Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits.
American journal of human genetics 2018 ; 104: 112-138.
Kraja AT, Graff M, Have CT, Yanek LR, Feitosa MF, Arking DE, Chasman DI, Young K, Ligthart S, Weiss S, Luan J, Giulianini F, Li-Gao R, Hartwig FP, Wang L, Richardson TG, Ghanbari M, Wojczynski MK, Lee WJ, Ryan KA, Bielinski SJ, Bowden DW, Broeckel U, Christensen K, Chu AY, Corley J, Cox SR, Uitterlinden AG, Rivadeneira F, Daw EW, van Heemst D, de Las Fuentes L, Tzoulaki I, Ahluwalia TS, de Mutsert R, Erzurumluoglu AM, Perry JA, Forouhi NG, Harris SE, Hemani G, Hunt SC, Irvin MR, Justice AE, Kerrison ND, Lin KH, Mathias RA, Lee JH, Nauck M, Noordam R, Ong KK, Pattie A, Petersmann A, Ribel-Madsen R, Rohde R, Sandow K, Schnurr TM, Sofer T, Starr JM, Teumer A, Timpson NJ, de Haan HG, Wang Y, Weeke PE, Williams C, Witte DR, Wareham NJ, Vestergaard H, Turner ST, Sheu WH, Rosendaal FR, Ikram MA, Franco OH, Ridker PM, Pedersen O, Nohr EA, Newman AB, Linneberg A, Langenberg C, Kilpeläinen TO, Kardia SLR, Jørgensen ME, Jørgensen T, Sørensen TIA, Homuth G, Hansen T, Goodarzi MO, Deary IJ, Christensen C, Chen YI, Chakravarti A, Brandslund I, Taylor KD, Wilson JG, Rodriguez S, Davies G, Horta BL, Rao DC, Grarup N, Arnett DK, Hayward C, Vaidya D, Mook-Kanamori DO, Levy D, Loos RJF, Dehghan A, Elliott P, Scott RA, Becker DM, de Andrade M, Province MA, Meigs JB, Rotter JI, and North KE
PubMed ID : 30595373
PMCID : PMC6323610
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.