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Region Hovedstaden - en del af Københavns Universitetshospital
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Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits

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  • 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
Vis graf over relationer

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.

OriginalsprogEngelsk
TidsskriftAmerican Journal of Human Genetics
Vol/bind104
Udgave nummer1
Sider (fra-til)112-138
Antal sider27
ISSN0002-9297
DOI
StatusUdgivet - 3 jan. 2019

ID: 56106589