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BIBTEX RIS

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

2018; Elsevier BV; Volume: 104; Issue: 1 Linguagem: Inglês

10.1016/j.ajhg.2018.12.001

1537-6605

Aldi T. Kraja, Chunyu Liu, Jessica L. Fetterman, Mariaelisa Graff, Henri Theil, C. Charles Gu, Lisa R. Yanek, Mary F. Feitosa, Dan E. Arking, Daniel I. Chasman, Kristin L. Young, Symen Ligthart, W. David Hill, Stefan Weiß, Jian’an Luan, Franco Giulianini, Ruifang Li‐Gao, Fernando Pires Hartwig, Shiow J. Lin, Lihua Wang, Tom G. Richardson, Jie Yao, Eliana Portilla-Fernández, Mohsen Ghanbari, Mary K. Wojczynski, Wen‐Jane Lee, Maria Argos, Sebastian M. Armasu, Ruteja A. Barve, Kathleen A. Ryan, Ping An, Thomas Baranski, Suzette J. Bielinski, Donald W. Bowden, Ulrich Broeckel, Kaare Christensen, Audrey Y. Chu, Janie Corley, Simon R. Cox, André 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 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 Jonsson, Anne E. Justice, Nicola D. Kerrison, Nicholas B. Larson, Keng-Hung Lin, Latisha Love‐Gregory, Rasika A. Mathias, Joseph H. Lee, Matthias Nauck, Raymond Noordam, Ken K. Ong, James S. 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 Weeke, Christine A. 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. Nøhr, Anne B. Newman, Allan Linneberg, Claudia Langenberg, Tuomas O. Kilpeläinen, Sharon L. R. Kardia, Marit E. Jørgensen, Torben Jørgensen, Thorkild I. A. Sørensen, Georg Homuth, Torben Hansen, Mark O. Goodarzi, Ian J. Deary, Cramer Christensen, Yii-Der Ida Chen, Aravinda Chakravarti, Ivan Brandslund, Klaus Bønnelykke, Kent D. Taylor, James G. Wilson, Santiago Rodrı́guez, Gail Davies, Bernardo Lessa Horta, Bharat Thyagarajan, D. C. Rao, Niels Grarup, Víctor G. Dávila‐Román, 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,

Metabolism and Genetic Disorders

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. 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.