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Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits.

TitleAssociations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits.
Publication TypeJournal Article
Year of Publication2019
AuthorsKraja AT, Liu C, Fetterman JL, et al.
Secondary AuthorsNorth KE
JournalAm J Hum Genet
Volume104
Issue1
Pagination112-138
Date Published2019 01 03
ISSN1537-6605
KeywordsAdipocytes, Body Mass Index, Cardiovascular Diseases, Cohort Studies, Diabetes Mellitus, DNA, Mitochondrial, Genes, Mitochondrial, Genetic Variation, Glucose, Glycated Hemoglobin A, Humans, Insulin, Metabolism, Mitochondria, Quantitative Trait Loci, Waist-Hip Ratio
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.

DOI10.1016/j.ajhg.2018.12.001
Alternate JournalAm J Hum Genet
PubMed ID30595373
PubMed Central IDPMC6323610
Grant ListK99 HL130580 / HL / NHLBI NIH HHS / United States
P30 ES010126 / ES / NIEHS NIH HHS / United States
R00 HL130580 / HL / NHLBI NIH HHS / United States
MR/L01632X/1 / MRC_ / Medical Research Council / United Kingdom
P30 DK056341 / DK / NIDDK NIH HHS / United States
MC_UU_12015/1 / MRC_ / Medical Research Council / United Kingdom
MC_UU_12015/2 / MRC_ / Medical Research Council / United Kingdom
K24 DK080140 / DK / NIDDK NIH HHS / United States
MR/S003886/1 / MRC_ / Medical Research Council / United Kingdom
U01 DK078616 / DK / NIDDK NIH HHS / United States
R01 GM075091 / GM / NIGMS NIH HHS / United States
P30 DK056336 / DK / NIDDK NIH HHS / United States
BB/F019394/1 / BB_ / Biotechnology and Biological Sciences Research Council / United Kingdom
G906919 / WT_ / Wellcome Trust / United Kingdom
U54 GM115428 / GM / NIGMS NIH HHS / United States
G9815508 / MRC_ / Medical Research Council / United Kingdom
R01 DK078616 / DK / NIDDK NIH HHS / United States
MC_UU_00007/10 / MRC_ / Medical Research Council / United Kingdom
MR/K002767/1 / MRC_ / Medical Research Council / United Kingdom
MR/L01341X/1 / MRC_ / Medical Research Council / United Kingdom
MR/R023484/1 / MRC_ / Medical Research Council / United Kingdom
K01 HL143142 / HL / NHLBI NIH HHS / United States
MC_UU_12015/5 / MRC_ / Medical Research Council / United Kingdom
/ WT_ / Wellcome Trust / United Kingdom
R01 HL131573 / HL / NHLBI NIH HHS / United States
R01 HD057194 / HD / NICHD NIH HHS / United States