期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 105, 期 1, 页码 15-28出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2019.05.002
关键词
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资金
- Novo Nordisk Foundation Center for Basic Metabolic Research
- NHGRI [F31 HG009850]
- European Research Council [323195: GLUCOSEGENES-FP7-IDEAS-ERC]
- NHLBI [T32 HL007055, T32 HL129982]
- Novo Nordisk Foundation Center for Protein Research [NNF17OC0027594, NNF14CC0001]
- Danish Council for Independent Research [DFF -6110-00183]
- Novo Nordisk Foundation [NNF17OC0026848]
- Li Ka Shing Foundation
- WT-SSI/John Fell funds
- NIHR Biomedical Research Centre, Oxford
- NIH [R01DK072193, R01DK093757]
- National Institute of Health Research Senior Investigator
- Dutch Science Organization (ZonMW-VENI Grant) [916.14.023, R01DK089256, R01HD057194, U01HG007416, R01DK101855]
- AHA [13GRNT16490017]
- National Institutes of Health [5T32GM67553]
- Academy of Finland Center of Excellence in Complex Disease Genetics [312062]
- Academy of Finland [285380]
- Finnish Foundation for Cardiovascular Research
- American Heart Association [15POST24470131, 17POST33650016, U54GM115428]
- National Institute of General Medical Sciences
- Wellcome Trust [WT083442AIA]
- Diabetes UK RD Lawrence fellowship [17/0005594, KL2TR001109]
- MRC [MC_UU_12015/1] Funding Source: UKRI
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.
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