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

Abstract

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 (ΔVO(2)60), 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 ΔVO(2)60 (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 ΔVO(2)60 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 ΔVO(2)60. 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 ΔVO(2)60 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.

Fig. 1

Family-based associations for ΔVO₂60 (labeled as DVO260) and correlated traits (ΔWORK60 and ΔQ60, labeled as DWORK60 and DQ60), with –log P values adjusted for multiple comparisons for chromosome 13q12.11-q12.3. The X-axis represents the SNP locations (in Mb units) and the Y-axis represents the –log P values for the association models (circle) or the LOD scores for the linkage models (solid lines). Noise was reduced by plotting only for –log P values that are at least 1.0. Linkage plots are presented for both micro satellites (original linkage scan) and SNPs (fine mapping). Blocks 1–6 represent arbitrary regions where the signals are large or concentrated. The top panel (a) represents the results for the single-SNP analyses. In the bottom panel (b), the superimposed square symbols represent the haplotype analysis results. SNP (or haplotype) signals that are located within genes are shown at the top of the bottom panel (SGCG, FLJ46358, MIPEP, ATP12A, ATP8A2, GSX1, FLT3, FLT1, PAN3). For the four best single-SNP results (–log P > 3.0), the closest genes are defined as Near FTHL7 (rs9506903 138,483 bp), Near LOC646208 (rs971206 6,460 bp), Near LOC100128337 (rs2104257 1,421 bp), Near LOC100129306 (rs7326591 69,878). See text for details