GWAS and ExWAS of blood Mitochondrial DNA copy number identifies 71 loci and highlights a potential causal role in dementia
- McMaster University, Canada
- Population Health Research Institute, Canada
- Hamilton Health Sciences, Canada
- National University of Ireland, Galway, Ireland
- 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.
-
UK Biobankhttps://www.ukbiobank.ac.uk.
Article and author information
Author details
Pedrum Mohammadi-Shemirani
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.
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
-
- 4,809
- views
-
- 677
- downloads
-
- 63
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
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)
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
Further reading
-
- Cancer Biology
- Genetics and Genomics
The expression of eukaryotic genes relies on the precise 3'-terminal cleavage and polyadenylation of newly synthesized pre-mRNA transcripts. Defects in these processes have been associated with various diseases, including cancer. While cancer-focused sequencing studies have identified numerous driver mutations in protein-coding sequences, noncoding drivers – particularly those affecting the cis-elements required for pre-mRNA cleavage and polyadenylation – have received less attention. Here, we systematically analysed somatic mutations affecting 3'UTR polyadenylation signals in human cancers using the Pan-Cancer Analysis of Whole Genomes (PCAWG) dataset. We found a striking enrichment of cancer-specific somatic mutations that disrupt strong and evolutionarily conserved cleavage and polyadenylation signals within tumour suppressor genes. Further bioinformatics and experimental analyses conducted as a part of our study suggest that these mutations have a profound capacity to downregulate the expression of tumour suppressor genes. Thus, this work uncovers a novel class of noncoding somatic mutations with significant potential to drive cancer progression.
-
- Developmental Biology
- Genetics and Genomics
O-GlcNAcylation is an essential intracellular protein modification mediated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Recently, missense mutations in OGT have been linked to intellectual disability, indicating that this modification is important for the development and functioning of the nervous system. However, the processes that are most sensitive to perturbations in O-GlcNAcylation remain to be identified. Here, we uncover quantifiable phenotypes in the fruit fly Drosophila melanogaster carrying a patient-derived OGT mutation in the catalytic domain. Hypo-O-GlcNAcylation leads to defects in synaptogenesis and reduced sleep stability. Both these phenotypes can be partially rescued by genetically or chemically targeting OGA, suggesting that a balance of OGT/OGA activity is required for normal neuronal development and function.
