1. Genetics and Genomics
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GWAS and ExWAS of blood Mitochondrial DNA copy number identifies 71 loci and highlights a potential causal role in dementia

  1. Michael Chong
  2. Pedrum Mohammadi-Shemirani
  3. Nicolas Perrot
  4. Walter Nelson
  5. Robert Morton
  6. Sukrit Narula
  7. Ricky Lali
  8. Irfan Khan
  9. Mohammad Khan
  10. Conor Judge
  11. Tafadzwa Machipisa
  12. Nathan Cawte
  13. Martin O'Donnell
  14. Marie Pigeyre
  15. Loubna Akhabir
  16. Guillaume Paré  Is a corresponding author
  1. McMaster University, Canada
  2. Population Health Research Institute, Canada
  3. Hamilton Health Sciences, Canada
  4. National University of Ireland, Galway, Ireland
  5. University of Cape Town, South Africa
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Cite this article as: eLife 2022;11:e70382 doi: 10.7554/eLife.70382

Abstract

Background: Mitochondrial DNA copy number (mtDNA-CN) is an accessible blood-based measurement believed to capture underlying mitochondrial function. The specific biological processes underpinning its regulation, and whether those processes are causative for disease, is an area of active investigation.

Methods: We developed a novel method for array-based mtDNA-CN estimation suitable for biobank-scale studies, called 'AutoMitoC'. We applied AutoMitoC to 395,781 UKBiobank study participants and performed genome and exome-wide association studies, identifying novel common and rare genetic determinants. Finally, we performed two-sample Mendelian Randomization to assess whether genetically low mtDNA-CN influenced select mitochondrial phenotypes.

Results: Overall, genetic analyses identified 71 loci for mtDNA-CN, which implicated several genes involved in rare mtDNA depletion disorders, dNTP metabolism, and the mitochondrial central dogma. Rare variant analysis identified SAMHD1 mutation carriers as having higher mtDNA-CN (beta=0.23 SDs; 95% CI, 0.18- 0.29; P=2.6x10-19), a potential therapeutic target for patients with mtDNA depletion disorders, but at increased risk of breast cancer (OR=1.91; 95% CI, 1.52-2.40; P=2.7x10-8). Finally, Mendelian randomization analyses suggest a causal effect of low mtDNA-CN on dementia risk (OR=1.94 per 1 SD decrease in mtDNA-CN; 95% CI, 1.55-2.32; P=7.5x10-4).

Conclusions: Altogether, our genetic findings indicate that mtDNA-CN is a complex biomarker reflecting specific mitochondrial processes related to mtDNA regulation, and that these processes are causally related to human diseases.

Funding: No funds supported this specific investigation. Awards and positions supporting authors include: Canadian Institutes of Health Research (CIHR) Frederick Banting and Charles Best Canada Graduate Scholarships Doctoral Award (MC, PM); CIHR Post-Doctoral Fellowship Award (RM); Wellcome Trust Grant number: 099313/B/12/A; Crasnow Travel Scholarship; Bongani Mayosi UCT-PHRI Scholarship 2019/2020 (TM); Wellcome Trust Health Research Board Irish Clinical Academic Training (ICAT) Programme Grant Number: 203930/B/16/Z (CJ); European Research Council COSIP Grant Number: 640580 (MO); E.J. Moran Campbell Internal Career Research Award (MP); CISCO Professorship in Integrated Health Systems and Canada Research Chair in Genetic and Molecular Epidemiology (GP).

Data availability

Individual-level UKBiobank genotypes and phenotypes can be acquired upon successful application (https://bbams.ndph.ox.ac.uk/ams/). All individual-level UKBiobank data was accessed as part of application # 15255. FinnGen summary statistics are freely available to download (https://www.finngen.fi/en/access_results). All data products generated as part of this study will be made publicly accessible. Specifically, the AutoMitoC array-based mtDNA-CN estimation pipeline is available on GitHub (https://github.com/GMELab/AutoMitoC). The mtDNA-CN estimates derived in UKBiobank participants have been returned to the UKBiobank and made accessible to researchers through the data showcase (https://biobank.ndph.ox.ac.uk/showcase/). Summary-level association statistics from GWAS have been made publicly available for download from the GWAS catalogue:GCST90026371 (Trans-ethnic meta-analysis: http://ftp.ebi.ac.uk/pub/databases/gwas/summary_statistics/GCST90026001-GCST90027000/GCST90026371/)GCST90026372 (European: http://ftp.ebi.ac.uk/pub/databases/gwas/summary_statistics/GCST90026001-GCST90027000/GCST90026372/)GCST90026373 (South Asian: http://ftp.ebi.ac.uk/pub/databases/gwas/summary_statistics/GCST90026001-GCST90027000/GCST90026373/)GCST90026374 (African: http://ftp.ebi.ac.uk/pub/databases/gwas/summary_statistics/GCST90026001-GCST90027000/GCST90026374/).All remaining data are available in the main text or supplementary materials.

The following previously published data sets were used

Article and author information

Author details

  1. Michael Chong

    Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0555-4622
  2. Pedrum Mohammadi-Shemirani

    Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6740-7858
  3. Nicolas Perrot

    Population Health Research Institute, Hamilton, Canada
    Competing interests
    The authors declare that no competing interests exist.
  4. Walter Nelson

    Centre for Data Science and Digital Health, Hamilton Health Sciences, Hamilton, Canada
    Competing interests
    The authors declare that no competing interests exist.
  5. Robert Morton

    Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0099-4167
  6. Sukrit Narula

    Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada
    Competing interests
    The authors declare that no competing interests exist.
  7. Ricky Lali

    Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada
    Competing interests
    The authors declare that no competing interests exist.
  8. Irfan Khan

    Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada
    Competing interests
    The authors declare that no competing interests exist.
  9. Mohammad Khan

    Department of Medicine, McMaster University, Hamilton, Canada
    Competing interests
    The authors declare that no competing interests exist.
  10. Conor Judge

    National University of Ireland, Galway, Galway, Ireland
    Competing interests
    The authors declare that no competing interests exist.
  11. Tafadzwa Machipisa

    Department of Medicine, University of Cape Town, Cape Town, South Africa
    Competing interests
    The authors declare that no competing interests exist.
  12. Nathan Cawte

    Population Health Research Institute, Hamilton, Canada
    Competing interests
    The authors declare that no competing interests exist.
  13. Martin O'Donnell

    National University of Ireland, Galway, Galway, Ireland
    Competing interests
    The authors declare that no competing interests exist.
  14. Marie Pigeyre

    Department of Medicine, McMaster University, Hamilton, Canada
    Competing interests
    The authors declare that no competing interests exist.
  15. Loubna Akhabir

    Department of Medicine, McMaster University, Hamilton, Canada
    Competing interests
    The authors declare that no competing interests exist.
  16. Guillaume Paré

    Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada
    For correspondence
    pareg@mcmaster.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6795-4760

Funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. No external funding was received for this work.

Ethics

Human subjects: Approval was received to use UKBiobank study data in this work under application ID # 15255 ("Identification of the shared biological and sociodemographic factors underlying cardiovascular disease and dementia risk"). The UKBiobank study obtained ethics approval from the North West Multi-centre Research Ethics Committee which encompasses the UK (REC reference: 11/NW/0382). All research participants provided informed consent.

Reviewing Editor

  1. Magnus Nordborg, Austrian Academy of Sciences, Austria

Publication history

  1. Received: May 14, 2021
  2. Accepted: January 11, 2022
  3. Accepted Manuscript published: January 13, 2022 (version 1)

Copyright

© 2022, Chong et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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