Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation
Longchamps RJ., Yang SY., Castellani CA., Shi W., Lane J., Grove ML., Bartz TM., Sarnowski C., Liu C., Burrows K., Guyatt AL., Gaunt TR., Kacprowski T., Yang J., De Jager PL., Yu L., Bergman A., Xia R., Fornage M., Feitosa MF., Wojczynski MK., Kraja AT., Province MA., Amin N., Rivadeneira F., Tiemeier H., Uitterlinden AG., Broer L., Van Meurs JBJ., Van Duijn CM., Raffield LM., Lange L., Rich SS., Lemaitre RN., Goodarzi MO., Sitlani CM., Mak ACY., Bennett DA., Rodriguez S., Murabito JM., Lunetta KL., Sotoodehnia N., Atzmon G., Ye K., Barzilai N., Brody JA., Psaty BM., Taylor KD., Rotter JI., Boerwinkle E., Pankratz N., Arking DE.
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).