Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology

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

doi:10.1016/j.ajhg.2019.05.002

Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology

Am J Hum Genet. 2019 Jul 3;105(1):15-28. doi: 10.1016/j.ajhg.2019.05.002. Epub 2019 Jun 6.

Authors

Cassandra N Spracklen¹, Tugce Karaderi², Hanieh Yaghootkar³, Claudia Schurmann⁴, Rebecca S Fine⁵, Zoltan Kutalik⁶, Michael H Preuss⁴, Yingchang Lu⁷, Laura B L Wittemans⁸, Linda S Adair⁹, Matthew Allison¹⁰, Najaf Amin¹¹, Paul L Auer¹², Traci M Bartz¹³, Matthias Blüher¹⁴, Michael Boehnke¹⁵, Judith B Borja¹⁶, Jette Bork-Jensen¹⁷, Linda Broer¹⁸, Daniel I Chasman¹⁹, Yii-Der Ida Chen²⁰, Paraskevi Chirstofidou²¹, Ayse Demirkan¹¹, Cornelia M van Duijn¹¹, Mary F Feitosa²², Melissa E Garcia²³, Mariaelisa Graff²⁴, Harald Grallert²⁵, Niels Grarup¹⁷, Xiuqing Guo²⁰, Jeffrey Haesser²⁶, Torben Hansen¹⁷, Tamara B Harris²⁷, Heather M Highland²⁸, Jaeyoung Hong²⁹, M Arfan Ikram³⁰, Erik Ingelsson³¹, Rebecca Jackson³², Pekka Jousilahti³³, Mika Kähönen³⁴, Jorge R Kizer³⁵, Peter Kovacs¹⁴, Jennifer Kriebel²⁵, Markku Laakso³⁶, Leslie A Lange³⁷, Terho Lehtimäki³⁸, Jin Li³⁹, Ruifang Li-Gao⁴⁰, Lars Lind⁴¹, Jian'an Luan⁴², Leo-Pekka Lyytikäinen⁴³, Stuart MacGregor⁴⁴, David A Mackey⁴⁵, Anubha Mahajan⁴⁶, Massimo Mangino⁴⁷, Satu Männistö³³, Mark I McCarthy⁴⁸, Barbara McKnight⁴⁹, Carolina Medina-Gomez³⁰, James B Meigs⁵⁰, Sophie Molnos²⁵, Dennis Mook-Kanamori⁵¹, Andrew P Morris⁵², Renee de Mutsert⁴⁰, Mike A Nalls⁵³, Ivana Nedeljkovic¹¹, Kari E North²⁸, Craig E Pennell⁵⁴, Aruna D Pradhan¹⁹, Michael A Province²², Olli T Raitakari⁵⁵, Chelsea K Raulerson¹, Alex P Reiner²⁶, Paul M Ridker¹⁹, Samuli Ripatti⁵⁶, Neil Roberston⁴⁶, Jerome I Rotter²⁰, Veikko Salomaa³³, America A Sandoval-Zárate⁵⁷, Colleen M Sitlani⁵⁸, Tim D Spector²¹, Konstantin Strauch⁵⁹, Michael Stumvoll¹⁴, Kent D Taylor²⁰, Betina Thuesen⁶⁰, Anke Tönjes¹⁴, Andre G Uitterlinden³⁰, Cristina Venturini²¹, Mark Walker⁶¹, Carol A Wang⁵⁴, Shuai Wang²⁹, Nicholas J Wareham⁴², Sara M Willems⁴², Ko Willems van Dijk⁶², James G Wilson⁶³, Ying Wu¹, Jie Yao²⁰, Kristin L Young²⁸, Claudia Langenberg⁴², Timothy M Frayling⁶⁴, Tuomas O Kilpeläinen⁶⁵, Cecilia M Lindgren⁶⁶, Ruth J F Loos⁶⁷, Karen L Mohlke⁶⁸

Affiliations

¹ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
² The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7FZ, UK; 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.
³ Genetics of Complex Traits, University of Exeter Medical School, Royal Devon & Exeter Hospital, Exeter EX2 5DW, UK; Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, UK.
⁴ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁵ Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁶ Genetics of Complex Traits, University of Exeter Medical School, Royal Devon & Exeter Hospital, Exeter EX2 5DW, UK; University Center for Primary Care and Public Health, University of Lausanne, Lausanne 1010, Switzerland; Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland.
⁷ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN 37203-1738, USA; Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁸ The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7FZ, UK; MRC Epidemiology Unit, University of Cambridge, Cambridge CB2 0QQ, UK.
⁹ Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27516, USA.
¹⁰ Department of Family Medicine and Public Health, University of California, San Diego, CA 92093, USA.
¹¹ Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3015CN, the Netherlands.
¹² Joseph J. Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA.
¹³ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA; Department of Biostatistics, University of Washington, Seattle, WA 98101, USA.
¹⁴ Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig, Leipzig 4103, Germany.
¹⁵ Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
¹⁶ Office of Population Studies Foundation, Inc, Cebu City, Philippines; Department of Nutrition and Dietetics, University of San Carlos, Cebu City, Philippines.
¹⁷ Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark.
¹⁸ Department of Internal Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam 3000 CA, the Netherlands.
¹⁹ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02115, USA.
²⁰ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
²¹ Department of Twin Research and Genetic Epidemiology, Kings College London, London SE1 7EH, UK.
²² Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
²³ National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA.
²⁴ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Carolina Center for Genome Sciences, Chapel Hill, NC 27599, USA.
²⁵ 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.
²⁶ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
²⁷ Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIH, Bethesda, MD 20892, USA.
²⁸ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
²⁹ Department of Biostatistics, Boston University School of Public Health, Boston, MA 2118, USA.
³⁰ Department of Internal Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam 3000 CA, the Netherlands; Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, Rotterdam 3000 CA, the Netherlands.
³¹ Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Palo Alto, CA 94304, USA; Stanford Cardiovascular Institute, Stanford University of Medicine, Palo Alto, CA 94304, USA; Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala 75185, Sweden; Stanford Diabetes Research Center, Stanford University, Stanford, CA 94305, USA.
³² Division of Endocrinology, Diabetes, and Metabolism, Ohio State University, Columbus, OH 43210, USA.
³³ Department of Public Health Solutions, National Institute for Health and Welfare, Helsinki 00271, Finland.
³⁴ 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.
³⁵ Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
³⁶ Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University of Hospital, Kuopio 70029 KYS, Finland.
³⁷ Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado-Denver, Denver, CO 80045, USA.
³⁸ 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.
³⁹ Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Palo Alto, CA 94304, USA.
⁴⁰ Department of Clinical Epidemiology, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands.
⁴¹ Department of Medical Sciences, Uppsala University, Uppsala 75185, Sweden.
⁴² MRC Epidemiology Unit, University of Cambridge, Cambridge CB2 0QQ, UK.
⁴³ 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.
⁴⁴ QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
⁴⁵ Faculty of Health and Medical Sciences, The University of Western Australia, Perth, WA 6009, Australia; Centre for Ophthalmology and Visual Science, Lions Eye Institute, The University of Western Australia, Perth, WA 6009, Australia.
⁴⁶ The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7FZ, UK; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK.
⁴⁷ Department of Twin Research and Genetic Epidemiology, Kings College London, London SE1 7EH, UK; NIHR Biomedical Research Centre, Guy's and St Thomas' Foundation Trust, London SE1 9RT, UK.
⁴⁸ The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7FZ, UK; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK; Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford OX3 7FZ, UK.
⁴⁹ Department of Biostatistics, University of Washington, Seattle, WA 98101, USA.
⁵⁰ Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Program in Population and Medical Genetics, Broad Institute, Cambridge, MA 02114, USA.
⁵¹ Department of Clinical Epidemiology, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands; Department of Public Health and Primary Care, Leiden University Medical Center, Leiden 2334 ZA, the Netherlands.
⁵² The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7FZ, UK; Department of Biostatistics, University of Liverpool, Liverpool L69 3GL, UK.
⁵³ Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD 20892, USA; Data Tecnica International, Glen Echo, MD 20812, USA.
⁵⁴ School of Medicine and Public Health, Faculty of Medicine and Health, The University of Newcastle, Newcastle, NSW 2305, Australia.
⁵⁵ 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.
⁵⁶ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Public Health, University of Helsinki, Helsinki 00014, Finland; Institute for Molecular Medicine Finland, Helsinki 00014, Finland.
⁵⁷ Institute for Molecular Medicine Finland, Helsinki 00014, Finland.
⁵⁸ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA.
⁵⁹ 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.
⁶⁰ Center for Clinical Research and Disease Prevention, Bispebjerg and Frederiksberg Hospital, The Capital Region, Copenhagen 2400, Denmark.
⁶¹ Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle, UK.
⁶² Department of Internal Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden 2333 ZA, the Netherlands; Department of Human Genetics, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands.
⁶³ Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
⁶⁴ Genetics of Complex Traits, University of Exeter Medical School, Royal Devon & Exeter Hospital, Exeter EX2 5DW, UK.
⁶⁵ Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark; Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁶⁶ The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7FZ, UK; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7LF, UK.
⁶⁷ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Mindich Child Health and Development Institute, Ichan School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: ruth.loos@mssm.edu.
⁶⁸ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: mohlke@med.unc.edu.

Abstract

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.

Keywords: adiponectin; cardio metabolic traits; exome; genetics; genome-wide association study; lipids; obesity.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adiponectin / genetics*
Adipose Tissue / metabolism
Adipose Tissue / pathology*
Adolescent
Adult
Aged
Aged, 80 and over
Black or African American / genetics
Exome / genetics*
Female
Genetic Predisposition to Disease*
Hispanic or Latino / genetics
Humans
Lipids / analysis*
Male
Middle Aged
Obesity / etiology*
Obesity / pathology
Phenotype
Polymorphism, Single Nucleotide*
Quantitative Trait Loci
White People / genetics
Young Adult

Substances

ADIPOQ protein, human
Adiponectin
Lipids

Abstract

Publication types

MeSH terms

Substances

Grants and funding