Fine mapping of a QTL on chromosome 13 for submaximal exercise capacity training response: the HERITAGE Family Study

Although regular exercise improves submaximal aerobic capacity, there is large variability in its response to exercise training. While this variation is thought to be partly due to genetic differences, relatively little is known about the causal genes. Submaximal aerobic capacity traits in the current report include the responses of oxygen consumption (ΔVO₂60), power output (ΔWORK60), and cardiac output (ΔQ60) at 60% of VO₂max to a standardized 20-week endurance exercise training program. Genome-wide linkage analysis in 475 HERITAGE Family Study Caucasians identified a locus on chromosome 13q for ΔVO₂60 (LOD = 3.11). Follow-up fine mapping involved a dense marker panel of over 1,800 single-nucleotide polymorphisms (SNPs) in a 7.9-Mb region (21.1–29.1 Mb from p-terminus). Single-SNP analyses found 14 SNPs moderately associated with both ΔVO₂60 at P ≤ 0.005 and the correlated traits of ΔWORK60 and ΔQ60 at P < 0.05. Haplotype analyses provided several strong signals (P < 1.0 × 10⁻⁵) for ΔVO₂60. Overall, association analyses narrowed the target region and included potential biological candidate genes (MIPEP and SGCG). Consistent with maximal heritability estimates of 23%, up to 20% of the phenotypic variance in ΔVO₂60 was accounted for by these SNPs. These results implicate candidate genes on chromosome 13q12 for the ability to improve submaximal exercise capacity in response to regular exercise. Submaximal exercise at 60% of maximal capacity is an exercise intensity that falls well within the range recommended in the Physical Activity Guidelines for Americans and thus has potential public health relevance.