부산대학교 도서관

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 x 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 x 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 x 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. [ABSTRACT FROM AUTHOR]