Title | Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Kraja AT, Liu C, Fetterman JL, et al. |
Secondary Authors | North KE |
Journal | Am J Hum Genet |
Volume | 104 |
Issue | 1 |
Pagination | 112-138 |
Date Published | 2019 01 03 |
ISSN | 1537-6605 |
Keywords | Adipocytes, 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. |
DOI | 10.1016/j.ajhg.2018.12.001 |
Alternate Journal | Am J Hum Genet |
PubMed ID | 30595373 |
PubMed Central ID | PMC6323610 |
Grant List | K99 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 |