Large meta-analysis of genome-wide association studies identifies five loci for lean body mass

Abstract

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 × 10−8) or suggestively genome wide (p < 2.3 × 10−6). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.

Genome-wide association study of appendicular lean mass in UK Biobank cohort

“…Our findings of >700 variants are expected for a complex trait with a high heritability, particularly considering another trait with comparable heritability, height, which detected also ~700 variants [49]. Interestingly, the majority loci in previous smaller GWAS [13] or meta-analysis [15] of lean mass are also significant in the present study, providing replication evidence from independent samples.…”

“…To test whether lean mass has a shared genetic etiology with other diseases and relevant traits, a genetic correlation analysis was performed with the LDSC method [17]. Here, ALM studied in our study is strongly genetically correlated with DXA-derived whole body lean mass and the ALM, which were studied by a previous GWAS meta-analysis [15] (r g =0.87 and 0.78) ( Figure 5 ). Furthermore, ALM is modestly correlated with BMI (r g =0.31).…”

“…Of the above identified loci, 17 were reported by GWAS or meta-analysis of DXA-derived lean mass [13, 15, 19]; 104 were reported by a study of electronic impedance measured lean mass in a subset UKB cohort subjects (N=155,961) [20].…”

“…As a notable example, a recent large meta-analysis of GWAS amassed 20 cohorts of European ancestry with a total sample size of >38,000 for whole body lean mass (WBM) and of >28,000 for appendicular lean mass (ALM) [15]. However, despite of the large sample used, the percent variance explained by the identified SNPs was still only 0.23% and 0.16% for WBM and ALM, respectively, suggesting that most of the heritability of LBM was still undetected.…”

A linear mixed model approach to study multivariate gene-environment interactions

“…These included a variant (rs11259931) in ADAMTSL3, which codes for a glycoprotein 21 . The same variant and variants in LD (r 2 >0.53) have previously been linked to BMI-related traits, including lean body mass 22 , waist circumference 23 , hip circumference adjusted for BMI 24 and height 25 . A second example is rs11880064 in PEPD, which encodes for a protein involved in the final stage of degradation of endogenous and dietary proteins.…”