Table 3.

Four mitochondrial pathways enriched in the total T2D cis-genes.

MSigDB C2 Gene Set (Source)	(A) Gene set enrichment			(B) GSEA in meta-analyzed case vs control gene expression data
	# cis-genes	p-value (random)	p-value (structured)	Skeletal Muscle	Adipose	Liver	Pancreas
BCAA degradation	5	0.020	0.027	↓<2.5E-04	↓1.7E-04	↓6.0E-03	↓2.5E-04
Biotin carboxylases	2	0.022	0.019	↓9.0E-03	↓2.5E-04	0.20 (n.s.)	↓7.5E-04
Propanoate metabolism	4	0.025	0.042	↓<2.5E-04	↓1.7E-04	0.13 (n.s.)	↓3.3E-04
Butanoate metabolism	4	0.032	0.042	↓9.0E-03	↓1.7E-04	0.14 (n.s.)	↓2.5E-04

(A) Four curated mitochondrial gene sets showed evidence of enrichment by count among the total 763 T2D cis-genes (p-value<0.05), compared to the genomic background. All gene sets were curated from the KEGG database excluding biotin carboxylases which was manually defined. Empirical p-values were calculated using a permutation approach by selecting genes at random from the genomic background (random) or from within ±1.5Mb of each other (structured) (the distance used to investigate putative cis-genes). (B) FDR values from GSEA for the same four gene sets, showing significant enrichment for decreased expression in meta-analyzed case-control gene expression datasets. ↓ indicates a significant enrichment for decreased expression compared to the background and no arrow indicates an enrichment for mixed differential expression (both increased and decreased). n.s., not significant (p-value > 0.05).