Mitochondrial DNA copy number (mtDNA-CN) measured from blood specimens is a minimally invasive marker of mitochondrial function that exhibits both inter-individual and intercellular variation. To identify genes involved in regulating mitochondrial function, we performed a genome-wide association study (GWAS) in 465,809 White individuals from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (UKB). We identified 133 SNPs with statistically significant, independent effects associated with mtDNA-CN across 100 loci. A combination of fine-mapping, variant annotation, and co-localization analyses was used to prioritize genes within each of the 133 independent sites. Putative causal genes were enriched for known mitochondrial DNA depletion syndromes (p = 3.09 × 10–15) and the gene ontology (GO) terms for mtDNA metabolism (p = 1.43 × 10–8) and mtDNA replication (p = 1.2 × 10–7). A clustering approach leveraged pleiotropy between mtDNA-CN associated SNPs and 41 mtDNA-CN associated phenotypes to identify functional domains, revealing three distinct groups, including platelet activation, megakaryocyte proliferation, and mtDNA metabolism. Finally, using mitochondrial SNPs, we establish causal relationships between mitochondrial function and a variety of blood cell-related traits, kidney function, liver function and overall (p = 0.044) and non-cancer mortality (p = 6.56 × 10–4).

Blood-derived mitochondrial DNA copy number (mtDNA-CN) is a minimally invasive proxy measure of mitochondrial function that exhibits both inter-individual and intercellular variation. While mtDNA-CN has been previously associated with various aging-related diseases, little is known about the genetic factors that may modulate this phenotype. We performed a genome-wide association study (GWAS) in 465,809 individuals of White (European) ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (UKB). We identified 129 SNPs with statistically significant, independent effects associated with mtDNA-CN across 96 loci. A combination of fine-mapping, variant annotation, co-localization, and gene set enrichment analyses were used to prioritize genes within each of the 129 independent sites. Putative causal genes were enriched for known mitochondrial DNA depletion syndromes (p = 3.09 × 10−15) and the gene ontology (GO) terms for mtDNA metabolism (p = 1.43 × 10−8) and mtDNA replication (p = 1.2 × 10−7). A clustering approach leveraged pleiotropy between mtDNA-CN associated SNPs and 42 mtDNA-CN associated phenotypes to identify functional domains, revealing five distinct groups, including platelet activation, megakaryocyte proliferation, and mtDNA metabolism. In conclusion, in a GWAS of mtDNA-CN conducted in >450,000 individuals, we identified SNPs within loci that implicate novel pathways that provide a framework for defining the underlying mechanisms involved in genetic control of mtDNA-CN.