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.

Copyright © 2018 American Society of Human Genetics. All rights reserved.

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TitleAssociations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits.
DateJanuary 3rd, 2019
Issue nameAmerican journal of human genetics
Issue numberv104.1:112-138
DOI10.1016/j.ajhg.2018.12.001
PubMed30595373
AuthorsKraja AT, Liu C, Fetterman JL, Graff M, Have CT, Gu C, Yanek LR, Feitosa MF, Arking DE, Chasman DI, Young K, Ligthart S, Hill WD, Weiss S, Luan J, Giulianini F, Li-Gao R, Hartwig FP, Lin SJ, Wang L, Richardson TG, Yao J, Fernandez EP, Ghanbari M, Wojczynski MK, Lee WJ, Argos M, Armasu SM, Barve RA, Ryan KA, An P, Baranski TJ, Bielinski SJ, Bowden DW, Broeckel U, Christensen K, Chu AY, Corley J, Cox SR, Uitterlinden AG, Rivadeneira F, Cropp CD, Daw EW, van Heemst D, de Las Fuentes L, Gao H, Tzoulaki I, Ahluwalia TS, de Mutsert R, Emery LS, Erzurumluoglu AM, Perry JA, Fu M, Forouhi NG, Gu Z, Hai Y, Harris SE, Hemani G, Hunt SC, Irvin MR, Jonsson AE, Justice AE, Kerrison ND, Larson NB, Lin KH, Love-Gregory LD, Mathias RA, Lee JH, Nauck M, Noordam R, Ong KK, Pankow J, Patki A, Pattie A, Petersmann A, Qi Q, Ribel-Madsen R, Rohde R, Sandow K, Schnurr TM, Sofer T, Starr JM, Taylor AM, Teumer A, Timpson NJ, de Haan HG, Wang Y, Weeke PE, Williams C, Wu H, Yang W, Zeng D, Witte DR, Weir BS, Wareham NJ, Vestergaard H, Turner ST, Torp-Pedersen C, Stergiakouli E, Sheu WH, Rosendaal FR, Ikram MA, Franco OH, Ridker PM, Perls TT, 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, Bonnelykke K, Taylor KD, Wilson JG, Rodriguez S, Davies G, Horta BL, Thyagarajan B, Rao DC, Grarup N, Davila-Roman VG, Hudson G, Guo X, Arnett DK, Hayward C, Vaidya D, Mook-Kanamori DO, Tiwari HK, Levy D, Loos RJF, Dehghan A, Elliott P, Malik AN, Scott RA, Becker DM, de Andrade M, Province MA, Meigs JB, Rotter JI & North KE
KeywordsBMI, HOMA-B, HOMA-IR, HbA1c, MT-nDNA candidate genes, glucose, insulin, mitochondria, mtDNA, waist-to-hip ratio
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