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

Gavin Hudson, Aurora Gomez-Duran, Ian J. Wilson, Patrick F. Chinnery Mail


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.

Citation: Hudson G, Gomez-Duran A, Wilson IJ, Chinnery PF (2014) Recent Mitochondrial DNA Mutations Increase the Risk of Developing Common Late-Onset Human Diseases. PLoS Genet 10(5): e1004369. doi:10.1371/journal.pgen.1004369

Editor: Takashi Gojobori, National Institute of Genetics, Japan

Received: January 27, 2014; Accepted: March 24, 2014; Published: May 22, 2014

Copyright: © 2014 Hudson et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This study used genotype data from cases and population controls that were generated by the Wellcome Trust Case Control Consortium 2 (a full list of the investigators who contributed to the generation of the data is available from The population controls were from the 1958 British Birth Cohort collection funded by the Medical Research Council (grant G0000934) and The Wellcome Trust (grant 068545) and from the UK Blood Services Collection of Common Controls funded by The Wellcome Trust. GH is a Parkinson's UK Senior Fellow supported by the Henry Smith Charity. PFC is a Wellcome Trust Senior Fellow in Clinical Science (101876/Z/13/Z), and a UK NIHR Senior Investigator. PFC receives additional support from the Wellcome Trust Centre for Mitochondrial Research (096919Z/11/Z), the Medical Research Council (UK) Centre for Translational Muscle Disease research (G0601943), and EU FP7 TIRCON, and the National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

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