We first analyzed a set of 16 nuclear regulators of mitochondrial genes assembled based on the literature (listed in Table S11) [35], [44]–[48], using the latest DIAGRAM+ T2D GWA meta-analysis of 8,130 cases and 38,987 controls from eight GWA studies [36]. Since no individual mitochondria regulator was found to date to be significantly associated with T2D at genome-wide significance, we tested the hypothesis that common variants in more than one regulator may affect T2D risk (possibly through OXPHOS downregulation) in the diabetic populations analyzed here. Upon applying MAGENTA to the set of nuclear regulators we did not observe significant enrichment of T2D associations compared to the genomic background of gene scores (Table 3; = 0.19; Quantile-quantile plot of gene p-values in Figure S7A). The peroxisome proliferator-activated receptor delta, PPARD (Entrez ID 5467) [44], received the best T2D gene p-value, although it was not gene-wide significant ( = 0.0089). The gene scores of the 16 known nuclear regulators of mitochondrial functions are listed in Table S11.
