Large-scale blood mitochondrial genome-wide study provides novel insights into mitochondrial disease-related traits

Background/Objectives Whole genome sequencing (WGS) from large cohorts enables the study of mitochondrial DNA (mtDNA) variation on human health. We aimed to investigate the influence of common, rare, and pathogenic mtDNA variants on 15 mitochondrial disease-related phenotypes. Methods Using WGS from 179,862 individuals from in the UK Biobank, we identified mtDNA variants using MitoHPC. We performed extensive association analyses with 15 mitochondrial disease-relevant phenotypes. We compared the results for the m.3243A>G variant with those from a clinically referred patient cohort. Results Of 15,881 mtDNA variants, 12 homoplasmic and one heteroplasmic variant had genome-wide significant associations. All homoplasmic variants increased aspartate aminotransferase level and three were novel, low frequency, variants (MAF∼0.002 and beta∼0.3 SD). Only m.3243A>G (MAF=0.0002) associated with diabetes (OR=5.6, 95%CI [3.2-9.9]), deafness (OR=12.3, 95%CI [6.2-24.4]) and heart failure (OR=39.5, 95%CI [9.76-160.1]). Multi-system disease risk and penetrance of all three traits increased with m.3243A>G level. Diabetes risk was further influenced by common nuclear genome variation. The penetrance of diabetes with m.3243A>G in the UK Biobank was lower than clinically referred patients, partly attributed to lower heteroplasmy. Of 73 pathogenic mitochondrial disease variants, most were rare in the population with low penetrance. Conclusion Our study highlights the utility of WGS for investigating mitochondrial genetics within a large, unselected population. We identified novel associations and demonstrated that pathogenic mitochondrial variants have lower penetrance in clinically unselected than clinically referred settings. m.3243A>G associated with mitochondrial-related phenotypes at higher heteroplasmy. Our findings suggest potential benefits of reporting incidentally identified m.3243A>G at high heteroplasmy levels. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This research has been conducted using the UK Biobank Resource. This work was carried out under UK Biobank project number 9072. The current work is funded by Diabetes UK (19/0005994 and 21/0006335), MRC (MR/T00200X/1) and Wellcome Trust Institutional Strategic Support Fund awarded to University of Exeter. KAP is funded by Wellcome Trust (219606/Z/19/Z), ATH is supported by Wellcome Trust Senior Investigator award (WT098395/Z/12/Z) and SJP is funded by the Wellcome Career Re-entry Fellowship (204709/Z/16/Z) and the Wellcome Centre for Mitochondrial Research (203105/Z/16/Z). The work is supported by the National Institute for Health Research (NIHR) Exeter Biomedical Research Centre, Exeter, UK. The Wellcome Trust, MRC and NIHR had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The views expressed are those of the author(s) and not necessarily those of the Wellcome Trust, Department of Health, NHS or NIHR. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics Committee of Wales Research Ethics Committee 5 gave ethical approval for this work (22/WA/0268) Ethics Committee of North West Centre for Research Ethics gave ethical approval for this work (11/NW/0328) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data supporting the findings of this study are available within the article and its Supplementary Data files. Additional information for reproducing the results described in the article is available upon reasonable request and subject to a data use agreement. The UK Biobank dataset is available from .