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Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology
Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA.
Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7FZ, England;Eastern Mediterranean Univ, Fac Arts & Sci, Dept Biol Sci, Gazimagusa, Cyprus;Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Prot Res, DK-2200 Copenhagen, Denmark;Tech Univ Denmark, DTU Hlth Technol, DK-2800 Lyngby, Denmark.
Univ Exeter, Sch Med, Royal Devon & Exeter Hosp, Genet Complex Traits, Exeter EX2 5DW, Devon, England;Univ Westminster, Sch Life Sci, Res Ctr Optimal Hlth, London, England.
Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.
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2019 (English)In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 105, no 1, p. 15-28Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
CELL PRESS , 2019. Vol. 105, no 1, p. 15-28
National Category
Medical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-391019DOI: 10.1016/j.ajhg.2019.05.002ISI: 000473723000003PubMedID: 31178129OAI: oai:DiVA.org:uu-391019DiVA, id: diva2:1344284
Funder
EU, European Research Council, 323195: GLUCOSEGENES-FP7-IDEAS-ERCNovo Nordisk, NNF17OC0027594Novo Nordisk, NNF14CC0001Academy of Finland, 285380Wellcome trust, WT083442AIAAvailable from: 2019-08-20 Created: 2019-08-20 Last updated: 2019-08-20Bibliographically approved

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Ingelsson, ErikLind, Lars

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