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

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.

Reviewing Editor

  1. Magnus Nordborg, Austrian Academy of Sciences, Austria

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.

Version history

  1. Preprint posted: April 14, 2021 (view preprint)
  2. Received: May 14, 2021
  3. Accepted: January 11, 2022
  4. Accepted Manuscript published: January 13, 2022 (version 1)
  5. Version of Record published: February 23, 2022 (version 2)

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.

Metrics

  • 4,100
    Page views
  • 583
    Downloads
  • 31
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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
(2022)
GWAS and ExWAS of blood Mitochondrial DNA copy number identifies 71 loci and highlights a potential causal role in dementia
eLife 11:e70382.
https://doi.org/10.7554/eLife.70382

Share this article

https://doi.org/10.7554/eLife.70382

Further reading

    1. Chromosomes and Gene Expression
    2. Genetics and Genomics
    Erandi Velazquez-Miranda, Ming He
    Insight

    Endothelial cell subpopulations are characterized by unique gene expression profiles, epigenetic landscapes and functional properties.

    1. Genetics and Genomics
    2. Immunology and Inflammation
    Xinjian Ye, Yijing Bai ... Qianming Chen
    Research Article

    Periodontitis drives irreversible destruction of periodontal tissue and is prone to exacerbating inflammatory disorders. Systemic immunomodulatory management continues to be an attractive approach in periodontal care, particularly within the context of ‘predictive, preventive, and personalized’ periodontics. The present study incorporated genetic proxies identified through genome-wide association studies for circulating immune cells and periodontitis into a comprehensive Mendelian randomization (MR) framework. Univariable MR, multivariable MR, subgroup analysis, reverse MR, and Bayesian model averaging (MR-BMA) were utilized to investigate the causal relationships. Furthermore, transcriptome-wide association study and colocalization analysis were deployed to pinpoint the underlying genes. Consequently, the MR study indicated a causal association between circulating neutrophils, natural killer T cells, plasmacytoid dendritic cells, and an elevated risk of periodontitis. MR-BMA analysis revealed that neutrophils were the primary contributors to periodontitis. The high-confidence genes S100A9 and S100A12, located on 1q21.3, could potentially serve as immunomodulatory targets for neutrophil-mediated periodontitis. These findings hold promise for early diagnosis, risk assessment, targeted prevention, and personalized treatment of periodontitis. Considering the marginal association observed in our study, further research is required to comprehend the biological underpinnings and ascertain the clinical relevance thoroughly.