Multi-ancestry whole genome sequencing analysis of lean body mass

Lean body mass is a crucial physiological component of body composition. Although lean body mass has a high heritability, studies evaluating the genetic determinants of lean mass (LM) have to date been limited largely to genome-wide association studies (GWAS) and common variants. Using whole genome sequencing (WGS)-based studies, we aimed to discover novel genetic variants associated with LM in population-based cohorts with multiple ancestries. We describe the largest WGS-based meta-analysis of lean body mass to date, encompassing 10,729 WGS samples from six TOPMed cohorts and the Louisiana Osteoporosis Study (LOS) cohort, measured with dual-energy X-ray absorptiometry. We identify seven genome-wide loci significantly associated with LM not reported by previous GWAS. We partially replicate these associations in UK Biobank samples. In rare variant analysis, we discover one novel protein-coding gene, DMAC1, associated with both whole-body LM and appendicular LM in females, and a long non-coding RNA gene linked to appendicular LM in males. Both genes exhibit notably high expression levels in skeletal muscle tissue. We investigate the functional roles of two novel lean-mass-related genes, EMP2 and SSUH2, in animal models. EMP2 deficiency in Drosophila leads to significantly reduced mobility without altering muscle tissue or body fat morphology, whereas an SSUH2 gene mutation in zebrafish stimulates muscle fiber growth. Our comprehensive analysis, encompassing a large-scale WGS meta-analysis and functional investigations, reveals novel genomic loci and genes associated with lean mass traits, shedding new insights into pathways influencing muscle metabolism and muscle mass regulation.