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

Abstract

(The American Journal of Human Genetics 105, 15–28; July 3, 2019) In the originally published version of this article, the effect sizes for the previously reported loci achieving exome-wide significance (indicated with asterisks in the table below) were incorrect. The table has now been corrected online, and the authors apologize for this error.Table 1Adiponectin Loci in Sex-Combined and Sex-Specific Meta-analyses (Additive, adjBMI)VariantChrPositionNearest GeneAnnotationEAEAFSex-CombinedWomenMenSex Diff.EffectpNEffectpNEffectpNpaTest for sex difference; values significant at the table-wide Bonferroni threshold of 0.05/20 = 2.5E−03Loci Achieving Exome-wide Significancers2276853347,282,303KIF9missense (p.Arg638Gly)A0.594−0.0333.35E−0865,521−0.0391.98E−0631,788−0.0294.18E−0433,7334.17E−01rs3087866349,054,692DALRD3missense (p.Gln299Arg)C0.786−0.0402.14E−0865,521−0.0345.88E−0431,788−0.0463.67E−0633,7333.86E−01rs13133548489,740,128FAM13AintronicA0.489−0.0395.91E−1265,521−0.0333.24E−0531,788−0.0411.98E−0733,7334.61E−01rs131073254103,188,709SLC39A8missense (p.Ala391Thr)T0.0470.0721.05E−0759,6060.0781.13E−0531,7880.0501.25E−0233,7332.98E−01rs10282707717,911,038SNX13intronicT0.383−0.0401.96E−1056,826−0.0241.07E−0224,421−0.0533.44E−1032,4052.00E−02rs37350807150,217,309GIMAP7missense (p.Arg83Cys)T0.245−0.0497.70E−1365,521−0.0362.72E−0431,788−0.0576.22E−1033,7331.05E−01rs119935548145,111,529OPLAHsynonymous (p.Phe612Phe)G0.1010.0303.75E−0361,4310.0769.76E−0829,427−0.0114.66E−0132,0042.52E−05rs1086166112107,174,646RIC8BintronicC0.229−0.0401.75E−0959,489−0.0354.74E−0427,455−0.0463.17E−0632,0344.42E−01rs1451194001684,075,593SLC38A8missense (p.Pro57Leu)A0.005−0.3008.95E−1359,107−0.3061.78E−0328,412−0.2961.80E−1030,6959.23E−01Previously Reported Loci Achieving Exome-wide Significancers27915521219,652,033LYPLAL1intergenicC0.676−0.052∗1.75E−1455,387−0.0558.97E−0926,391−0.0547.16E−0928,9969.68E−01rs29436412227,093,745IRS1intergenicC0.646−0.058∗1.76E−2165,521−0.0482.21E−0831,788−0.0692.56E−1633,7337.30E−02rs13303352,558,008STAB1missense (p.Met2506Thr)C0.5690.058∗2.69E−2161,4310.0618.28E−1329,4270.0604.74E−1232,0049.53E−01rs173665683186,570,453ADIPOQncRNA/exonicA0.118−0.226∗1.43E−14551,153−0.2161.61E−6431,788−0.2395.86E−8925,8491.97E−01rs4311394553,300,662ARL15intronicG0.2570.258∗1.68E−1059,931−0.0461.54E−0628,914−0.0443.84E−0631,0179.13E−01rs71343751220,473,758PDE3AintergenicA0.4100.053∗3.69E−2065,5210.0542.88E−1131,7880.0535.36E−1133,7339.14E−01rs1105740512122,781,897CLIP1intronicA0.086−0.077∗2.90E−1465,521−0.0921.74E−1031,788−0.0681.24E−0633,7332.29E−01rs1105735312124,265,687DNAH10missense (p.Ser167Pro)C0.6450.054∗2.74E−1965,5210.0613.47E−1331,7880.0472.19E−0833,7332.17E−01rs29259791681,534,790CMIPintronicC0.6930.080∗1.38E−3761,8010.0936.72E−2629,7670.0721.91E−1632,0348.80E−02rs38651881682,650,717CDH13intergenicT0.472−0.034∗1.14E−0859,420−0.0427.28E−0728,616−0.0271.11E−0330,8042.27E−01rs48058851933,906,123PEPDintronicC0.6030.063∗2.85E−2561,4310.0764.63E−1929,4270.0525.77E−2832,0045.20E−02Loci achieving exome-wide significance (p < 2E−07) in sex-combined and/or sex-specific all-ancestry meta-analyses. Beta effect size from an additive model corresponding to the effect allele for inverse-normal transformed adiponectin levels adjusted for age, BMI, and other study-specific covariates. The smallest p value for each variant is shown in bold. Physical positions based on hg19. Abbreviation: Chr, chromosome; EA, effect allele; EAF, effect allele frequency; N, sample size.a Test for sex difference; values significant at the table-wide Bonferroni threshold of 0.05/20 = 2.5E−03 Open table in a new tab Loci achieving exome-wide significance (p < 2E−07) in sex-combined and/or sex-specific all-ancestry meta-analyses. Beta effect size from an additive model corresponding to the effect allele for inverse-normal transformed adiponectin levels adjusted for age, BMI, and other study-specific covariates. The smallest p value for each variant is shown in bold. Physical positions based on hg19. Abbreviation: Chr, chromosome; EA, effect allele; EAF, effect allele frequency; N, sample size. Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid BiologySpracklen et al.The American Journal of Human GeneticsJune 6, 2019In BriefCirculating 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. Full-Text PDF Open Archive