Integrative pathway analysis of a genome-wide association study of V_(O_(2max)) response to exercise training

摘要

We previously reported the findings from a genome-wide association study of the response of maximal oxygen uptake (V_(O_(2max))) to an exercise program. Here we follow up on these results to generate hypotheses on genes, pathways, and systems involved in the ability to respond to exercise training. A systems biology approach can help us better establish a comprehensive physiological description of what underlies V_(O_(2max))trainability. The primary material for this exploration was the individual single -nucleotide polymorphism (SNP), SNP-gene mapping, and statistical significance levels. We aimed to generate novel hypotheses through analyses that go beyond statistical association of single-locus markers. This was accomplished through three complementary approaches: 1) building de novo evidence of gene candidacy through informatics-driven literature mining; 2) aggregating evidence from statistical associations to link variant enrichment in biological pathways to V_(O_(2max)) trainability; and 3) predicting possible consequences of variants residing in the pathways of interest. We started with candidate gene prioritization followed by pathway analysis focused on overrep-resentation analysis and gene set enrichment analysis. Subsequently, leads were followed using in silico analysis of predicted SNP functions. Pathways related to cellular energetics (pantothenate and CoA biosynthesis; PPAR signaling) and immune functions (complement and coagulation cascades) had the highest levels of SNP burden. In particular, long-chain fatty acid transport and fatty acid oxidation genes and sequence variants were found to influence differences in V_(O_(2max)) trainability. Together, these methods allow for the hypothesis-driven ranking and prioritization of genes and pathways for future experimental testing and validation.