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Penetrance and expressivity of mitochondrial variants in a large clinically unselected population

Lookup NU author(s): Dr Roisin Boggan, Dr Sarah PickettORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© The Author(s) 2023. Published by Oxford University Press. Whole genome sequencing (WGS) from large clinically unselected cohorts provides a unique opportunity to assess the penetrance and expressivity of rare and/or known pathogenic mitochondrial variants in population. Using WGS from 179 862 clinically unselected individuals from the UK Biobank, we performed extensive single and rare variant aggregation association analyses of 15 881 mtDNA variants and 73 known pathogenic variants with 15 mitochondrial disease-relevant phenotypes. We identified 12 homoplasmic and one heteroplasmic variant (m.3243A>G) with genome-wide significant associations in our clinically unselected cohort. Heteroplasmic m.3243A>G (MAF = 0.0002, a known pathogenic variant) was associated with diabetes, deafness and heart failure and 12 homoplasmic variants increased aspartate aminotransferase levels including three low-frequency variants (MAF ~0.002 and beta~0.3 SD). Most pathogenic mitochondrial disease variants (n = 66/74) were rare in the population (<1:9000). Aggregated or single variant analysis of pathogenic variants showed low penetrance in unselected settings for the relevant phenotypes, except m.3243A>G. Multi-system disease risk and penetrance of diabetes, deafness and heart failure greatly increased with m.3243A>G level ≥ 10%. The odds ratio of these traits increased from 5.61, 12.3 and 10.1 to 25.1, 55.0 and 39.5, respectively. Diabetes risk with m.3243A>G was further influenced by type 2 diabetes genetic risk. Our study of mitochondrial variation in a large-unselected population identified novel associations and demonstrated that pathogenic mitochondrial variants have lower penetrance in clinically unselected settings. m.3243A>G was an exception at higher heteroplasmy showing a significant impact on health making it a good candidate for incidental reporting.


Publication metadata

Author(s): Cannon SJ, Hall T, Hawkes G, Colclough K, Boggan RM, Wright CF, Pickett SJ, Hattersley AT, Weedon MN, Patel KA

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2024

Volume: 33

Issue: 5

Pages: 465-474

Print publication date: 01/03/2024

Online publication date: 21/11/2023

Acceptance date: 10/11/2023

Date deposited: 05/03/2024

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press

URL: https://doi.org/10.1093/hmg/ddad194

DOI: 10.1093/hmg/ddad194

Data Access Statement: 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 https://biobank.ctsu.ox.ac.uk.

PubMed id: 37988592


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Funding

Funder referenceFunder name
19/0005994
204709/Z/16/ZWellcome Trust
21/0006335
219606/Z/19/Z
203105/Z/16/ZWellcome Trust
Diabetes UK
National Institute for Health Research (NIHR) Exeter Biomedical Research Centre
UK Biobank Resource
WT098395/Z/12/Z
Wellcome Trust Institutional Strategic Support Fund

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