Yann C. Klimentidis, Jennifer W. Bea, Patricia Thompson, Walter T. Klimecki, Chengcheng Hu, Guanglin Wu, Skye Nicholas, Kelli K. Ryckman, Zhao Chen

Low lean mass (LM) is a risk factor for chronic disease, a major cause of disability and diminished quality of life, and is a heritable trait. However, relatively few specific genetic factors have been identified as potentially influencing this trait. In this study, we selected 1,493 single-nucleotide polymorphisms (SNPs) in 155 candidate genes involved in anabolic, catabolic, growth hormone, and other related pathways, and examined their association with LM, assessed by dual energy x-ray absorptiometry, in a sample of 2,760 non-Hispanic and Hispanic White postmenopausal women from the Women's Health Initiative (WHI) Observational Study. We assessed replication of our top findings in a meta-analysis of twenty genome-wide association studies (n=38,292) conducted by the CHARGE Consortium Musculoskeletal Working Group. We identified 32 SNPs that had significant associations with LM in the WHI cohort. In the replication stage, we find that SNP rs2276541 in the activin A receptor, type IIB (ACVR2B) was significantly associated with LM (β=0.15; p=2.17 x 10). ACVR2B codes for a receptor for a negative regulator of skeletal muscle, mysostatin, and has previously been identified in a candidate gene study as a determinant of skeletal muscle mass. Our findings support a previously proposed role of ACVR2B allelic variation as a determinant of muscle mass and extend prior findings in men to women. Additional large-scale studies will be needed to confirm our findings in different populations.