Citation
Kraja, Aldi T.; Liu, Chunyu; Fetterman, Jessica L.; Graff, Mariaelisa; Have, Christian Theil; Gu, C. Charles; Yanek, Lisa R.; Feitosa, Mary F.; Arking, Dan E.; & Chasman, Daniel I., et al. (2019). Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits. American Journal of Human Genetics, 104(1), 112-138. PMCID: PMC6323610Abstract
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.URL
http://dx.doi.org/10.1016/j.ajhg.2018.12.001Reference Type
Journal ArticleYear Published
2019Journal Title
American Journal of Human GeneticsAuthor(s)
Kraja, Aldi T.Liu, Chunyu
Fetterman, Jessica L.
Graff, Mariaelisa
Have, Christian Theil
Gu, C. Charles
Yanek, Lisa R.
Feitosa, Mary F.
Arking, Dan E.
Chasman, Daniel I.
Young, Kristin L.
Ligthart, Symen
Hill, W. David
Weiss, Stefan
Luan, Jian'an
Giulianini, Franco
Li-Gao, Ruifang
Hartwig, Fernando Pires
Lin, Shiow
Wang, Lihua
Richardson, Tom G.
Yao, Jie
Fernandez, Eliana P.
Ghanbari, Mohsen
Wojczynski, Mary K.
Lee, Wen-Jane
Argos, Maria
Armasu, Sebastian M.
Barve, Ruteja A.
Ryan, Kathleen A.
An, Ping
Baranski, Thomas J.
Bielinski, Suzette J.
Bowden, Donald W.
Broeckel, Ulrich
Christensen, Kaare
Chu, Audrey Y.
Corley, Janie
Cox, Simon R.
Uitterlinden, Andre G.
Rivadeneira, Fernando
Cropp, Cheryl D.
Daw, E. Warwick
van Heemst, Diana
de Las Fuentes, Lisa
Gao, He
Tzoulaki, Ioanna
Ahluwalia, Tarunveer S.
de Mutsert, Renee
Emery, Leslie S.
Erzurumluoglu, A. Mesut
Perry, James A.
Fu, Mao
Forouhi, Nita G.
Gu, Zhenglong
Hai, Yang
Harris, Sarah E.
Hemani, Gibran
Hunt, Steven C.
Irvin, Marguerite Ryan
Jonsson, Anna E.
Justice, Anne E.
Kerrison, Nicola D.
Larson, Nicholas B.
Lin, Keng-Hung
Love-Gregory, Latisha D.
Mathias, Rasika A.
Lee, Joseph H.
Nauck, Matthias
Noordam, Raymond
Ong, Ken K.
Pankow, James R.
Patki, Amit
Pattie, Alison
Petersmann, Astrid
Qi, Qibin
Ribel-Madsen, Rasmus
Rohde, Rebecca R.
Sandow, Kevin
Schnurr, Theresia M.
Sofer, Tamar
Starr, John M.
Taylor, Adele M.
Teumer, Alexander
Timpson, Nicholas J.
de Haan, Hugoline G.
Wang, Yujie
Weeke, Peter E.
Williams, Christine
Wu, Hongsheng
Yang, Wei
Zeng, Donglin
Witte, Daniel R.
Weir, Bruce S.
Wareham, Nicholas J.
Vestergaard, Henrik
Turner, Stephen T.
Torp-Pedersen, Christian
Stergiakouli, Evie
Sheu, Wayne Huey-Herng
Rosendaal, Frits R.
Ikram, M. Arfan
Franco, Oscar H.
Ridker, Paul M.
Perls, Thomas T.
Pedersen, Oluf
Nohr, Ellen A.
Newman, Anne B.
Linneberg, Allan
Langenberg, Claudia
Kilpelainen, Tuomas O.
Kardia, Sharon L. R.
Jorgensen, Marit E.
Jorgensen, Torben
Sorensen, Thorkild I. A.
Homuth, Georg
Hansen, Torben
Goodarzi, Mark O.
Deary, Ian J.
Christensen, Cramer
Chen, Yii-Der Ida
Chakravarti, Aravinda
Brandslund, Ivan
Bonnelykke, Klaus
Taylor, Kent D.
Wilson, James G.
Rodriguez, Santiago
Davies, Gail
Horta, Bernardo L.
Thyagarajan, Bharat
Rao, Dabeeru C.
Grarup, Niels
Davila-Roman, Victor G.
Hudson, Gavin
Guo, Xiuqing
Arnett, Donna K.
Hayward, Caroline
Vaidya, Dhananjay
Mook-Kanamori, Dennis O.
Tiwari, Hemant K.
Levy, Daniel
Loos, Ruth J. F.
Dehghan, Abbas
Elliott, Paul
Malik, Afshan N.
Scott, Robert A.
Becker, Diane M.
de Andrade, Mariza
Province, Michael A.
Meigs, James B.
Rotter, Jerome I.
North, Kari E.