Mitochondria (MT), the major site of cellular energy production, are under dual genetic control by 37 mitochondrial DNA (mtDNA) genes and numerous nuclear genes (MT-nDNA). In the CHARGEmtDNA+ Consortium, we studied genetic associations of mtDNA and MT-nDNA associations with body mass index (BMI), waist-hip-ratio (WHR), glucose, insulin, HOMA-B, HOMA-IR, and HbA1c. This 45-cohort collaboration comprised 70,775 (insulin) to 170,202 (BMI) pan-ancestry individuals. Validation and imputation of mtDNA variants was followed by single-variant and gene-based association testing. We report two significant common variants, one in MT-ATP6 associated (p ≤ 5E−04) with WHR and one in the D-loop with glucose. Five rare variants in MT-ATP6, MT-ND5, and MT-ND6 associated with BMI, WHR, or insulin. Gene-based meta-analysis identified MT-ND3 associated with BMI (p ≤ 1E−03). We considered 2,282 MT-nDNA candidate gene associations compiled from online summary results for our traits (20 unique studies with 31 dataset consortia's genome-wide associations [GWASs]). Of these, 109 genes associated (p ≤ 1E−06) with at least 1 of our 7 traits. We assessed regulatory features of variants in the 109 genes, cis- and trans-gene expression regulation, and performed enrichment and protein-protein interactions analyses. Of the identified mtDNA and MT-nDNA genes, 79 associated with adipose measures, 49 with glucose/insulin, 13 with risk for type 2 diabetes, and 18 with cardiovascular disease, indicating for pleiotropic effects with health implications. Additionally, 21 genes related to cholesterol, suggesting additional important roles for the genes identified. Our results suggest that mtDNA and MT-nDNA genes and variants reported make important contributions to glucose and insulin metabolism, adipocyte regulation, diabetes, and cardiovascular disease.
Bibliographical noteFunding Information:
A.E. Justice is supported by a K99/R00 from the National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI) ( 5K99HL130580-02 and 5R00HL130580-04 ). G. Hudson has received funding support by Wellcome Trust Centre for Mitochondrial Research , Grant Code G906919 . J.I.R., X.G., Y.-D.I.C., K.D.T., Y.H., K.S., and J.Y. have received NIH support for research related to mitochondria. A.T.K., C. Liu, J.L.F., M. Graff, C.T.H., C.G., L.R.Y., M.F.F., D.E.A., D.I.C., K.Y., W.D.H., S.J.L., L.W., T.J.B., L.D.L.-G., T.I.A.S., G. Hudson, D.L., A.N.M., D.M.B., M.A.P., J.B.M., J.I.R., and K.E.N. were the writing group for this paper. M.A.P. and K.E.N. are from the CHARGE ADIPOSITY working group; J.I.R. and J.B.M. are from the CHARGE DIABETES working group.
© 2018 American Society of Human Genetics
- MT-nDNA candidate genes
- waist-to-hip ratio