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Leisure-time physical activity (LTPA) is a well-established modifiable lifestyle determinant for multiple cardiometabolic outcomes. However, current understanding of the genetic architecture that may determine LTPA remains very limited. Therefore, we aimed to examine the role of genetic factors in affecting LTPA, which has yet to be investigated comprehensively and in-depth.We conducted a genomewide analysis using 1000 Genomes Project imputed data from the Women’s Health Initiative (n = 11,865), the Jackson Heart Study (n = 3015), and the Framingham Heart Study (n = 7339). A series of secondary analyses, including candidate gene analysis, sequence kernel association tests, pathway analysis, functional annotation, and expression quantitative trait loci analysis, were performed to follow-up on the primary findings.Ethnicity-specific genetic signals were investigated, respectively, for African Americans and European Americans. Two variants, rs116550874 (meta-analysis: P = 1.63 × 10−7) and rs3792874 (meta-analysis: P = 8.33 × 10−7), were associated with LTPA in African Americans; rs28524846 (meta-analysis: P = 1.30 × 10−6) was identified for EA. We also replicated four previously reported loci (GABRG3, CYP19A1, PAPSS2, and CASR; P for lead single nucleotide polymorphisms < 0.005). Further fine-mapping and functional annotation suggested that several identified loci (novel and replicated) are involved in 1) the homeostatic drive coupled with the reward system and 2) the development and regulation of the capacity to perform LTPA.To our knowledge, our analysis is the first to comprehensively investigate the genomewide signals for LTPA in multiple ethnicities. These findings support the notion that genetic predisposition plays a critical role in determining LTPA, of which the biological and clinical implications warrants further investigation.