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

Authors:
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 Wang Tom 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 I A 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

Am J Hum Genet 2019 01 27;104(1):112-138. Epub 2018 Dec 27.

Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27516, USA. Electronic address:

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.

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http://dx.doi.org/10.1016/j.ajhg.2018.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323610PMC
January 2019
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