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Using WGS from 179\u2009862 clinically unselected individuals from the UK Biobank, we performed extensive single and rare variant aggregation association analyses of 15\u2009881 mtDNA variants and 73 known pathogenic variants with 15 mitochondrial disease-relevant phenotypes. We identified 12 homoplasmic and one heteroplasmic variant (m.3243A&amp;gt;G) with genome-wide significant associations in our clinically unselected cohort. Heteroplasmic m.3243A&amp;gt;G (MAF\u2009=\u20090.0002, 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\u2009=\u200966\/74) were rare in the population (&amp;lt;1:9000). Aggregated or single variant analysis of pathogenic variants showed low penetrance in unselected settings for the relevant phenotypes, except m.3243A&amp;gt;G. Multi-system disease risk and penetrance of diabetes, deafness and heart failure greatly increased with m.3243A&amp;gt;G level \u2265\u200910%. 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&amp;gt;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&amp;gt;G was an exception at higher heteroplasmy showing a significant impact on health making it a good candidate for incidental reporting.<\/jats:p>","DOI":"10.1093\/hmg\/ddad194","type":"journal-article","created":{"date-parts":[[2023,11,13]],"date-time":"2023-11-13T09:15:45Z","timestamp":1699866945000},"page":"465-474","source":"Crossref","is-referenced-by-count":16,"title":["Penetrance and expressivity of mitochondrial variants in a large clinically unselected population"],"prefix":"10.1093","volume":"33","author":[{"given":"Stuart J","family":"Cannon","sequence":"first","affiliation":[{"name":"Department of Clinical and Biomedical Sciences, University of Exeter , 79 Heavitree Road, Exeter, EX2 4TH , United 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M","family":"Boggan","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research , Translational and Clinical Research Institute, , Framlington Place, Newcastle upon Tyne, NE2 4HH , United Kingdom"},{"name":"Newcastle University , Translational and Clinical Research Institute, , Framlington Place, Newcastle upon Tyne, NE2 4HH , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline F","family":"Wright","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biomedical Sciences, University of Exeter , 79 Heavitree Road, Exeter, EX2 4TH , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah J","family":"Pickett","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research , Translational and Clinical Research Institute, , Framlington Place, Newcastle upon Tyne, NE2 4HH , United Kingdom"},{"name":"Newcastle University , Translational and Clinical Research Institute, , Framlington Place, Newcastle upon Tyne, NE2 4HH , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew T","family":"Hattersley","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biomedical Sciences, University of Exeter , 79 Heavitree Road, Exeter, EX2 4TH , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael N","family":"Weedon","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biomedical Sciences, University of Exeter , 79 Heavitree Road, Exeter, EX2 4TH , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kashyap A","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biomedical Sciences, University of Exeter , 79 Heavitree Road, Exeter, EX2 4TH , United 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