Association of 3p27.1 Variants with Whole Body Lean Mass Identified by a Genome-wide Association Study

Abstract

Whole body lean mass (WBLM) is a heritable trait predicting sarcopenia. To identify genomic locus underlying WBLM, we performed a genome-wide association study of fat-adjusted WBLM in the Framingham Heart Study (FHS, N = 6,004), and replicated in the Kansas City Osteoporosis Study (KCOS, N = 2,207). We identified a novel locus 3p27.1 that was associated with WBLM (lead SNP rs3732593 P = 7.19 × 10 −8 ) in the discovery FHS sample, and the lead SNP was successfully replicated in the KCOS sample (one-sided P = 0.04). Bioinformatics analysis found that this SNP and its adjacent SNPs had the function of regulating enhancer activity in skeletal muscle myoblasts cells, further confirming the regulation of WBLM by this locus. Our finding provides new insight into the genetics of WBLM and enhance our understanding of sarcopenia.Sarcopenia is defined as a progressive, and generalized loss of skeletal muscle mass, strength and function 1 . Sarcopenia plays a vital role in the frailty process, also being a key player in its incubation period and it causes serious consequences through frailty, such as decreased function, disability and eventual death 2,3 . According to Khosla et al. 4 , the age-and sex-adjusted prevalence of sarcopenia varied from 6 to 15% among subjects 65 years of age or over. The muscular tissue, as characterized by Lean Body Mass (LBM), is frequently used to predict sarcopenia. LBM can be measured accurately by dual energy X-ray absorptiometry (DXA).Previous studies showed that LBM is under genetic control, with heritability over 50% 5,6 . Previous studies have identified dozens of genomic loci associated with LBM 7-11 . Among them, Zillikens et al. 12 identified five loci in/ near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO that were associated with lean body mass. conducted a bivariate genome-wide association meta-analysis of pediatric musculoskeletal traits and revealed pleiotropic effects at the SREBF1/TOM1L2 locus. However, to date, the identified loci only explain a small proportion of the variation observed for a particular phenotype, and the majority of hidden heritability is yet to be identified.In this study, we performed a GWAS of WBLM using the Framingham Heart Study (FHS) as discovery sample and the Kansas City Osteoporosis Study (KCOS) as replication sample. In addition, we conducted a serious of bioinformatic analysis to explore the functional relevance of the identified variants. Materials and MethodsAll the methods were conducted in accordance with the guidelines and regulations of the Soochow university institutional review board (for the Framingham heart study sample) and the University of Missouri Kansas City institutional review board (for the Kansas City osteoporosis study). The Institutional Review Boards of University of Missouri Kansas City and the Soochow university approved the study. All participants signed informed consent before participating.

Identification and Characterization of Genomic Predictors of Sarcopenia and Sarcopenic Obesity Using UK Biobank Data

“…Several studies have investigated the association between the DNA polymorphisms and sarcopenia-related traits outside of the UK Biobank project using GWAS [ 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ] or a candidate gene [ 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 ] approaches. Apart from the classical skeletal muscle traits (lean mass, absolute and relative skeletal muscle mass, skeletal muscle mass index, muscle thickness, anatomical cross-sectional area of muscle groups, etc.…”