Although the expression of multiple OXPHOS genes is downregulated in skeletal muscle of patients with diabetes [9], and OXPHOS activity is reduced in diabetic and insulin-resistant individuals, we did not find evidence that OXPHOS genes lie near genetic variants that affect T2D risk or related glycemic traits. This is consistent with a previously reported pathway analysis of one of the T2D GWA studies included in the DIAGRAM+ meta-analysis [27]. Lack of enrichment in the OXPHOS genes suggests that either the changes in expression are an effect and not a cause of diabetes, or that one or few regulators of OXPHOS [35] contain yet undetected rare or common variants, or inherited epigenetic changes associated with T2D or a related phenotype. Since, to date, there is no conclusive evidence for a strong association of any of the 16 known nuclear regulators of mitochondrial genes to T2D, we tested whether several regulators might harbor common variants with modest effect on T2D risk in the population. In our analysis we could not find strong support for this possibility. Our simulations suggest that we would
