Ying Wu, Lindsay L. Waite, Anne U. Jackson, Wayne H.-H. Sheu, Steven Buyske, Devin Absher, Donna K. Arnett, Eric Boerwinkle, Lori L. Bonnycastle, Cara L. Carty, Iona Cheng, Barbara Cochran, Damien C. Croteau-Chonka, Logan Dumitrescu, Charles B. Eaton, Nora Franceschini, Xiuqing Guo, Brian E. Henderson, Lucia A. Hindorff, Eric Kim, Leena Kinnunen, Pirjo Komulainen, Wen-Jane Lee, Loic Le Marchand, Yi Lin, Jaana Lindström, Oddgeir Lingaas-Holmen, Sabrina L. Mitchell, Narisu Narisu, Jennifer G. Robinson, Fred Schumacher, Alena Stančáková, Jouko Sundvall, Yun-Ju Sung, Amy J. Swift, Wen-Chang Wang, Lynne Wilkens, Tom Wilsgaard, Alicia M. Young, Linda S. Adair, Christie M. Ballantyne, Petra Bůžková, Aravinda Chakravarti, Francis S. Collins, David Duggan, Alan B. Feranil, Low-Tone Ho, Yi-Jen Hung, Steven C. Hunt, Kristian Hveem, Jyh-Ming J. Juang, Antero Y. Kesäniemi, Johanna Kuusisto, Markku Laakso, Timo A. Lakka, I.-Te Lee, Mark F. Leppert, Tara C. Matise, Leena Moilanen, Inger Njølstad, Ulrike Peters, Thomas Quertermous, Rainer Rauramaa, Jerome I. Rotter, Jouko Saramies, Jaakko Tuomilehto, Matti Uusitupa, Tzung-Dau Wang, Michael Boehnke, Christopher A. Haiman, Yii-Der I. Chen, Charles Kooperberg, Themistocles L. Assimes, Dana C. Crawford, Chao A. Hsiung, Kari E. North, Karen L. Mohlke
Genome-wide association studies (GWAS) have identified ~100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trait-influencing variants remain unknown. We conducted a trans-ethnic fine-mapping study at 18, 22, and 18 GWAS loci on the Metabochip for their association with triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, in individuals of African American (n = 6,832), East Asian (n = 9,449), and European (n = 10,829) ancestry. We aimed to identify the variants with strongest association at each locus, identify additional and population-specific signals, refine association signals, and assess the relative significance of previously described functional variants. Among the 58 loci, 33 exhibited evidence of association at P<1×10-4 in at least one ancestry group. Sequential conditional analyses revealed that ten, nine, and four loci in African Americans, Europeans, and East Asians, respectively, exhibited two or more signals. At these loci, accounting for all signals led to a 1.3- to 1.8-fold increase in the explained phenotypic variance compared to the strongest signals. Distinct signals across ancestry groups were identified at PCSK9 and APOA5. Trans-ethnic analyses narrowed the signals to smaller sets of variants at GCKR, PPP1R3B, ABO, LCAT, and ABCA1. Of 27 variants reported previously to have functional effects, 74% exhibited the strongest association at the respective signal. In conclusion, trans-ethnic high-density genotyping and analysis confirm the presence of allelic heterogeneity, allow the identification of population-specific variants, and limit the number of candidate SNPs for functional studies.
Department of Genetics, University of North Carolina, Chapel Hill, NC, United States; HudsonAlpha Institute for Biotechnology, Huntsville, AL, United States; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, United States; Division of Endocrine and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; School of Medicine, National Yang-Ming University, Taipei, Taiwan; College of Medicine, National Defense Medical Center, Taipei, Taiwan; Department of Statistics and Biostatistics, Rutgers University, Piscataway, NJ, United States; Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, United States; The Human Genetics Center, University of Texas Health Science Center, Houston, TX, United States; Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States; Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, United States; University of Hawaii Cancer Center, Honolulu, HI, United States; Department of Molecular Physiology and Biophysics, Center for Human Genetics Research, Vanderbilt University, Nashville, TN, United States; Departments of Family Medicine and Epidemiology, Alpert Medical School, Brown University, Providence, RI, United States; Department of Epidemiology, University of North Carolina, Chapel Hill, NC, United States; Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States; Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States; Office of Population Genomics, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States; Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland; Kuopio Research Institute of Exercise Medicine, Kuopio, Finland; Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan; HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway; University of Iowa, Iowa City, IA, United States; Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland; National Institute for Health and Welfare, Disease Risk Unit, Helsinki, Finland; Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States; Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan; Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway; Department of Nutrition, University of North Carolina, Chapel Hill, NC, United States; Baylor College of Medicine, Houston, TX, United States; Department of Biostatistics, University of Washington, Seattle, WA, United States; Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States; Translational Genomics Research Institute, Phoenix, AZ, United States; Office of Population Studies Foundation, University of San Carlos, Cebu, Philippines; Department of Internal Medicine and Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan; Division of Endocrinology and Metabolism, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; Department of Internal Medicine, University of Utah, Salt Lake City, UT, United States; Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Institute of Clinical Medicine, Department of Medicine, University of Oulu and Clinical Research Center, Oulu University Hospital, Oulu, Finland; Institute of Biomedicine/Physiology, University of Eastern Finland, Kuopio, Kuopio Campus, Finland; Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT, United States; Department of Genetics, Rutgers University, Piscataway, NJ, United States; Department of Medicine, Kuopio University Hospital, Kuopio, Finland; Pirkanmaa Hospital District, Tampere, Finland; School of Public Health, University of Washington, Seattle, WA, United States; Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States; Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland; South Karelia Central Hospital, Lappeenranta, Finland; South Ostrobothnia Central Hospital, Seinäjoki, Finland; Red RECAVA Grupo RD06/0014/0015, Hospital Universitario La Paz, Madrid, Spain; Centre for Vascular Prevention, Danube-University Krems, Krems, Austria; Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Research Unit, Kuopio University Hospital, Kuopio, Finland; Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, NC, United States
