Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Canada; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada; Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton Health Sciences, Hamilton, Canada
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada; Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton Health Sciences, Hamilton, Canada; Thrombosis and Atherosclerosis Research Institute, Hamilton, Canada
Nicolas Perrot
Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton Health Sciences, Hamilton, Canada
Walter Nelson
Centre for Data Science and Digital Health, Hamilton Health Sciences, Hamilton, Canada
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada; Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton Health Sciences, Hamilton, Canada
Sukrit Narula
Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton Health Sciences, Hamilton, Canada; Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada
Ricky Lali
Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton Health Sciences, Hamilton, Canada; Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada
Irfan Khan
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada; Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton Health Sciences, Hamilton, Canada
Mohammad Khan
Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton Health Sciences, Hamilton, Canada; Department of Medicine, McMaster University, Michael G. DeGroote School of Medicine, Hamilton, Canada
Conor Judge
Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton Health Sciences, Hamilton, Canada; National University of Ireland, Galway, Galway, Ireland
Tafadzwa Machipisa
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada; Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton Health Sciences, Hamilton, Canada; Department of Medicine, University of Cape Town & Groote Schuur Hospital, Cape Town, South Africa; Hatter Institute for Cardiovascular Diseases Research in Africa (HICRA) & Cape Heart Institute (CHI), Department of Medicine, University of Cape Town, Cape Town, South Africa
Nathan Cawte
Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton Health Sciences, Hamilton, Canada
Martin O'Donnell
Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton Health Sciences, Hamilton, Canada; National University of Ireland, Galway, Galway, Ireland
Marie Pigeyre
Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton Health Sciences, Hamilton, Canada; Department of Medicine, McMaster University, Michael G. DeGroote School of Medicine, Hamilton, Canada
Loubna Akhabir
Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton Health Sciences, Hamilton, Canada; Department of Medicine, McMaster University, Michael G. DeGroote School of Medicine, Hamilton, Canada
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Canada; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada; Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton Health Sciences, Hamilton, Canada; Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada; Department of Medicine, McMaster University, Michael G. DeGroote School of Medicine, Hamilton, Canada
Background: Mitochondrial DNA copy number (mtDNA-CN) is an accessible blood-based measurement believed to capture underlying mitochondrial (MT) 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 ‘automatic mitochondrial copy (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 MT phenotypes. Results: Overall, genetic analyses identified 71 loci for mtDNA-CN, which implicated several genes involved in rare mtDNA depletion disorders, deoxynucleoside triphosphate (dNTP) metabolism, and the MT 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=2.6 × 10-19), 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=2.7 × 10-8). 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=7.5 × 10-4). Conclusions: Altogether, our genetic findings indicate that mtDNA-CN is a complex biomarker reflecting specific MT 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)
