Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits.
Adipocytes
/ metabolism
Body Mass Index
Cardiovascular Diseases
/ genetics
Cohort Studies
DNA, Mitochondrial
/ genetics
Diabetes Mellitus
/ genetics
Genes, Mitochondrial
/ genetics
Genetic Variation
/ genetics
Glucose
/ metabolism
Glycated Hemoglobin
/ metabolism
Humans
Insulin
/ metabolism
Metabolism
/ genetics
Mitochondria
/ genetics
Quantitative Trait Loci
Waist-Hip Ratio
BMI
HOMA-B
HOMA-IR
HbA1c
MT-nDNA candidate genes
glucose
insulin
mitochondria
mtDNA
waist-to-hip ratio
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
03 01 2019
03 01 2019
Historique:
received:
01
07
2018
accepted:
06
12
2018
pubmed:
1
1
2019
medline:
5
11
2019
entrez:
1
1
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30595373
pii: S0002-9297(18)30452-X
doi: 10.1016/j.ajhg.2018.12.001
pmc: PMC6323610
pii:
doi:
Substances chimiques
DNA, Mitochondrial
0
Glycated Hemoglobin A
0
Insulin
0
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
112-138Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK078616
Pays : United States
Organisme : NHLBI NIH HHS
ID : K99 HL130580
Pays : United States
Organisme : NIEHS NIH HHS
ID : P30 ES010126
Pays : United States
Organisme : Medical Research Council
ID : MC_PC_19009
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12015/1
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : R00 HL130580
Pays : United States
Organisme : Medical Research Council
ID : MR/L01341X/1
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : K24 DK080140
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK020541
Pays : United States
Organisme : NHLBI NIH HHS
ID : K01 HL143142
Pays : United States
Organisme : Wellcome Trust
ID : G906919
Pays : United Kingdom
Organisme : NIGMS NIH HHS
ID : U54 GM115428
Pays : United States
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/F019394/1
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : P30 DK079626
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK056341
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL105756
Pays : United States
Organisme : Medical Research Council
ID : MR/S003886/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12015/2
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R023484/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L01632X/1
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : U01 DK078616
Pays : United States
Organisme : Medical Research Council
ID : MC_UU_00007/10
Pays : United Kingdom
Organisme : NIGMS NIH HHS
ID : R01 GM075091
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK056336
Pays : United States
Organisme : Medical Research Council
ID : G9815508
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : R01 HL131573
Pays : United States
Organisme : Wellcome Trust
ID : 208806/Z/17/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12015/5
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/K002767/1
Pays : United Kingdom
Informations de copyright
Copyright © 2018 American Society of Human Genetics. All rights reserved.
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