Biological pathway-based genome-wide association analysis identified the vasoactive intestinal peptide (VIP) pathway important for obesity

Abstract

Recent genome-wide association (GWA) studies have identified a number of novel genes/variants predisposing to obesity. However, most GWA studies have focused on individual single-nucleotide polymorphism (SNPs)/genes with a strong statistical association with a phenotypic trait without considering potential biological interplay of the tested genes. In this study, we performed biological pathway-based GWA analysis for BMI and body fat mass. We used individual level genotype data generated from 1,000 unrelated US whites that were genotyped for ~500,000 SNPs. Statistical analysis of pathways was performed using a modification of the Gene Set Enrichment Algorithm. A total of 963 pathways extracted from the BioCarta, Kyoto Encyclopedia of Genes and Genomes (KEGG), Ambion GeneAssist, and Gene Ontology (GO) databases were analyzed. Among all of the pathways analyzed, the vasoactive intestinal peptide (VIP) pathway was most strongly associated with fat mass (nominal P = 0.0009) and was the third most strongly associated pathway with BMI (nominal P = 0.0006). After multiple testing correction, the VIP pathway achieved false-discovery rate (FDR) q values of 0.042 and 0.120 for fat mass and BMI, respectively. Our study is the first to demonstrate that the VIP pathway may play an important role in development of obesity. The study also highlights the importance of pathway-based GWA analysis in identification of additional genes/variants for complex human diseases.

Figure 1

Pathway-based genome-wide association results for BMI and fat mass. The y axis is the −log10 P value of all the 963 pathways with BMI and fat mass. The arrow points to the VIP pathway. VIP, vasoactive intestinal peptide.

Figure 2

Functional interactions among the genes in the VIP pathway. VIP, vasoactive intestinal peptide.

Figure 3

Running-sum plot for the VIP pathway. The figure includes the location of the maximum enrichment score (ES) and the leading-edge subset. The x axis is the rank of the 23 genes in the VIP pathway in the whole gene list generated by ranking all the genes by their association significance with BMI and fat mass from the largest to smallest. The y axis represents the running enrichment score. ES is the maximum deviation from zero achieved in the running-sum walk. The bar plot at the top of the figure also shows the distribution of the 23 genes from the VIP pathway in the whole gene list with the leading-edge genes indicated. VIP, vasoactive intestinal peptide.