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

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.