. Domingues, Ayse Demirkan, André G. Uitterlinden, Gerhard Liebisch, A. Cecile J.W. Janssens, Peter Ugocsai, Peter P. Pramstaller, Joshua C. Bis, Susan Campbell, Maksim Struchalin, Epidemiology, Internal Medicine, Clinical Genetics, Groningen Biomolecular Sciences and Biotechnology, Bioinformatics, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Stem Cell Aging Leukemia and Lymphoma (SALL)

Subjects
Apolipoprotein E, Cancer Research, Medicin och hälsovetenskap, Epidemiology, Medical and Health Sciences, Biochemistry, Carotid Intima-Media Thickness, DISEASE, chemistry.chemical_compound, 0302 clinical medicine, Delta-5 Fatty Acid Desaturase, PHOSPHATIDYLCHOLINE, Databases, Genetic, Phospholipids/blood, CARDIoGRAM Consortium, European Continental Ancestry Group/genetics, Genetics (clinical), Phospholipids, chemistry.chemical_classification, 0303 health sciences, Genome, Sphingolipids/blood, Single Nucleotide, LYSOPHOSPHATIDYLCHOLINE, Lipids, HIGH-THROUGHPUT QUANTIFICATION, 3. Good health, Lysophosphatidylcholine, Glycerophospholipid, Fatty acid elongation, Medicine, lipids (amino acids, peptides, and proteins), FATTY-ACIDS, Sphingomyelin, Diabetes Mellitus, Type 2/blood, Human, Research Article, SUSCEPTIBILITY LOCI, lcsh:QH426-470, Membrane lipids, European Continental Ancestry Group, Biology, DIAGRAM Consortium, Polymorphism, Single Nucleotide, White People, HUMAN PLATELETS, 03 medical and health sciences, Databases, SDG 3 - Good Health and Well-being, Genetic, Diabetes Mellitus, Genetics, Humans, ddc:610, TANDEM MASS-SPECTROMETRY, Polymorphism, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Type 2/blood, 0604 Genetics, Sphingolipids, Population Biology, Genome, Human, MEMBRANE-LIPIDS, Fatty acid, Human Genetics, Sphingolipid, lcsh:Genetics, Metabolism, chemistry, ATHEROSCLEROSIS, Diabetes Mellitus, Type 2, Genetic Loci, CHARGE Consortium, 030217 neurology & neurosurgery, EUROSPAN consortium, Developmental Biology, Genome-Wide Association Study
Abstract

Phospho- and sphingolipids are crucial cellular and intracellular compounds. These lipids are required for active transport, a number of enzymatic processes, membrane formation, and cell signalling. Disruption of their metabolism leads to several diseases, with diverse neurological, psychiatric, and metabolic consequences. A large number of phospholipid and sphingolipid species can be detected and measured in human plasma. We conducted a meta-analysis of five European family-based genome-wide association studies (N = 4034) on plasma levels of 24 sphingomyelins (SPM), 9 ceramides (CER), 57 phosphatidylcholines (PC), 20 lysophosphatidylcholines (LPC), 27 phosphatidylethanolamines (PE), and 16 PE-based plasmalogens (PLPE), as well as their proportions in each major class. This effort yielded 25 genome-wide significant loci for phospholipids (smallest P-value = 9.88×10−204) and 10 loci for sphingolipids (smallest P-value = 3.10×10−57). After a correction for multiple comparisons (P-value, Author Summary Phospho- and sphingolipids are integral to membrane formation and are involved in crucial cellular functions such as signalling, membrane fluidity, membrane protein trafficking, neurotransmission, and receptor trafficking. In addition to severe monogenic diseases resulting from defective phospho- and sphingolipid function and metabolism, the evidence suggests that variations in these lipid levels at the population level are involved in the determination of cardiovascular and neurologic traits and subsequent disease. We took advantage of modern laboratory methods, including microarray-based genotyping and electrospray ionization tandem mass spectrometry, to hunt for genetic variation influencing the levels of more than 350 phospho- and sphingolipid phenotypes. We identified nine novel loci, in addition to confirming a number of previously described loci. Several other genetic regions provided substantial evidence of their involvement in these traits. All of these loci are strong candidates for further research in the field of lipid biology and are likely to yield considerable insights into the complex metabolic pathways underlying circulating phospho- and sphingolipid levels. Understanding these mechanisms might help to illuminate factors leading to the development of common cardiovascular and neurological diseases and might provide molecular targets for the development of new therapies.

Published
2012

27. A genome-wide association study of depressive symptoms

Author

Hek, K. (Karin), Demirkan, A. (Ayşe), Lahti, J. (Jari), Terracciano, A., Teumer, A. (Alexander), Cornelis, M. (Marilyn), Amin, N. (Najaf), Bakshis, E. (Erin), Baumert, J. (Jens), Ding, J. (Jingzhong), Liu, Y. (YongMei), Marciante, K. (Kristin), Meirelles, O., Nalls, M.A. (Michael), Sun, Y.V. (Yan), Vogelzangs, N. (Nicole), Yu, L. (Lei), Bandinelli, S. (Stefania), Benjamin, E.J. (Emelia), Bennett, D.A. (David), Boomsma, D.I. (Dorret), Cannas, A., Coker, L.H. (Laura), Geus, E.J.C. (Eco) de, Jager, P.L. (Philip) de, Diez Roux, A.V. (Ana), Purcell, S. (Shaun), Hu, F.B. (Frank), Rimm, E., Hunter, D.J. (David), Jensen, M.K. (Majken), Curhan, G.C. (Gary), Rice, K.M. (Kenneth), Penman, A.D. (Alan), Rotter, J.I. (Jerome), Sotoodehnia, N. (Nona), Emeny, R. (Rebecca), Eriksson, J.G. (Johan), Evans, D.A. (Denis), Ferrucci, L. (Luigi), Fornage, M. (Myriam), Gudnason, V. (Vilmundur), Hofman, A. (Albert), Illig, T. (Thomas), Kardia, S.L.R. (Sharon), Kelly-Hayes, M. (Margaret), Koenen, M.E. (Marjorie), Kraft, P. (Peter), Kuningas, M. (Maris), Massaro, J. (Joseph), Melzer, D. (David), Mulas, A. (Antonella), Mulder, C.L. (Niels), Murray, A. (Anna), Oostra, B.A. (Ben), Palotie, A. (Aarno), Penninx, B.W.J.H. (Brenda), Petersmann, A. (Astrid), Pilling, L.C. (Luke), Psaty, B.M. (Bruce), Rawal, R. (Rajesh), Reiman, E.M. (Eric), Schulz, A. (Ansgar), Shulman, L. (Lee), Singleton, A.B. (Andrew), Smith, A.V. (Davey), Sutin, A.R., Uitterlinden, A.G. (André), Völzke, H. (Henry), Widen, E. (Elisabeth), Yaffe, K. (Kristine), Zonderman, A.B. (Alan), Cucca, F. (Francesco), Harris, T.B. (Tamara), Ladwig, K.-H. (Karl-Heinz), Llewellyn, D.J. (David), Räikkönen, K. (Katri), Tanaka, T. (Toshiko), Duijn, C.M. (Cornelia) van, Grabe, H.J. (Hans Jörgen), Launer, L.J. (Lenore), Lunetta, K.L. (Kathryn), Mosley, T.H. (Thomas), Newman, A.B. (Anne), Tiemeier, H.W. (Henning), Murabito, J. (Joanne), Hek, K. (Karin), Demirkan, A. (Ayşe), Lahti, J. (Jari), Terracciano, A., Teumer, A. (Alexander), Cornelis, M. (Marilyn), Amin, N. (Najaf), Bakshis, E. (Erin), Baumert, J. (Jens), Ding, J. (Jingzhong), Liu, Y. (YongMei), Marciante, K. (Kristin), Meirelles, O., Nalls, M.A. (Michael), Sun, Y.V. (Yan), Vogelzangs, N. (Nicole), Yu, L. (Lei), Bandinelli, S. (Stefania), Benjamin, E.J. (Emelia), Bennett, D.A. (David), Boomsma, D.I. (Dorret), Cannas, A., Coker, L.H. (Laura), Geus, E.J.C. (Eco) de, Jager, P.L. (Philip) de, Diez Roux, A.V. (Ana), Purcell, S. (Shaun), Hu, F.B. (Frank), Rimm, E., Hunter, D.J. (David), Jensen, M.K. (Majken), Curhan, G.C. (Gary), Rice, K.M. (Kenneth), Penman, A.D. (Alan), Rotter, J.I. (Jerome), Sotoodehnia, N. (Nona), Emeny, R. (Rebecca), Eriksson, J.G. (Johan), Evans, D.A. (Denis), Ferrucci, L. (Luigi), Fornage, M. (Myriam), Gudnason, V. (Vilmundur), Hofman, A. (Albert), Illig, T. (Thomas), Kardia, S.L.R. (Sharon), Kelly-Hayes, M. (Margaret), Koenen, M.E. (Marjorie), Kraft, P. (Peter), Kuningas, M. (Maris), Massaro, J. (Joseph), Melzer, D. (David), Mulas, A. (Antonella), Mulder, C.L. (Niels), Murray, A. (Anna), Oostra, B.A. (Ben), Palotie, A. (Aarno), Penninx, B.W.J.H. (Brenda), Petersmann, A. (Astrid), Pilling, L.C. (Luke), Psaty, B.M. (Bruce), Rawal, R. (Rajesh), Reiman, E.M. (Eric), Schulz, A. (Ansgar), Shulman, L. (Lee), Singleton, A.B. (Andrew), Smith, A.V. (Davey), Sutin, A.R., Uitterlinden, A.G. (André), Völzke, H. (Henry), Widen, E. (Elisabeth), Yaffe, K. (Kristine), Zonderman, A.B. (Alan), Cucca, F. (Francesco), Harris, T.B. (Tamara), Ladwig, K.-H. (Karl-Heinz), Llewellyn, D.J. (David), Räikkönen, K. (Katri), Tanaka, T. (Toshiko), Duijn, C.M. (Cornelia) van, Grabe, H.J. (Hans Jörgen), Launer, L.J. (Lenore), Lunetta, K.L. (Kathryn), Mosley, T.H. (Thomas), Newman, A.B. (Anne), Tiemeier, H.W. (Henning), and Murabito, J. (Joanne)

Abstract

Background: Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms. Methods: In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p<1×10-5) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies. Results: The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05×10-7). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, p = 9.19×10-3). This 5q21 region reached genome-wide significance (p = 4.78×10-8) in the overall meta-analysis combining discovery and replication studies (n = 51,258). Conclusions: The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms.

Published
2013
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28. Four novel loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation In vivo

Author

Ikram MK, Sim X, Jensen RA, Cotch MF, Hewitt AW, Ikram MA, Wang JJ, Klein R, Klein BE, Breteler MM, Cheung N, Liew G, Mitchell P, Uitterlinden AG, Rivadeneira F, Hofman A, de Jong PT, van Duijn CM, Kao L, Cheng CY, Smith AV, Glazer NL, Lumley T, McKnight B, Psaty BM, Jonasson F, Eiriksdottir G, Aspelund T, Newton Cheh C, Johnson T, Gateva V, Tobin MD, Bochud M, Coin L, Najjar S, Zhao JH, Heath SC, Eyheramendy S, Wallace C, Chambers JC, Khaw KT, Polidoro S, Grobbee DE, Onland Moret NC, Allione A, Di Gregorio A, Guarrera S, Ricceri F, Romanazzi V, Sacerdote C, Vineis P, Barroso I, O'Reilly PF, Peltonen L, Pouta A, de Jong PE, Snieder P, Tognoni G, Lakatta EG, Sanna S, Scheet P, Schlessinger D, Scuteri A, Galan P, Gut IV, Hercberg S, van der Schouw YT, Numans ME, Matullo G, Navis G, Berglund G, Bandinelli S, Ferrucci L, Watkins H, Tuomilehto J, Altshuler D, Wareham NJ, Uda M, Jarvelin MR, Mooser V, Melander O, Loos RFJ, Elliott P, Abecasis GR, Caulfield M, Munroe PB, Harris TB, Launer LJ, Taylor KD, Li X, Iyengar SK, Xi Q, Sivakumaran TA, Mackey DA, Macgregor S, Martin NG, Young TL, Bis JC, Wiggins KL, Heckbert SR, Hammond CJ, Andrew T, Fahy S, Attia J, Holliday EG, Scott RJ, Islam FM, Rotter JI, McAuley AK, Boerwinkle E, Tai ES, Gudnason V, Siscovick DS, Vingerling JR, Wong TY, PANICO, SALVATORE, Ophthalmology, Epidemiology, Internal Medicine, Faculteit der Geneeskunde, Ikram, Mk, Xueling, S, Jensen, Ra, Cotch, Mf, Hewitt, Aw, Ikram, Ma, Wang, Jj, Klein, R, Klein, Be, Breteler, Mm, Cheung, N, Liew, G, Mitchell, P, Uitterlinden, Ag, Rivadeneira, F, Hofman, A, de Jong, Pt, van Duijn, Cm, Kao, L, Cheng, Cy, Smith, Av, Glazer, Nl, Lumley, T, Mcknight, B, Psaty, Bm, Jonasson, F, Eiriksdottir, G, Aspelund, T, Panico, Salvatore, Global BPgen, Consortium, Harris, Tb, Launer, Lj, Taylor, Kd, Li, X, Iyengar, Sk, Xi, Q, Sivakumaran, Ta, Mackey, Da, Macgregor, S, Martin, Ng, Young, Tl, Bis, Jc, Wiggins, Kl, Heckbert, Sr, Hammond, Cj, Andrew, T, Fahy, S, Attia, J, Holliday, Eg, Scott, Rj, Islam, Fm, Rotter, Ji, Mcauley, Ak, Boerwinkle, E, Tai, E, Gudnason, V, Siscovick, D, Vingerling, Jr, 2010 Oct 28, Wong T. Y. PLoS G. e. n. e. t., 6:e1001184, Sim, X, Newton Cheh, C, Johnson, T, Gateva, V, Tobin, Md, Bochud, M, Coin, L, Najjar, S, Zhao, Jh, Heath, Sc, Eyheramendy, S, Wallace, C, Chambers, Jc, Khaw, Kt, Polidoro, S, Grobbee, De, Onland Moret, Nc, Allione, A, Di Gregorio, A, Guarrera, S, Ricceri, F, Romanazzi, V, Sacerdote, C, Vineis, P, Barroso, I, O'Reilly, Pf, Peltonen, L, Pouta, A, de Jong, Pe, Snieder, P, Tognoni, G, Lakatta, Eg, Sanna, S, Scheet, P, Schlessinger, D, Scuteri, A, Galan, P, Gut, Iv, Hercberg, S, van der Schouw, Yt, Numans, Me, Matullo, G, Navis, G, Berglund, G, Bandinelli, S, Ferrucci, L, Watkins, H, Tuomilehto, J, Altshuler, D, Wareham, Nj, Uda, M, Jarvelin, Mr, Mooser, V, Melander, O, Loos, Rfj, Elliott, P, Abecasis, Gr, Caulfield, M, Munroe, Pb, Wong, Ty, Medical Research Council (MRC), and Department of Public Health

Subjects
Male, Cancer Research, Pathology, VESSEL DIAMETERS, Genome-wide association study, 030204 cardiovascular system & hematology, QH426-470, DISEASE, Pathogenesis, Cohort Studies, chemistry.chemical_compound, 0302 clinical medicine, Cardiovascular Disorders/Vascular Biology, Child, Genetics (clinical), Genetics, Aged, 80 and over, 0303 health sciences, education.field_of_study, Middle Aged, 314 Health sciences, 3. Good health, Cardiovascular Diseases, Child, Preschool, Chromosomes, Human, Pair 5, Chromosomes, Human, Pair 6, Female, Research Article, Adult, medicine.medical_specialty, Adolescent, ANTIHYPERTENSIVE DRUG THERAPIES, Population, European Continental Ancestry Group, Locus (genetics), Single-nucleotide polymorphism, ATHEROSCLEROSIS RISK, Biology, Polymorphism, Single Nucleotide, White People, Microcirculation, 03 medical and health sciences, Young Adult, AGE, Meta-Analysis as Topic, SDG 3 - Good Health and Well-being, Genetics and Genomics/Population Genetics, medicine, SNP, Humans, GENOME-WIDE ASSOCIATION, education, Molecular Biology, Ecology, Evolution, Behavior and Systematics, METAANALYSIS, Global BPgen Consortium, 030304 developmental biology, Aged, 0604 Genetics, Chromosomes, Human, Pair 12, Retinal Vessels, Retinal, CHARGE CONSORTIUM, RETINAL VASCULAR CALIBER, chemistry, Genetic Loci, Ophthalmology/Retinal Disorders, genome-wide association study, microcirculation, GENE/ENVIRONMENT SUSCEPTIBILITY-REYKJAVIK, Chromosomes, Human, Pair 19, Developmental Biology, Genome-Wide Association Study
Abstract

There is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n = 6,652). All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP) spread across five loci were significantly associated (p, Author Summary The microcirculation plays an important role in the development of cardiovascular diseases. Retinal vascular caliber changes reflect early microvascular disease and predict incident cardiovascular events. In order to identify genetic variants associated with retinal vascular caliber, we performed a genome-wide association study and analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n = 6,652). We found evidence for association of four loci with retinal venular caliber: on chromosomes 19q13 within the RASIP1 locus, 6q24 adjacent to the VTA1 and NMBR loci, 12q24 in the region of ATXN2,SH2B3 and PTPN11 loci, and 5q14 adjacent to the MEF2C locus. In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. In the present study, we demonstrate that four novel loci were associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. Our findings will help focus research on novel genes and pathways involving the microcirculation and its role in the development of cardiovascular disease.

Published
2010

29. Four Novel Loci (19q13, 6q24, 12q24, and 5q14) Influence the Microcirculation In Vivo

Author

University of Helsinki, Department of Public Health, Ikram, M. Kamran, Xueling, Sim, Jensen, Richard A., Cotch, Mary Frances, Hewitt, Alex W., Ikram, M. Arfan, Wang, Jie Jin, Klein, Ronald, Klein, Barbara E. K., Breteler, Monique M. B., Cheung, Ning, Liew, Gerald, Mitchell, Paul, Uitterlinden, Andre G., Rivadeneira, Fernando, Hofman, Albert, de Jong, Paulus T. V. M., van Duijn, Cornelia M., Kao, Linda, Cheng, Ching-Yu, Smith, Albert Vernon, Glazer, Nicole L., Lumley, Thomas, McKnight, Barbara, Psaty, Bruce M., Jonasson, Fridbert, Eiriksdottir, Gudny, Aspelund, Thor, Harris, Tamara B., Launer, Lenore J., Taylor, Kent D., Li, Xiaohui, Iyengar, Sudha K., Xi, Quansheng, Sivakumaran, Theru A., Mackey, David A., MacGregor, Stuart, Martin, Nicholas G., Young, Terri L., Bis, Josh C., Wiggins, Kerri L., Heckbert, Susan R., Hammond, Christopher J., Andrew, Toby, Fahy, Samantha, Attia, John, Holliday, Elizabeth G., Scott, Rodney J., Islam, F. M. Amirul, Rotter, Jerome I., McAuley, Annie K., Boerwinkle, Eric, Tai, E. Shyong, Gudnason, Vilmundur, Siscovick, David S., Vingerling, Johannes R., Wong, Tien Y., Tuomilehto, Jaakko, Global BPgen Consortium, University of Helsinki, Department of Public Health, Ikram, M. Kamran, Xueling, Sim, Jensen, Richard A., Cotch, Mary Frances, Hewitt, Alex W., Ikram, M. Arfan, Wang, Jie Jin, Klein, Ronald, Klein, Barbara E. K., Breteler, Monique M. B., Cheung, Ning, Liew, Gerald, Mitchell, Paul, Uitterlinden, Andre G., Rivadeneira, Fernando, Hofman, Albert, de Jong, Paulus T. V. M., van Duijn, Cornelia M., Kao, Linda, Cheng, Ching-Yu, Smith, Albert Vernon, Glazer, Nicole L., Lumley, Thomas, McKnight, Barbara, Psaty, Bruce M., Jonasson, Fridbert, Eiriksdottir, Gudny, Aspelund, Thor, Harris, Tamara B., Launer, Lenore J., Taylor, Kent D., Li, Xiaohui, Iyengar, Sudha K., Xi, Quansheng, Sivakumaran, Theru A., Mackey, David A., MacGregor, Stuart, Martin, Nicholas G., Young, Terri L., Bis, Josh C., Wiggins, Kerri L., Heckbert, Susan R., Hammond, Christopher J., Andrew, Toby, Fahy, Samantha, Attia, John, Holliday, Elizabeth G., Scott, Rodney J., Islam, F. M. Amirul, Rotter, Jerome I., McAuley, Annie K., Boerwinkle, Eric, Tai, E. Shyong, Gudnason, Vilmundur, Siscovick, David S., Vingerling, Johannes R., Wong, Tien Y., Tuomilehto, Jaakko, and Global BPgen Consortium

Published
2010

30. Correction: The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study

Author

Winkler, Thomas W, Justice, Anne E, Graff, Mariaelisa, Barata, Llilda, Feitosa, Mary F, Chu, Su, Czajkowski, Jacek, Esko, Tõnu, Fall, Tove, Kilpeläinen, Tuomas O, Lu, Yingchang, Mägi, Reedik, Mihailov, Evelin, Pers, Tune H, Rüeger, Sina, Teumer, Alexander, Ehret, Georg B, Ferreira, Teresa, Heard-Costa, Nancy L, Karjalainen, Juha, Lagou, Vasiliki, Mahajan, Anubha, Neinast, Michael D, Prokopenko, Inga, Simino, Jeannette, Teslovich, Tanya M, Jansen, Rick, Westra, Harm-Jan, White, Charles C, Absher, Devin, Ahluwalia, Tarunveer S, Ahmad, Shafqat, Albrecht, Eva, Alves, Alexessander Couto, Bragg-Gresham, Jennifer L, De Craen, Anton JM, Bis, Joshua C, Bonnefond, Amélie, Boucher, Gabrielle, Cadby, Gemma, Cheng, Yu-Ching, Chiang, Charleston WK, Delgado, Graciela, Demirkan, Ayse, Dueker, Nicole, Eklund, Niina, Eiriksdottir, Gudny, Eriksson, Joel, Feenstra, Bjarke, Fischer, Krista, Frau, Francesca, Galesloot, Tessel E, Geller, Frank, Goel, Anuj, Gorski, Mathias, Grammer, Tanja B, Gustafsson, Stefan, Haitjema, Saskia, Hottenga, Jouke-Jan, Huffman, Jennifer E, Jackson, Anne U, Jacobs, Kevin B, Johansson, Åsa, Kaakinen, Marika, Kleber, Marcus E, Lahti, Jari, Mateo Leach, Irene, Lehne, Benjamin, Liu, Youfang, Lo, Ken Sin, Lorentzon, Mattias, Luan, Jian'an, Madden, Pamela AF, Mangino, Massimo, McKnight, Barbara, Medina-Gomez, Carolina, Monda, Keri L, Montasser, May E, Müller, Gabriele, Müller-Nurasyid, Martina, Nolte, Ilja M, Panoutsopoulou, Kalliope, Pascoe, Laura, Paternoster, Lavinia, Rayner, Nigel W, Renström, Frida, Rizzi, Federica, Rose, Lynda M, Ryan, Kathy A, Salo, Perttu, Sanna, Serena, Scharnagl, Hubert, Shi, Jianxin, Smith, Albert Vernon, Southam, Lorraine, Stančáková, Alena, Steinthorsdottir, Valgerdur, Strawbridge, Rona J, Sung, Yun Ju, Tachmazidou, Ioanna, Tanaka, Toshiko, Thorleifsson, Gudmar, Trompet, Stella, Pervjakova, Natalia, Tyrer, Jonathan P, Vandenput, Liesbeth, Van Der Laan, Sander W, Van Der Velde, Nathalie, Van Setten, Jessica, Van Vliet-Ostaptchouk, Jana V, Verweij, Niek, Vlachopoulou, Efthymia, Waite, Lindsay L, Wang, Sophie R, Wang, Zhaoming, Wild, Sarah H, Willenborg, Christina, Wilson, James F, Wong, Andrew, Yang, Jian, Yengo, Loïc, Yerges-Armstrong, Laura M, Yu, Lei, Zhang, Weihua, Zhao, Jing Hua, Andersson, Ehm A, Bakker, Stephan JL, Baldassarre, Damiano, Banasik, Karina, Barcella, Matteo, Barlassina, Cristina, Bellis, Claire, Benaglio, Paola, Blangero, John, Blüher, Matthias, Bonnet, Fabrice, Bonnycastle, Lori L, Boyd, Heather A, Bruinenberg, Marcel, Buchman, Aron S, Campbell, Harry, Chen, Yii-Der Ida, Chines, Peter S, Claudi-Boehm, Simone, Cole, John, Collins, Francis S, De Geus, Eco JC, De Groot, Lisette CPGM, Dimitriou, Maria, Duan, Jubao, Enroth, Stefan, Eury, Elodie, Farmaki, Aliki-Eleni, Forouhi, Nita G, Friedrich, Nele, Gejman, Pablo V, Gigante, Bruna, Glorioso, Nicola, Go, Alan S, Gottesman, Omri, Gräßler, Jürgen, Grallert, Harald, Grarup, Niels, Gu, Yu-Mei, Broer, Linda, Ham, Annelies C, Hansen, Torben, Harris, Tamara B, Hartman, Catharina A, Hassinen, Maija, Hastie, Nicholas, Hattersley, Andrew T, Heath, Andrew C, Henders, Anjali K, Hernandez, Dena, Hillege, Hans, Holmen, Oddgeir, Hovingh, Kees G, Hui, Jennie, Husemoen, Lise L, Hutri-Kähönen, Nina, Hysi, Pirro G, Illig, Thomas, De Jager, Philip L, Jalilzadeh, Shapour, Jørgensen, Torben, Jukema, J Wouter, Juonala, Markus, Kanoni, Stavroula, Karaleftheri, Maria, Khaw, Kay Tee, Kinnunen, Leena, Kittner, Steven J, Koenig, Wolfgang, Kolcic, Ivana, Kovacs, Peter, Krarup, Nikolaj T, Kratzer, Wolfgang, Krüger, Janine, Kuh, Diana, Kumari, Meena, Kyriakou, Theodosios, Langenberg, Claudia, Lannfelt, Lars, Lanzani, Chiara, Lotay, Vaneet, Launer, Lenore J, Leander, Karin, Lindström, Jaana, Linneberg, Allan, Liu, Yan-Ping, Lobbens, Stéphane, Luben, Robert, Lyssenko, Valeriya, Männistö, Satu, Magnusson, Patrik K, McArdle, Wendy L, Menni, Cristina, Merger, Sigrun, Milani, Lili, Montgomery, Grant W, Morris, Andrew P, Narisu, Narisu, Nelis, Mari, Ong, Ken K, Palotie, Aarno, Pérusse, Louis, Pichler, Irene, Pilia, Maria G, Pouta, Anneli, Rheinberger, Myriam, Ribel-Madsen, Rasmus, Richards, Marcus, Rice, Kenneth M, Rice, Treva K, Rivolta, Carlo, Salomaa, Veikko, Sanders, Alan R, Sarzynski, Mark A, Scholtens, Salome, Scott, Robert A, Scott, William R, Sebert, Sylvain, Sengupta, Sebanti, Sennblad, Bengt, Seufferlein, Thomas, Silveira, Angela, Slagboom, P Eline, Smit, Jan H, Sparsø, Thomas H, Stirrups, Kathleen, Stolk, Ronald P, Stringham, Heather M, Swertz, Morris A, Swift, Amy J, Syvänen, Ann-Christine, Tan, Sian-Tsung, Thorand, Barbara, Tönjes, Anke, Tremblay, Angelo, Tsafantakis, Emmanouil, Van Der Most, Peter J, Völker, Uwe, Vohl, Marie-Claude, Vonk, Judith M, Waldenberger, Melanie, Walker, Ryan W, Wennauer, Roman, Widén, Elisabeth, Willemsen, Gonneke, Wilsgaard, Tom, Wright, Alan F, Zillikens, M Carola, Van Dijk, Suzanne C, Van Schoor, Natasja M, Asselbergs, Folkert W, De Bakker, Paul IW, Beckmann, Jacques S, Beilby, John, Bennett, David A, Bergman, Richard N, Bergmann, Sven, Böger, Carsten A, Boehm, Bernhard O, Boerwinkle, Eric, Boomsma, Dorret I, Bornstein, Stefan R, Bottinger, Erwin P, Bouchard, Claude, Chambers, John C, Chanock, Stephen J, Chasman, Daniel I, Cucca, Francesco, Cusi, Daniele, Dedoussis, George, Erdmann, Jeanette, Eriksson, Johan G, Evans, Denis A, De Faire, Ulf, Farrall, Martin, Ferrucci, Luigi, Ford, Ian, Franke, Lude, Franks, Paul W, Froguel, Philippe, Gansevoort, Ron T, Gieger, Christian, Grönberg, Henrik, Gudnason, Vilmundur, Gyllensten, Ulf, Hall, Per, Hamsten, Anders, Van Der Harst, Pim, Hayward, Caroline, Heliövaara, Markku, Hengstenberg, Christian, Hicks, Andrew A, Hingorani, Aroon, Hofman, Albert, Hu, Frank, Huikuri, Heikki V, Hveem, Kristian, James, Alan L, Jordan, Joanne M, Jula, Antti, Kähönen, Mika, Kajantie, Eero, Kathiresan, Sekar, Kiemeney, Lambertus ALM, Kivimaki, Mika, Knekt, Paul B, Koistinen, Heikki A, Kooner, Jaspal S, Koskinen, Seppo, Kuusisto, Johanna, Maerz, Winfried, Martin, Nicholas G, Laakso, Markku, Lakka, Timo A, Lehtimäki, Terho, Lettre, Guillaume, Levinson, Douglas F, Lind, Lars, Lokki, Marja-Liisa, Mäntyselkä, Pekka, Melbye, Mads, Metspalu, Andres, Mitchell, Braxton D, Moll, Frans L, Murray, Jeffrey C, Musk, Arthur W, Nieminen, Markku S, Njølstad, Inger, Ohlsson, Claes, Oldehinkel, Albertine J, Oostra, Ben A, Palmer, Lyle J, Pankow, James S, Pasterkamp, Gerard, Pedersen, Nancy L, Pedersen, Oluf, Penninx, Brenda W, Perola, Markus, Peters, Annette, Polašek, Ozren, Pramstaller, Peter P, Psaty, Bruce M, Qi, Lu, Quertermous, Thomas, Raitakari, Olli T, Rankinen, Tuomo, Rauramaa, Rainer, Ridker, Paul M, Rioux, John D, Rivadeneira, Fernando, Rotter, Jerome I, Rudan, Igor, Den Ruijter, Hester M, Saltevo, Juha, Sattar, Naveed, Schunkert, Heribert, Schwarz, Peter EH, Shuldiner, Alan R, Sinisalo, Juha, Snieder, Harold, Sørensen, Thorkild IA, Spector, Tim D, Staessen, Jan A, Stefania, Bandinelli, Thorsteinsdottir, Unnur, Stumvoll, Michael, Tardif, Jean-Claude, Tremoli, Elena, Tuomilehto, Jaakko, Uitterlinden, André G, Uusitupa, Matti, Verbeek, André LM, Vermeulen, Sita H, Viikari, Jorma S, Vitart, Veronique, Völzke, Henry, Vollenweider, Peter, Waeber, Gérard, Walker, Mark, Wallaschofski, Henri, Wareham, Nicholas J, Watkins, Hugh, Zeggini, Eleftheria, ArcOGEN Consortium, CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global-BPGen Consortium, ICBP Consortium, MAGIC Consortium, Chakravarti, Aravinda, Clegg, Deborah J, Cupples, L Adrienne, Gordon-Larsen, Penny, Jaquish, Cashell E, Rao, DC, Abecasis, Goncalo R, Assimes, Themistocles L, Barroso, Inês, Berndt, Sonja I, Boehnke, Michael, Deloukas, Panos, Fox, Caroline S, Groop, Leif C, Hunter, David J, Ingelsson, Erik, Kaplan, Robert C, McCarthy, Mark I, Mohlke, Karen L, O'Connell, Jeffrey R, Schlessinger, David, Strachan, David P, Stefansson, Kari, Van Duijn, Cornelia M, Hirschhorn, Joel N, Lindgren, Cecilia M, Heid, Iris M, North, Kari E, Borecki, Ingrid B, Kutalik, Zoltán, and Loos, Ruth JF

Subjects
GLGC Consortium, Global-BPGen Consortium, MAGIC Consortium, CHARGE Consortium, ICBP Consortium, DIAGRAM Consortium, 3. Good health, arcOGEN Consortium
Abstract

[This corrects the article DOI: 10.1371/journal.pgen.1005378.].

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