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Cited by 148Genetic Associations and EpidemiologyMitochondrial Function and PathologyForensic and Genetic Research

The DOI matches its Crossref record; 68 of the 68 references it cites were found in a registry or an index.

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

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Hudson, Gavin, Gomez-Duran, Aurora, Wilson, Ian J., Chinnery, Patrick F.·2014·PLoS Genetics
DOI 10.1371/journal.pgen.1004369PMC PMC4031051
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Abstract

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.

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Crossref · 10.1371/journal.pgen.1004369

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Figure 1 Circularised Manhattan plots of imputed P values showing the association between mtDNA variants and eight complex traits. Radial axis: –log(P-value) (where dark inner circle indicates P = 0.05 threshold). Circumference: position on the mitochondrial genome based on the revised Cambridge Reference Sequence (rCRS, NC_012920) numbering in an anti-clockwise direction from 12 o'clock. Each gene is colour coded, as shown on the figure.
Figure 1 Circularised Manhattan plots of imputed P values showing the association between mtDNA variants and eight complex traits. Radial axis: –log(P-value) (where dark inner circle indicates P = 0.05 threshold). Circumference: position on the mitochondrial genome based on the revised Cambridge Reference Sequence (rCRS, NC_012920) numbering in an anti-clockwise direction from 12 o'clock. Each gene is colour coded, as shown on the figure.CC BY · PubMed Central
Figure 2 High-resolution map of the non-coding region of mtDNA (d-loop) showing allele frequencies in 7,729 control subjects and the position of alleles associated with eight common human diseases; where: AS = ankylosing spondylitis, IS = ischaemic stroke, MS = multiple sclerosis, PD = Parkinson's disease, PBC = primary biliary cirrhosis, UC = ulcerative colitis and SP = schizophrenia. Alleles associated with multiple diseases are shown in Table 2. Alleles associated with single diseases are shown in Table S1. Y-axis: minor allele frequency (MAF) in 7,729 control subjects. X-axis: position on the mitochondrial genome based on the revised Cambridge Reference Sequence (rCRS, NC_012920) with corresponding regions annotated below.
Figure 2 High-resolution map of the non-coding region of mtDNA (d-loop) showing allele frequencies in 7,729 control subjects and the position of alleles associated with eight common human diseases; where: AS = ankylosing spondylitis, IS = ischaemic stroke, MS = multiple sclerosis, PD = Parkinson's disease, PBC = primary biliary cirrhosis, UC = ulcerative colitis and SP = schizophrenia. Alleles associated with multiple diseases are shown in Table 2. Alleles associated with single diseases are shown in Table S1. Y-axis: minor allele frequency (MAF) in 7,729 control subjects. X-axis: position on the mitochondrial genome based on the revised Cambridge Reference Sequence (rCRS, NC_012920) with corresponding regions annotated below.CC BY · PubMed Central

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Metadata

Authors
Hudson, G., Gomez-Duran, A., Wilson, I. J., & Chinnery, P. F.
Affiliations
Wellcome Centre for Mitochondrial Research (GB)
Corresponding author
Chinnery, Patrick F.
ORCID
Venue
PLoS Genetics
Publisher
Public Library of Science (PLoS)
Published
2014-05-22
Volume
10
Issue
5
Pages
e1004369
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
DOI
10.1371/journal.pgen.1004369
PMC
PMC4031051
OpenAlex
W1987954830
Cited by
148
References
68
Citations by year
2026: 2 · 2025: 4 · 2024: 8 · 2023: 11 · 2022: 8 · 2021: 16 · 2020: 20 · 2019: 11 · 2018: 22 · 2017: 15 · 2016: 12 · 2015: 15 · 2014: 4
FWCI
9.95
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Genetics (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
  • Newcastle University ePrints (Newcastle Univesity) (cc-by)
Funders
  • Wellcome Trust (EU-FP7-, 096919, 096919/Z/11/Z, 101876/B/13/Z, G0000934, 10187 6/Z/13/Z, 101876, 068545, G0601943)
  • National Institute for Health and Care Research (G0000934, 101876/Z/13/Z, G0601943)
  • Parkinson's UK (F-1202)
  • Newcastle University
  • Henry Smith Charity
  • Newcastle upon Tyne Hospitals NHS Foundation Trust
  • Medical Research Council (MR/K000608/1, G0601943, G0000934, EU FP7)
  • NIHR Newcastle Biomedical Research Centre
  • Wellcome Trust Centre for Mitochondrial Research (096919Z/11/Z)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Forensic and Genetic Research
Keywords
mitochondrial DNA variants, late-onset disease, missing heritability, disease risk, mitochondrial genome, oxidative phosphorylation, nuclear-mitochondrial interactions
MeSH terms
Brain Ischemia, Colitis, Ulcerative, DNA, Mitochondrial, Humans, Liver Cirrhosis, Biliary, Multiple Sclerosis, Mutation, Oxidative Phosphorylation, Parkinson Disease, Phylogeny, Schizophrenia, Spondylitis, Ankylosing

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