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Genetics and Epigenetics

Genome-wide association studies suggest sex-specific loci associated with abdominal and visceral fat

Abstract

Background:

To identify loci associated with abdominal fat and replicate prior findings, we performed genome-wide association (GWA) studies of abdominal fat traits: subcutaneous adipose tissue (SAT); visceral adipose tissue (VAT); total adipose tissue (TAT) and visceral to subcutaneous adipose tissue ratio (VSR).

Subjects and Methods:

Sex-combined and sex-stratified analyses were performed on each trait with (TRAIT–BMI) or without (TRAIT) adjustment for body mass index (BMI), and cohort-specific results were combined via a fixed effects meta-analysis. A total of 2513 subjects of European descent were available for the discovery phase. For replication, 2171 European Americans and 772 African Americans were available.

Results:

A total of 52 single-nucleotide polymorphisms (SNPs) encompassing 7 loci showed suggestive evidence of association (P<1.0 × 10−6) with abdominal fat in the sex-combined analyses. The strongest evidence was found on chromosome 7p14.3 between a SNP near BBS9 gene and VAT (rs12374818; P=1.10 × 10−7), an association that was replicated (P=0.02). For the BMI-adjusted trait, the strongest evidence of association was found between a SNP near CYCSP30 and VAT–BMI (rs10506943; P=2.42 × 10−7). Our sex-specific analyses identified one genome-wide significant (P<5.0 × 10−8) locus for SAT in women with 11 SNPs encompassing the MLLT10, DNAJC1 and EBLN1 genes on chromosome 10p12.31 (P=3.97 × 10–8 to 1.13 × 10−8). The THNSL2 gene previously associated with VAT in women was also replicated (P=0.006). The six gene/loci showing the strongest evidence of association with VAT or VAT-BMI were interrogated for their functional links with obesity and inflammation using the Biograph knowledge-mining software. Genes showing the closest functional links with obesity and inflammation were ADCY8 and KCNK9, respectively.

Conclusions:

Our results provide evidence for new loci influencing abdominal visceral (BBS9, ADCY8, KCNK9) and subcutaneous (MLLT10/DNAJC1/EBLN1) fat, and confirmed a locus (THNSL2) previously reported to be associated with abdominal fat in women.

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Acknowledgements

We thank Mrs Allison Templet and Mrs Robin Post for their support in the development and submission of this manuscript. The Quebec Family Study (QFS) was supported for three decades by multiple grants from the Medical Research Council of Canada and the Canadian Institutes for Health Research. This project was supported by a team grant from the Canadian Institute for Health Research (FRCN-CCT-83028). We thank all PIs who contributed to the HERITAGE Family Study in the past via support from the National Heart, Lung, and Blood Institute (NHLBI) through the following grants: C Bouchard (HL-45670); AS Leon (HL-47323); DC Rao (HL-47317); JS Skinner (HL-47327); JH Wilmore (HL-47321). We also acknowledge grant 8P20 GM-1033528 (COBRE center grant to Pennington Biomedical Research Center, PI: Thomas Gettys, supporting M.A. Sarzynski). The Pennington Center Longitudinal Study is partially supported by a Nutrition Obesity Research Center (NIH 2P30DK072476) grant from the National Institutes of Health and by 1 U54 GM104940 from the National Institute of General Medical Sciences of the National Institutes of Health which funds the Louisiana Clinical and Translational Science Center. The Coronary Artery Risk Development in Young Adults Study (CARDIA) is conducted and supported by the NHLBI in collaboration with the University of Alabama at Birmingham (HHSN268201300025C and HHSN268201300026C), Northwestern University (HHSN268201300027C), University of Minnesota (HHSN268201300028C), Kaiser Foundation Research Institute (HHSN268201300029C), and Johns Hopkins University School of Medicine (HHSN268200900041C). CARDIA is also partially supported by the Intramural Research Program of the National Institute on Aging (NIA) and an intra-agency agreement between NIA and NHLBI (AG0005). This manuscript has been reviewed by CARDIA for scientific content. The CARDIA CT Scan year 25 data were obtained with the support of NHLBI (R01-HL-098445). C. Bouchard is partially funded by the John W. Barton Sr. Chair in Genetics and Nutrition.

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The funders had no role in the study design, data collection, decision to publish, or preparation of the manuscript. The funding agencies had no role in the design of the present study, collection and analysis of the data and the decision to publish. None of the authors are employed by institutions that stand to gain or lose financially as a result of this publication.

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Correspondence to C Bouchard.

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Supplementary Information accompanies this paper on International Journal of Obesity website

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Sung, Y., Pérusse, L., Sarzynski, M. et al. Genome-wide association studies suggest sex-specific loci associated with abdominal and visceral fat. Int J Obes 40, 662–674 (2016). https://doi.org/10.1038/ijo.2015.217

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