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.