Cassandra N. Spracklen, Tugce Karaderi, Hanieh Yaghootkar, Claudia Schurmann, Rebecca S. Fine, Zoltan Kutalik, Michael H. Preuss, Yingchang Lu, Laura B.L. Wittemans, Linda S. Adair, Matthew Allison, Najaf Amin, Paul L. Auer, Traci M. Bartz, Matthias Blüher, Michael Boehnke, Judith B. Borja, Jette Bork-Jensen, Linda Broer, Daniel I. Chasman, Yii-Der Ida Chen, Paraskevi Chirstofidou, Ayse Demirkan, Cornelia M. van Duijn, Mary F. Feitosa, Melissa E. Garcia, Mariaelisa Graff, Harald Grallert, Niels Grarup, Xiuqing Guo, Jeffrey Haesser, Torben Hansen, Tamara B. Harris, Heather M. Highland, Jaeyoung Hong, M. Arfan Ikram, Erik Ingelsson, Rebecca Jackson, Pekka Jousilahti, Mika Kähönen, Jorge R. Kizer, Peter Kovacs, Jennifer Kriebel, Markku Laakso, Leslie A. Lange, Terho Lehtimäki, Jin Li, Ruifang Li-Gao, Lars Lind, Jian'an Luan, Leo-Pekka Lyytikäinen, Stuart MacGregor, David A. Mackey, Anubha Mahajan, Massimo Mangino, Satu Männistö, Mark I. McCarthy, Barbara McKnight, Carolina Medina-Gomez, James B. Meigs, Sophie Molnos, Dennis Mook-Kanamori, Andrew P. Morris, Renee de Mutsert, Mike A. Nalls, Ivana Nedeljkovic, Kari E. North, Craig E. Pennell, Aruna D. Pradhan, Michael A. Province, Olli T. Raitakari, Chelsea K. Raulerson, Alex P. Reiner, Paul M. Ridker, Samuli Ripatti, Neil Roberston, Jerome I. Rotter, Veikko Salomaa, America A. Sandoval-Zárate, Colleen M. Sitlani, Tim D. Spector, Konstantin Strauch, Michael Stumvoll, Kent D. Taylor, Betina Thuesen, Anke Tönjes, Andre G. Uitterlinden, Cristina Venturini, Mark Walker, Carol A. Wang, Shuai Wang, Nicholas J. Wareham, Sara M. Willems, Ko Willems van Dijk, James G. Wilson, Ying Wu, Jie Yao, Kristin L. Young, Claudia Langenberg, Timothy M. Frayling, Tuomas O. Kilpeläinen, Cecilia M. Lindgren, Ruth J.F. Loos, Karen L. Mohlke
Circulating levels of adiponectin, an adipocyte-secreted protein associated with cardiovascular and metabolic risk, are highly heritable. To gain insights into the biology that regulates adiponectin levels, we performed an exome array meta-analysis of 265,780 genetic variants in 67,739 individuals of European, Hispanic, African American, and East Asian ancestry. We identified 20 loci associated with adiponectin, including 11 that had been reported previously (p < 2 × 10−7). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r2 > .60) spanning as much as 900 kb. To identify potential genes and mechanisms through which the previously unreported association signals act to affect adiponectin levels, we assessed cross-trait associations, expression quantitative trait loci in subcutaneous adipose, and biological pathways of nearby genes. Eight of the nine loci were also associated (p < 1 × 10−4) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels. © 2019 American Society of Human Genetics
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, 27599, NC, United States; The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7FZ, United Kingdom; Department of Biological Sciences, Faculty of Arts and Sciences, Eastern Mediterranean University, Famagusta, Cyprus; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark; DTU Health Technology, Technical University of Denmark, Lyngby, 2800, Denmark; Genetics of Complex Traits, University of Exeter Medical School, Royal Devon & Exeter Hospital, Exeter, EX2 5DW, United Kingdom; Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, United Kingdom; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, United States; Department of Genetics, Harvard Medical School, Boston, 02115, MA, United States; Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, 02115, MA, United States; Broad Institute of MIT and Harvard, Cambridge, 02142, MA, United States; University Center for Primary Care and Public Health, University of Lausanne, Lausanne, 1010, Switzerland; Swiss Institute of Bioinformatics, Lausanne, 1015, Switzerland; Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, 37203-1738, TN, United States; Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, United States; MRC Epidemiology Unit, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom; Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, 27516, NC, United States; Department of Family Medicine and Public Health, University of California, San Diego, 92093, CA, United States; Department of Epidemiology, Erasmus University Medical Center, Rotterdam, 3015CN, Netherlands; Joseph J. Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, 53201, WI, United States; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, 98101, WA, United States; Department of Biostatistics, University of Washington, Seattle, 98101, WA, United States; Medical Department III – Endocrinology, Nephrology, Rheumatology, University of Leipzig, Leipzig, 4103, Germany; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, 48109, MI, United States; Office of Population Studies Foundation, Inc, Cebu City, Philippines; Department of Nutrition and Dietetics, University of San Carlos, Cebu City, Philippines; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark; Department of Internal Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam, 3000, CA, Netherlands; Division of Preventive Medicine, Brigham and Women's Hospital, Boston, 02215, MA, United States; Harvard Medical School, Boston, 02115, MA, United States; The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, 90502, CA, United States; Department of Twin Research and Genetic Epidemiology, Kings College London, London, SE1 7EH, United Kingdom; Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, 63110, MO, United States; National Heart, Lung, and Blood Institute, Bethesda, 20892, MD, United States; Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, 27599, NC, United States; Carolina Center for Genome Sciences, Chapel Hill, 27599, NC, United States; Research Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München Research Center for Environmental Health, München-Neuherberg, 85764, Germany; German Center for Diabetes Research, München-Neuherberg, 85765, Germany; Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, 98109, WA, United States; Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIH, Bethesda, 20892, MD, United States; Department of Biostatistics, Boston University School of Public Health, Boston, 2118, MA, United States; Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, 3000, CA, Netherlands; Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Palo Alto, 94304, CA, United States; Stanford Cardiovascular Institute, Stanford University of Medicine, Palo Alto, 94304, CA, United States; Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, 75185, Sweden; Stanford Diabetes Research Center, Stanford University, Stanford, 94305, CA, United States; Division of Endocrinology, Diabetes, and Metabolism, Ohio State University, Columbus, 43210, OH, United States; Department of Public Health Solutions, National Institute for Health and Welfare, Helsinki, 00271, Finland; Department of Clinical Physiology, Tampere University Hospital, Tampere, 33522, Finland; Department of Clinical Physiology, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, 33522, Finland; Department of Medicine, Albert Einstein College of Medicine, Bronx, 10461, NY, United States; Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, 10461, NY, United States; Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University of Hospital, Kuopio, 70029, KYS, Finland; Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado-Denver, Denver, 80045, CO, United States; Department of Clinical Chemistry, Fimlab Laboratories, Tampere, 33520, Finland; Department of Clinical Chemistry, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, 33522, Finland; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, 2333, ZA, Netherlands; Department of Medical Sciences, Uppsala University, Uppsala, 75185, Sweden; Department of Clinical Chemistry, Fimlab Laboratories, Tampere, 33522, Finland; Department of Clinical Chemistry, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, 33521, Finland; QIMR Berghofer Medical Research Institute, Brisbane, 4006, QLD, Australia; Faculty of Health and Medical Sciences, The University of Western Australia, Perth, 6009, WA, Australia; Centre for Ophthalmology and Visual Science, Lions Eye Institute, The University of Western Australia, Perth, 6009, WA, Australia; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 7FZ, United Kingdom; NIHR Biomedical Research Centre, Guy's and St Thomas’ Foundation Trust, London, SE1 9RT, United Kingdom; Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, OX3 7FZ, United Kingdom; Division of General Internal Medicine, Massachusetts General Hospital, Boston, 02114, MA, United States; Department of Medicine, Harvard Medical School, Boston, 02115, MA, United States; Program in Population and Medical Genetics, Broad Institute, Cambridge, 02114, MA, United States; Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, 2334, ZA, Netherlands; Department of Biostatistics, University of Liverpool, Liverpool, L69 3GL, United Kingdom; Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, 20892, MD, United States; Data Tecnica International, Glen Echo, 20812, MD, United States; School of Medicine and Public Health, Faculty of Medicine and Health, The University of Newcastle, Newcastle, 2305, NSW, Australia; Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland; Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland; Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland; Public Health, University of Helsinki, Helsinki, 00014, Finland; Institute for Molecular Medicine Finland, Helsinki, 00014, Finland; Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, 85764, Germany; Chair of Genetic Epidemiology, Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, 81377, Germany; Center for Clinical Research and Disease Prevention, Bispebjerg and Frederiksberg Hospital, The Capital Region, Copenhagen, 2400, Denmark; Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle, United Kingdom; Department of Internal Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, 2333, ZA, Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden, 2333, ZA, Netherlands; Department of Human Genetics, Leiden University Medical Center, Leiden, 2333, ZA, Netherlands; Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, 39216, MS, United States; Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, United States; Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7LF, United Kingdom; The Mindich Child Health and Development Institute, Ichan School of Medicine at Mount Sinai, New York, 10029, NY, United States
