| Literature DB >> 30595373 |
Aldi T Kraja1, Chunyu Liu2, Jessica L Fetterman3, Mariaelisa Graff4, Christian Theil Have5, Charles Gu6, Lisa R Yanek7, Mary F Feitosa8, Dan E Arking9, Daniel I Chasman10, Kristin Young4, Symen Ligthart11, W David Hill12, Stefan Weiss13, Jian'an Luan14, Franco Giulianini15, Ruifang Li-Gao16, Fernando P Hartwig17, Shiow J Lin8, Lihua Wang8, Tom G Richardson18, Jie Yao19, Eliana P Fernandez11, Mohsen Ghanbari11, Mary K Wojczynski8, Wen-Jane Lee20, Maria Argos21, Sebastian M Armasu22, Ruteja A Barve23, Kathleen A Ryan24, Ping An8, Thomas J Baranski25, Suzette J Bielinski26, Donald W Bowden27, Ulrich Broeckel28, Kaare Christensen29, Audrey Y Chu15, Janie Corley12, Simon R Cox12, Andre G Uitterlinden30, Fernando Rivadeneira30, Cheryl D Cropp31, E Warwick Daw8, Diana van Heemst32, Lisa de Las Fuentes33, He Gao34, Ioanna Tzoulaki35, Tarunveer S Ahluwalia36, Renée de Mutsert16, Leslie S Emery37, A Mesut Erzurumluoglu38, James A Perry24, Mao Fu24, Nita G Forouhi14, Zhenglong Gu39, Yang Hai19, Sarah E Harris40, Gibran Hemani18, Steven C Hunt41, Marguerite R Irvin42, Anna E Jonsson5, Anne E Justice43, Nicola D Kerrison14, Nicholas B Larson26, Keng-Hung Lin44, Latisha D Love-Gregory45, Rasika A Mathias46, Joseph H Lee47, Matthias Nauck48, Raymond Noordam32, Ken K Ong14, James Pankow49, Amit Patki50, Alison Pattie12, Astrid Petersmann48, Qibin Qi51, Rasmus Ribel-Madsen52, Rebecca Rohde4, Kevin Sandow19, Theresia M Schnurr5, Tamar Sofer53, John M Starr54, Adele M Taylor12, Alexander Teumer55, Nicholas J Timpson18, Hugoline G de Haan16, Yujie Wang4, Peter E Weeke56, Christine Williams8, Hongsheng Wu57, Wei Yang58, Donglin Zeng59, Daniel R Witte60, Bruce S Weir37, Nicholas J Wareham14, Henrik Vestergaard61, Stephen T Turner62, Christian Torp-Pedersen63, Evie Stergiakouli18, Wayne Huey-Herng Sheu64, Frits R Rosendaal16, M Arfan Ikram11, Oscar H Franco65, Paul M Ridker10, Thomas T Perls66, Oluf Pedersen5, Ellen A Nohr67, Anne B Newman68, Allan Linneberg69, Claudia Langenberg14, Tuomas O Kilpeläinen5, Sharon L R Kardia70, Marit E Jørgensen36, Torben Jørgensen71, Thorkild I A Sørensen72, Georg Homuth13, Torben Hansen5, Mark O Goodarzi73, Ian J Deary12, Cramer Christensen74, Yii-Der Ida Chen19, Aravinda Chakravarti75, Ivan Brandslund76, Klaus Bonnelykke77, Kent D Taylor19, James G Wilson78, Santiago Rodriguez18, Gail Davies12, Bernardo L Horta79, Bharat Thyagarajan80, D C Rao6, Niels Grarup5, Victor G Davila-Roman33, Gavin Hudson81, Xiuqing Guo19, Donna K Arnett82, Caroline Hayward83, Dhananjay Vaidya7, Dennis O Mook-Kanamori84, Hemant K Tiwari50, Daniel Levy85, Ruth J F Loos86, Abbas Dehghan34, Paul Elliott34, Afshan N Malik87, Robert A Scott14, Diane M Becker7, Mariza de Andrade22, Michael A Province8, James B Meigs88, Jerome I Rotter19, Kari E North89.
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.Entities:
Keywords: BMI; HOMA-B; HOMA-IR; HbA1c; MT-nDNA candidate genes; glucose; insulin; mitochondria; mtDNA; waist-to-hip ratio
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Year: 2018 PMID： 30595373 PMCID： PMC6323610 DOI： 10.1016/j.ajhg.2018.12.001
Source DB: PubMed Journal: Am J Hum Genet ISSN： 0002-9297 Impact factor: 11.025