Recent Mitochondrial DNA Mutations Increase the Risk of Developing Common Late-Onset Human Diseases

摘要

Mitochondrial DNA (mtDNA) is highly polymorphic at the population level, and specific mtDNA variants affect mitochondrial function. With emerging evidence that mitochondrial mechanisms are central to common human diseases, it is plausible that mtDNA variants contribute to the “missing heritability” of several complex traits. Given the central role of mtDNA genes in oxidative phosphorylation, the same genetic variants would be expected to alter the risk of developing several different disorders, but this has not been shown to date. Here we studied 38,638 individuals with 11 major diseases, and 17,483 healthy controls. Imputing missing variants from 7,729 complete mitochondrial genomes, we captured 40.41% of European mtDNA variation. We show that mtDNA variants modifying the risk of developing one disease also modify the risk of developing other diseases, thus providing independent replication of a disease association in different case and control cohorts. High-risk alleles were more common than protective alleles, indicating that mtDNA is not at equilibrium in the human population, and that recent mutations interact with nuclear loci to modify the risk of developing multiple common diseases. Author Summary There is a growing body of evidence indicating that mitochondrial dysfunction, a result of genetic variation in the mitochondrial genome, is a critical component in the aetiology of a number of complex traits. Here, we take advantage of recent technical and methodological advances to examine the role of common mitochondrial DNA variants in several complex diseases. By examining over 50,000 individuals, from 11 different diseases we show that mitochondrial DNA variants can both increase or decrease an individual's risk of disease, replicating and expanding upon several previously reported studies. Moreover, by analysing several large disease groups in tandem, we are able to show a commonality of association, with the same mitochondrial DNA variants associated with several distinct disease phenotypes. These shared genetic associations implicate a shared underlying functional effect, likely changing cellular energy, which manifests as distinct phenotypes. Our study confirms the important role that mitochondrial DNA variation plays on complex traits and additionally supports the utility of a GWAS-based approach for analysing mitochondrial genetics.