Abstract
Body composition (fat, skeletal muscle and bone mass) is an important determinant of overall health and risk of endocrine disorders such as type 2 diabetes and osteoporosis. Although diet and physical activity are strongly implicated, body composition is also heritable. We conducted a discovery genome-wide association study on 31 phenotypes from the three-compartment body composition model (fat, lean and bone mass) in a set of 4 386 individuals (n = 2 109 males, n = 2 294 females) from the UK Biobank pilot imaging enhancement program that underwent a dual energy X-ray absorptiometry (DXA) scan for assessment of body composition and genetic screening. From 6 137 607 imputed single nucleotide polymorphisms (SNPs) we identified 17 body composition loci (P<5.0 x 10-8). GWAS from the combined dataset identified four statistically significant SNPs (rs7592270, rs145972737, rs13212044, rs77772562). In sex-stratified GWAS, 10 male specific SNPs across all traits were identified and five female specific SNPs. Of the 17 SNPs, six were in or close to a gene where there was a plausible functional connection. Three SNPs (rs7592270, rs77772562 and rs7552312) were correlated with obesity phenotypes, one SNP (rs2236705) with lean phenotypes and two with bone mass phenotypes (rs112098641 and rs113380185). These results highlight candidate genes and biological pathways related to body composition, including glucose metabolism and estrogen regulation, that are of interest to replicate in future studies.
Highlights
Body composition is implicated in the progression of many chronic diseases, including endocrine disorders such as type 2 diabetes (T2D) [1]
Six single nucleotide polymorphisms (SNPs) were linked to genes with known functional outcomes and help to explain the physiological mechanisms leading to body composition
These preliminary findings support the need for clinicians to consider the interconnection between fat, lean and bone mass and provide new insights into biological pathways, including glucose metabolism and estrogen regulation, that will inform future research aimed at understanding the complex biology of body composition
Summary
Body composition is implicated in the progression of many chronic diseases, including endocrine disorders such as type 2 diabetes (T2D) [1]. While previous GWAS have investigated the role of bone content of specific regions [6], few have investigated the genetics of total and regional bone mass These studies have advanced understanding of the role and potential mechanisms of common genetic variations in BMI and body fat distribution, including sexual dimorphisms in the genetic regulation of these traits. Pathway analyses suggest that adipose tissue deposition and BMI are closely linked with insulin regulation and lipid biology, and share pathways with T2D and glycaemic traits [2, 3] These phenotypes have been linked with skeletal growth processes [3], yet the common genetic variations in fat, lean and bone phenotypes remain unclear as they have not been investigation simultaneously. While dual energy X-ray absorptiometry (DXA) is the gold standard for assessing the three-compartment model of body composition, the high cost and exposure to radiation has largely precluded application in a large population cohort [8]
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