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

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Citation

Spracklen, Cassandra N.; Karaderi, Tugce; Yaghootkar, Hanieh; Schurmann, Claudia; Fine, Rebecca S.; Kutalik, Zoltan; Preuss, Michael H.; Lu, Yingchang; Wittemans, Laura B. L.; & Adair, Linda S., et al. (2019). Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology. American Journal of Human Genetics, 105(1), 15-28. PMCID: PMC6612516

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 x 10(-7)). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r(2) > .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 x 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.

URL

http://dx.doi.org/10.1016/j.ajhg.2019.05.002

Reference Type

Journal Article

Year Published

2019

Journal Title

American Journal of Human Genetics

Author(s)

Spracklen, Cassandra N.
Karaderi, Tugce
Yaghootkar, Hanieh
Schurmann, Claudia
Fine, Rebecca S.
Kutalik, Zoltan
Preuss, Michael H.
Lu, Yingchang
Wittemans, Laura B. L.
Adair, Linda S.
Allison, Matthew A.
Amin, Najaf
Auer, Paul L.
Bartz, Traci M.
Bluher, Matthias
Boehnke, Michael
Borja, Judith B.
Bork-Jensen, Jette
Broer, Linda
Chasman, Daniel I.
Chen, Yii-Der Ida
Chirstofidou, Paraskevi
Demirkan, Ayse
van Duijn, Cornelia M.
Feitosa, Mary F.
Garcia, Melissa E.
Graff, Mariaelisa
Grallert, Harald
Grarup, Niels
Guo, Xiuqing
Haessler, Jeffrey
Hansen, Torben
Harris, Tamara B.
Highland, Heather M.
Hong, Jaeyoung
Ikram, M. Arfan
Ingelsson, Erik
Jackson, Rebecca D.
Jousilahti, Pekka
Kahonen, Mika
Kizer, Jorge R.
Kovacs, Peter
Kriebel, Jennifer
Laakso, Markku
Lange, Leslie A.
Lehtimaki, Terho
Li, Jin
Li-Gao, Ruifang
Lind, Lars
Luan, Jian'an
Lyytikainen, Leo-Pekka
MacGregor, Stuart
Mackey, David A.
Mahajan, Anubha
Mangino, Massimo
Mannisto, Satu
McCarthy, Mark I.
McKnight, Barbara
Medina-Gomez, Carolina
Meigs, James B.
Molnos, Sophie
Mook-Kanamori, Dennis O.
Morris, Andrew P.
de Mutsert, Renee
Nalls, Mike A.
Nedeljkovic, Ivana
North, Kari E.
Pennell, Craig E.
Pradhan, Aruna D.
Province, Michael A.
Raitakari, Olli T.
Raulerson, Chelsea K.
Reiner, Alexander P.
Ridker, Paul M.
Ripatti, Samuli
Roberston, Neil
Rotter, Jerome I.
Salomaa, Veikko
Sandoval-Zarate, America A.
Sitlani, Colleen M.
Spector, Timothy D.
Strauch, Konstantin
Stumvoll, Michael
Taylor, Kent D.
Thuesen, Betina H.
Tonjes, Anke
Uitterlinden, Andre G.
Venturini, Cristina
Walker, Mark
Wang, Carol A.
Wang, Shuai
Wareham, Nicholas J.
Willems, Sara M.
Willems van Dijk, Ko
Wilson, James G.
Wu, Ying
Yao, Jie
Young, Kristin L.
Langenberg, Claudia
Frayling, Timothy M.
Kilpelainen, Tuomas O.
Lindgren, Cecilia M.
Loos, Ruth J. F.
Mohlke, Karen L.

PMCID

PMC6612516

ORCiD

Adair - 0000-0002-3670-8073
Highland - 000-0002-3583-8239
Graff - 0000-0001-6380-1735