Kraja, Aldi T; Liu, Chunyu; Fetterman, Jessica L; Graff, Mariaelisa; Have, Christian Theil; Gu, Charles; Yanek, Lisa R; Feitosa, Mary F; Arking, Dan E; Chasman, Daniel I; Young, Kristin; Ligthart, Symen; Hill, W David; Weiss, Stefan; Luan, Jian'an; Giulianini, Franco; Li-Gao, Ruifang; Hartwig, Fernando P; Lin, Shiow J; Wang, Lihua; ... (2019). Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits. American journal of human genetics, 104(1), pp. 112-138. Cell Press 10.1016/j.ajhg.2018.12.001
|
Text
Kraja AmJHumGenet 2019.pdf - Published Version Available under License Creative Commons: Attribution (CC-BY). Download (1MB) | Preview |
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.
Item Type: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Social and Preventive Medicine (ISPM) |
UniBE Contributor: |
Franco Duran, Oscar Horacio |
Subjects: |
600 Technology > 610 Medicine & health 300 Social sciences, sociology & anthropology > 360 Social problems & social services |
ISSN: |
0002-9297 |
Publisher: |
Cell Press |
Language: |
English |
Submitter: |
Doris Kopp Heim |
Date Deposited: |
03 Jan 2019 10:51 |
Last Modified: |
05 Dec 2022 15:24 |
Publisher DOI: |
10.1016/j.ajhg.2018.12.001 |
PubMed ID: |
30595373 |
Uncontrolled Keywords: |
BMI HOMA-B HOMA-IR HbA1c MT-nDNA candidate genes glucose insulin mitochondria mtDNA waist-to-hip ratio |
BORIS DOI: |
10.7892/boris.123129 |
URI: |
https://boris.unibe.ch/id/eprint/123129 |
Actions (login required)
 |
Edit item |