Genome-Wide Association Study of Exercise Behavior in Dutch and American Adults

Abstract

Introduction The objective of this study was to identify genetic variants that are associated with adult leisure-time exercise behavior using genome-wide association in two independent samples. Methods Exercise behavior was measured in 1,772 unrelated Dutch and 978 unrelated American adults with detailed questions about type, frequency and duration of exercise. Individuals were classified into regular exercisers or non-exercisers using a threshold of 4 METhours (metabolic equivalents*hours per week). Regular exercisers were further divided into 5 categories of METhours, ranging from moderate (>=4 METhours) to highly vigorous (>=40 METhours) exercisers. Genome-wide association analyses with a total of 470,719 SNPs were conducted in both samples independently using regression-based techniques in SNPtest, including sex, age and BMI as covariates. Results SNPs located in SGIP1, DNASE2B, PRSS16, ERCC2 and PAPSS2 were associated with exercise participation (combined p-value between 0.0004 and 4.5*10-6 with the same direction of allelic effects in both samples). Associations of candidate genes based on existing literature were replicated for the LEPR gene in the American sample (rs12405556, p=0.0005) and for the CYP19A1 gene in the Dutch sample (rs2470158, 0.0098). Conclusion Two genes (SGIP1 and LEPR) are expressed in the hypothalamus and involved in the regulation of energy homeostasis. Their effects were independent of BMI, suggesting a direct role of hypothalamic factors in the drive to exercise.

Driven to Be Inactive?—The Genetics of Physical Activity

“…In this study, De Moor and colleagues found that while not significant, suggestive associations were found with the location of the leptin receptor ( LEPR ) gene and the GABRG3 gene on chromosome 15 (15q12–13). However, none of the other potential candidate genes that had been suggested earlier angiotensin-converting enzyme ( ACE ), calcium sensing receptor ( CASR ), CYP19A1 , dopamine receptor 2 ( DRD2 ), and MC4R 67,66,69,70–72 localized within any of the three significant QTL found in this study.…”

“…Another study showed that LEPR was related to physical activity energy expenditure in young boys. 81 However, LEPR does not localize into any of the significant QTL in either human 66 or mouse 46,59 and does not show haplotype differences between high and low active animals. 77 …”

“…While it is possible that there are actually just a few genes that influence physical activity level, the likelihood is that the existing models have had limited power to detect numerous less-powerful QTL that may play a role in regulating physical activity; this is a point that has been made by both De Moor et al . 66 and Lightfoot et al . 46 and a point that needs to be addressed by using a GWAS approach and much larger datasets.…”

“…De Moor et al . 66 studied 2622 adults of European ancestry using an exercise participation survey and a moderately dense single nucleotide polymorphism (SNP) map of 1,607,535 measured or imputed common SNPs. This GWAS revealed 37 novel SNPs for exercise participation clustered in three distinct genomic regions.…”

“…51,77 Furthermore, DRD2 was also not replicated by the only GWAS using over one million SNP in Dutch and American adults. 66 Thus, while certainly a compelling candidate gene, further evidence is needed to strengthen the case of DRD2 as a gene regulating activity level.…”