Gene set of nuclear-encoded mitochondrial regulators is enriched for common inherited variation in obesity

Abstract

There are hints of an altered mitochondrial function in obesity. Nuclear-encoded genes are relevant for mitochondrial function (3 gene sets of known relevant pathways: (1) 16 nuclear regulators of mitochondrial genes, (2) 91 genes for oxidative phosphorylation and (3) 966 nuclear-encoded mitochondrial genes). Gene set enrichment analysis (GSEA) showed no association with type 2 diabetes mellitus in these gene sets. Here we performed a GSEA for the same gene sets for obesity. Genome wide association study (GWAS) data from a case-control approach on 453 extremely obese children and adolescents and 435 lean adult controls were used for GSEA. For independent confirmation, we analyzed 705 obesity GWAS trios (extremely obese child and both biological parents) and a population-based GWAS sample (KORA F4, n = 1,743). A meta-analysis was performed on all three samples. In each sample, the distribution of significance levels between the respective gene set and those of all genes was compared using the leading-edge-fraction-comparison test (cut-offs between the 50(th) and 95(th) percentile of the set of all gene-wise corrected p-values) as implemented in the MAGENTA software. In the case-control sample, significant enrichment of associations with obesity was observed above the 50(th) percentile for the set of the 16 nuclear regulators of mitochondrial genes (p(GSEA,50) = 0.0103). This finding was not confirmed in the trios (p(GSEA,50) = 0.5991), but in KORA (p(GSEA,50) = 0.0398). The meta-analysis again indicated a trend for enrichment (p(MAGENTA,50) = 0.1052, p(MAGENTA,75) = 0.0251). The GSEA revealed that weak association signals for obesity might be enriched in the gene set of 16 nuclear regulators of mitochondrial genes.

Figure 1. Empirical cumulative distribution functions (ECDF) of P_g in four different gene sets in the Discovery.

A case-control GWAS sample of 453 (extremely) obese cases and 435 lean controls was analyzed. In each panel the grey line represents the ECDF of the uniform distribution (null hypotheses of no association) and the black line represents the ECDF of the respective gene set. P_g, gene-wise corrected p-value.

Figure 2. Empirical cumulative distribution functions (ECDF) of P_g in all autosomal genes and gene set 1.

For independent confirmation of the initial finding, GSEA was performed in 705 obesity trios (A) and in 463 obese cases and 483 normal weight or lean controls of the KORA-CC sample (B). In addition, a meta-analysis of all three study samples (from Discovery and Confirmation) was performed (C). In each panel the grey line represents the ECDF of the uniform distribution (null hypotheses of no association) and the black line represents the ECDF of the respective gene set. P_g, gene-wise corrected p-value.