Genome-wide Association For Exercise Tolerance In The TIGER Study

Abstract

PURPOSE: The genetic basis of physical activity has been firmly established through both animal and human studies. The purpose of this study was to examine genetic variation across the genome for association to quantitative measures of exercise dose, intensity, duration, and adherence. METHODS: Young adults (18-35 y) underwent 15 weeks of aerobic exercise training while wearing computerized heart rate monitors. Exercise intensity was defined as age- and gender-specific percent heart rate reserve, and exercise dose was calculated as session duration adjusted for exercise intensity, summed over all exercise sessions. A total of 1,012 non-Hispanic white, 700 African American, and 332 Hispanic subjects were genotyped for ~200K genetic markers using the Illumina Metabochip, and genome-wide association analysis was performed using PLINK. Principal component analysis was used to control for racial/ethnic background and population substructure. RESULTS: SNPs in 10 genes exceeded a genome-wide significance of p<10-4.5, including FN3KRP, FAM148A, CUX2, RIPK2, ABCB11, B3GNTL1, BRE, BDNF, ZHX3, IDE, and TBCD. Pathways contributing to lipid metabolism, neural signaling, muscle contraction, and adiposity were significantly represented by SNPs with a nominal p<0.0001. The brain-derived neurotropic factor (BDNF) signaling pathway emerged as a central factor linking multiple other pathways, highlighting neural signaling as a target for exercise tolerance. Two SNPs in the CEP112 gene were significantly associated with exercise adherence (p<10-6); this gene has previously been implicated in smoking cessation, suggesting a common genetic pathway for persistent behavior. CONCLUSIONS: This study represents the first genome-wide analysis of exercise tolerance and adherence in a multi-racial sample of young adults; neural signaling pathways appear to be important in both outcomes.