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

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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 & 84 more 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

Original languageEnglish
Pages (from-to)15-28
Number of pages14
JournalAmerican Journal of Human Genetics
Volume105
Issue number1
DOIs
Published3 Jul 2019
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    • King's College London

    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.

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