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Sarcopenic obesity (SO) is an age-related disease characterized by the coexistence of excessive adiposity and low muscle mass or function. Although obesity and sarcopenia are heritable conditions, the genetic determinants of SO have not been fully understood. We conducted a large-scale exome-wide association analysis of SO in a sequenced sample of 2 887 cases and 113 284 controls and an imputed sample of 4 003 cases and 161 990 controls in the UK Biobank cohort. Single-variant association analysis identified one locus 1q41 (lead SNP rs1417066 , LYPLAL1-AS1 , odds ratio [OR] = 1.15, 95% confidence interval [CI] = [1.11–1.19], p  = 1.75 × 10−14) that was significantly associated with SO at the exome-wide significance level (p  < 1 × 10-8). Colocalization analysis in the Genotype-Tissue Expression expression quantitative trait locus database showed that LYPLAL1-AS1 was colocalized with SO in multiple musculoskeletal-related tissues. Gene-based burden test of rare loss-of-function variants identified 5 genes at the gene-wise significance level (p  < 4.3 × 10−6): PDE3B (OR = 2.48, p  = 1.10 × 10−6), MYOZ3 (OR = 25.49, p  = 1.41 × 10−7), SLC15A3 (OR = 4.75, p  = 6.82 × 10−7), RNF130 (OR = 25.83, p  = 4.07 × 10−6), and TNK2 (OR = 4.25, p  = 8.75 × 10−8). Overall, our study uncovered the genetic effects of both common and rare variants on SO susceptibility, expanded existing knowledge of the genetic architecture of SO, and improved understanding of the genetic mechanisms underlying SO. [ABSTRACT FROM AUTHOR]