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.
Download links
Further reading
-
- Genetics and Genomics
Resistance to anthelmintics, particularly the macrocyclic lactone ivermectin (IVM), presents a substantial global challenge for parasite control. We found that the functional loss of an evolutionarily conserved E3 ubiquitin ligase, UBR-1, leads to IVM resistance in Caenorhabditis elegans. Multiple IVM-inhibiting activities, including viability, body size, pharyngeal pumping, and locomotion, were significantly ameliorated in various ubr-1 mutants. Interestingly, exogenous application of glutamate induces IVM resistance in wild-type animals. The sensitivity of all IVM-affected phenotypes of ubr-1 is restored by eliminating proteins associated with glutamate metabolism or signaling: GOT-1, a transaminase that converts aspartate to glutamate, and EAT-4, a vesicular glutamate transporter. We demonstrated that IVM-targeted GluCls (glutamate-gated chloride channels) are downregulated and that the IVM-mediated inhibition of serotonin-activated pharynx Ca2+ activity is diminished in ubr-1. Additionally, enhancing glutamate uptake in ubr-1 mutants through ceftriaxone completely restored their IVM sensitivity. Therefore, UBR-1 deficiency-mediated aberrant glutamate signaling leads to ivermectin resistance in C. elegans.
-
- Genetics and Genomics
Osteoporosis, characterized by reduced bone density and strength, increases fracture risk, pain, and limits mobility. Established therapies of parathyroid hormone (PTH) analogs effectively promote bone formation and reduce fractures in severe osteoporosis, but their use is limited by potential adverse effects. In the pursuit of safer osteoporosis treatments, we investigated R25CPTH, a PTH variant wherein the native arginine at position 25 is substituted by cysteine. These studies were prompted by our finding of high bone mineral density in a hypoparathyroidism patient with the R25C homozygous mutation, and we explored its effects on PTH type-1 receptor (PTH1R) signaling in cells and bone metabolism in mice. Our findings indicate that R25CPTH(1–84) forms dimers both intracellularly and extracellularly, and the synthetic dimeric peptide, R25CPTH(1–34), exhibits altered activity in PTH1R-mediated cyclic AMP (cAMP) response. Upon a single injection in mice, dimeric R25CPTH(1–34) induced acute calcemic and phosphaturic responses comparable to PTH(1–34). Furthermore, repeated daily injections increased calvarial bone thickness in intact mice and improved trabecular and cortical bone parameters in ovariectomized (OVX) mice, akin to PTH(1–34). The overall results reveal a capacity of a dimeric PTH peptide ligand to activate the PTH1R in vitro and in vivo as PTH, suggesting a potential path of therapeutic PTH analog development.
