Xiaochen Lin1,2, Katie Kei-Hang Chan1,2,3, Yen-Tsung Huang1,4,5, X I Luo4, Liming Liang6, James Wilson7, Adolfo Correa8, Daniel Levy9,10, Simin Liu1,2,11. 1. Department of Epidemiology, Brown University, Providence, RI. 2. Center for Global Cardiometabolic Health, Brown University, Providence, RI. 3. Hong Kong Institute of Diabetes and Obesity, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong Special Administrative Region, CHINA. 4. Department of Biostatistics, Brown University, Providence, RI. 5. Institute of Statistical Science, Academia Sinica, Taipei, TAIWAN. 6. Department of Epidemiology and Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA. 7. Department of Physiology and Biophysics and Department of Medicine, University of Mississippi Medical Center, Jackson, MS. 8. The Jackson Heart Study and the Departments of Medicine and Pediatrics, University of Mississippi Medical Center, Jackson, MS. 9. The Framingham Heart Study, Framingham, MA. 10. The Population Sciences Branch, Nation Heart, Lung, and Blood Institute of the National Institute, Bethesda, MD. 11. Division of Endocrinology, Department of Medicine, Rhode Island Hospital, Providence, RI.
Abstract
PURPOSE: 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. METHODS: 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. RESULTS: Ethnicity-specific genetic signals were investigated, respectively, for African Americans and European Americans. Two variants, rs116550874 (meta-analysis: P = 1.63 × 10) and rs3792874 (meta-analysis: P = 8.33 × 10), were associated with LTPA in African Americans; rs28524846 (meta-analysis: P = 1.30 × 10) 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. CONCLUSIONS: 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.
PURPOSE: 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. METHODS: 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. RESULTS: Ethnicity-specific genetic signals were investigated, respectively, for African Americans and European Americans. Two variants, rs116550874 (meta-analysis: P = 1.63 × 10) and rs3792874 (meta-analysis: P = 8.33 × 10), were associated with LTPA in African Americans; rs28524846 (meta-analysis: P = 1.30 × 10) 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. CONCLUSIONS: 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.
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