Beyond apples and pears: sex-specific genetics of body fat percentage

Frontiers in Endocrinology

Endocrinology

Satya Dash¹  Tianyuan Lu²  Delnaz Roshandel³  Andrew D. Paterson⁴ 

[1] Department of Medicine, University Health Network, and University of Toronto, Toronto, ON, Canada;Department of Statistical Sciences, University of Toronto, Toronto, ON, Canada;Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada;Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada;Divisions of Epidemiology and Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada;

关键词: body fat percentage;    obesity;    genome-wide association study;    testosterone;    sex hormone binding globulin;   

DOI  :  10.3389/fendo.2023.1274791

 received in 2023-08-08, accepted in 2023-09-18,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionBiological sex influences both overall adiposity and fat distribution. Further, testosterone and sex hormone binding globulin (SHBG) influence adiposity and metabolic function, with differential effects of testosterone in men and women. Here, we aimed to perform sex-stratified genome-wide association studies (GWAS) of body fat percentage (BFPAdj) (adjusting for testosterone and sex hormone binding globulin (SHBG)) to increase statistical power.MethodsGWAS were performed in white British individuals from the UK Biobank (157,937 males and 154,337 females). To avoid collider bias, loci associated with SHBG or testosterone were excluded. We investigated association of BFPAdj loci with high density cholesterol (HDL), triglyceride (TG), type 2 diabetes (T2D), coronary artery disease (CAD), and MRI-derived abdominal subcutaneous adipose tissue (ASAT), visceral adipose tissue (VAT) and gluteofemoral adipose tissue (GFAT) using publicly available data from large GWAS. We also performed 2-sample Mendelian Randomization (MR) using identified BFPAdj variants as instruments to investigate causal effect of BFPAdj on HDL, TG, T2D and CAD in males and females separately.ResultsWe identified 195 and 174 loci explaining 3.35% and 2.60% of the variation in BFPAdj in males and females, respectively at genome-wide significance (GWS, p<5x10-8). Although the direction of effect at these loci was generally concordant in males and females, only 38 loci were common to both sexes at GWS. Seven loci in males and ten loci in females have not been associated with any adiposity/cardiometabolic traits previously. BFPAdj loci generally did not associate with cardiometabolic traits; several had paradoxically beneficial cardiometabolic effects with favourable fat distribution. MR analyses did not find convincing supportive evidence that increased BFPAdj has deleterious cardiometabolic effects in either sex with highly significant heterogeneity.ConclusionsThere was limited genetic overlap between BFPAdj in males and females at GWS. BFPAdj loci generally did not have adverse cardiometabolic effects which may reflect the effects of favourable fat distribution and cardiometabolic risk modulation by testosterone and SHBG.

【 授权许可】

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Copyright © 2023 Roshandel, Lu, Paterson and Dash