%0 Journal Article
%T Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits
%A A. Mesut Erzurumluoglu
%A Abbas Dehghan
%A Adele M. Taylor
%A Afshan N. Malik
%A Aldi T. Kraja
%A Alexander Teumer
%A Alison Pattie
%A Allan Linneberg
%A Amit Patki
%A Andre G. Uitterlinden
%A Anna E. Jonsson
%A Anne B. Newman
%A Anne E. Justice
%A Aravinda Chakravarti
%A Astrid Petersmann
%A Audrey Y. Chu
%A Bernardo L. Horta
%A Bharat Thyagarajan
%A Bruce S. Weir
%A Caroline Hayward
%A Charles Gu
%A Cheryl D. Cropp
%A Christian Theil Have
%A Christian Torp-Pedersen
%A Christine Williams
%A Chunyu Liu
%A Claudia Langenberg
%A Cramer Christensen
%A D.C. Rao
%A Dan E. Arking
%A Daniel I. Chasman
%A Daniel Levy
%A Daniel R. Witte
%A Dennis O. Mook-Kanamori
%A Dhananjay Vaidya
%A Diana van Heemst
%A Diane M. Becker
%A Donald W. Bowden
%A Donglin Zeng
%A Donna K. Arnett
%A E. Warwick Daw
%A Eliana P. Fernandez
%A Ellen A. Nohr
%A Evie Stergiakouli
%A Fernando P. Hartwig
%A Fernando Rivadeneira
%A Franco Giulianini
%A Frits R. Rosendaal
%A Gail Davies
%A Gavin Hudson
%A Georg Homuth
%A Gibran Hemani
%A He Gao
%A Hemant K. Tiwari
%A Henrik Vestergaard
%A Hongsheng Wu
%A Hugoline G. de Haan
%A Ian J. Deary
%A Ioanna Tzoulaki
%A Ivan Brandslund
%A James A. Perry
%A James B. Meigs
%A James G. Wilson
%A James Pankow
%A Janie Corley
%A Jerome I. Rotter
%A Jessica L. Fetterman
%A Jian¡¯an Luan
%A Jie Yao
%A John M. Starr
%A Joseph H. Lee
%A Kaare Christensen
%A Kathleen A. Ryan
%A Ken K. Ong
%A Keng-Hung Lin
%A Kent D. Taylor
%A Kevin Sandow
%A Klaus Bonnelykke
%A Kristin Young
%A Latisha D. Love-Gregory
%A Leslie S. Emery
%A Lihua Wang
%A Lisa R. Yanek
%A Lisa de las Fuentes
%A M. Arfan Ikram
%A Mao Fu
%A Marguerite R. Irvin
%A Maria Argos
%A Mariaelisa Graff
%A Marit E. J£¿rgensen
%A Mariza de Andrade
%A Mark O. Goodarzi
%A Mary F. Feitosa
%J Archive of "American Journal of Human Genetics".
%D 2019
%R 10.1016/j.ajhg.2018.12.001
%X 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 ¡Ü 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 ¡Ü 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 ¡Ü 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
%K mitochondria
%K mtDNA
%K MT-nDNA candidate genes
%K BMI
%K waist-to-hip ratio
%K glucose
%K insulin
%K HOMA-B
%K HOMA-IR
%K HbA1c
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323610/