Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits

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

*Corresponding author for this work

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Abstract

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.

Original languageEnglish
Pages (from-to)112-138
Number of pages27
JournalAmerican Journal of Human Genetics
Volume104
Issue number1
Early online date27 Dec 2018
DOIs
Publication statusPublished - 3 Jan 2019

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Keywords

  • BMI
  • glucose
  • HbA1c
  • HOMA-B
  • HOMA-IR
  • insulin
  • mitochondria
  • MT-nDNA candidate genes
  • mtDNA
  • waist-to-hip ratio

Cite this

Kraja, A. T., Liu, C., Fetterman, J. L., Graff, M., Have, C. T., Gu, C., Yanek, L. R., Feitosa, M. F., Arking, D. E., Chasman, D. I., Young, K., Ligthart, S., Hill, W. D., Weiss, S., Luan, J., Giulianini, F., Li-Gao, R., Hartwig, F. P., Lin, S. J., ... North, K. E. (2019). Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits. American Journal of Human Genetics, 104(1), 112-138. https://doi.org/10.1016/j.ajhg.2018.12.001