Genome-wide association study identifies a functional myostatin variant increasing lean mass in humans

Muscle mass is central to physical function and metabolic health ¹ , but can decrease with disease, aging ² and weight loss interventions ^3-5 . As such interventions become more widely used, agents that preserve or increase muscle mass are needed. To identify such therapeutic opportunities, we performed genome-wide association meta-analyses (GWAS) of arm, leg, trunk and total lean mass measured by dual-energy X-ray absorptiometry (DXA), a widely used method to estimate muscle mass. We identified 63 loci, including the rare missense variant in MSTN (p.Ile225Thr, rs143242500), which had the largest effect on leg lean mass (β = 0.28 SD [95% CI: 0.19, 0.37], P = 1.9 × 10 ^-9 ). MSTN encodes myostatin, a negative regulator of skeletal muscle mass and a therapeutic target for muscle wasting disorders ⁶ . p.Ile225Thr is the first genome-wide significant association in MSTN in humans with functional consequences and could provide further insight into long-term systemic effects of myostatin inhibition.