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Approved Research

Determining the carrier frequency of pathogenic heteroplasmic mitochondrial DNA variations in the UK Biobank cohort and their potential contribution to common traits.

Principal Investigator: Dr Sarah Pickett
Approved Research ID: 40518
Approval date: July 29th 2021

Lay summary

Mitochondria are uniquely controlled by both the nuclear genome and their own 16.6kb, circular genome that is present in multiple copies per cell and is maternally-inherited. Pathogenic sequence variation within mtDNA can give rise to mitochondrial diseases, which are a group of disorders that are highly clinically variable and can affect individuals at any age.

It is possible for more than one species of mtDNA molecule to be present within a cell; this is known as heteroplasmy. Many pathogenic mtDNA variants are heteroplasmic meaning that the level of variant present within an individual can range from 0-100%. Gaining an accurate measurement of the level within an individual is important for predicting their likely disease burden. We hypothesise that low levels could be associated with more common clinical phenotypes.

The current computational method for determining genetic variation within UK Biobank samples is tailored towards nuclear DNA variants and not heteroplasmic mtDNA variants. As a result, low levels of pathogenic mtDNA variants may not be detected.

We aim to use the raw fluorescent probe data from the UK Biobank genotyping array and whole exome sequencing data to determine the level of heteroplasmic mtDNA variants within individuals. This will allow us to determine the frequency of pathogenic mtDNA variants in the UK Biobank cohort and to test whether they are associated with phenotypes related to those seen in mitochondrial disease, such as diabetes, deafness, psychiatric disorders, migraine, epilepsy and cardiovascular disease. This will enhance our understanding of the aetiology of associated common phenotypes and allow us to re-evaluate the likely mechanism by which these variants cause mitochondrial disease.