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

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 CHARGEmtDNAþ 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 % 5EÀ04) 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 % 1EÀ03). 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 % 1EÀ06) 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.

Genetic and phenotypic landscape of the mitochondrial genome in the Japanese population

“…Mitochondrial function is regulated not only by the genes encoded in mtDNA but also by those in nDNA. As these two types of genes confer synergistic biological functions 6 , co-evolution of the genetic variants embedded within them 5 , namely "mtDNA-nDNA genotype association", has been suggested 17 . Thus, we tested the hypothesis that there might exist preferential transmission between nDNA and mtDNA at a genotype level.…”

“…Previous studies suggested mtDNA genetics risk on late-onset human clinical phenotypes 15,17,35 . In addition to validation of the previously suggested associations with renal functions, our study provided novel phenotypic associations in creatine kinase, an immune-related disease, and a liver function-related trait.…”

“…Considering population specificity of mtDNA haplotype structure, phenome-wide association study (PheWAS) utilizing a large-scale biobank cohort with the adjustment for population structure is required to robustly identify mtDNA variants associated with human complex traits. However, few studies have been conducted, especially in non-European population 17 .…”

The integrative biology of type 2 diabetes

“…There is increasing evidence supporting a hypothesis whereby gene variants in mitochondrial DNA (mtDNA) and mitochondrialfunction-related nuclear DNA contribute to insulin resistance and T2D 90 or abnormal exercise-induced responses 91 . Gene variants in mitochondrial-function-related nuclear DNA lead to relatively mildly impaired mitochondrial function, whereas classical mtDNA gene variants typically cause a severe reduction in mitochondrial function with neurological deficits and β-cell failure.…”

Comment on APLAR Grand Round: Phenotypes of single mtDNA deletions may unequivocally suggest mitochondrial disease

“…The presented patient had hyperlipidemia, which is commonly attributed to the alimentary habits of an individual. However, hyperlipidemia can be also a manifestation of a MID, which is frequently not appreciated. Elevated serum lipids in MID patients may represent a compensatory mechanism to provide fuel for alternative generation of adenosine triphosphate.…”