biostudies-literatureYang SYNational Institute of Neurological Disorders and StrokeUK Biobank ResourceCommon Fund of the Office of the Director of the National Institutes of HealthMedical Research CouncilNational Heart, Lung, and Blood InstituteNHLBI NIH HHSNational Cancer InstituteNational Institute of Mental HealthNational Institutes of HealthNational Human Genome Research InstituteNational Institute on Drug Abuse349-358https://www.ebi.ac.uk/biostudies/studies/S-EPMC7919448biostudies-literatureUnknown31(3)Mitochondrial DNA copy number (mtDNA-CN) is a proxy for mitochondrial function and is associated with aging-related diseases. However, it is unclear how mtDNA-CN measured in blood can reflect diseases that primarily manifest in other tissues. Using the Genotype-Tissue Expression Project, we interrogated relationships between mtDNA-CN measured in whole blood and gene expression from whole blood and 47 additional tissues in 419 individuals. mtDNA-CN was significantly associated with expression of 700 genes in whole blood, including nuclear genes required for mtDNA replication. Significant enrichment was observed for splicing and ubiquitin-mediated proteolysis pathways, as well as target genes for the mitochondrial transcription factor NRF1. In nonblood tissues, there were more significantly Genome researchBlood-derived mitochondrial DNA copy number is associated with gene expression across multiple tissues and is predictive for incident neurodegenerative disease.PMC7919448MC_PC_1722817731R01 HL131573R01HL13573MC_QA137853R01 HL144569R01HL144569Longchamps RJGuallar EArking DEPillalamarri VKO'Rourke BCastellani CAYang SYfalseBlood-derived mitochondrial DNA copy number is associated with gene expression across multiple tissues and is predictive for incident neurodegenerative disease.Mitochondrial DNA copy number (mtDNA-CN) is a proxy for mitochondrial function and is associated with aging-related diseases. However, it is unclear how mtDNA-CN measured in blood can reflect diseases that primarily manifest in other tissues. Using the Genotype-Tissue Expression Project, we interrogated relationships between mtDNA-CN measured in whole blood and gene expression from whole blood and 47 additional tissues in 419 individuals. mtDNA-CN was significantly associated with expression of 700 genes in whole blood, including nuclear genes required for mtDNA replication. Significant enrichment was observed for splicing and ubiquitin-mediated proteolysis pathways, as well as target genes for the mitochondrial transcription factor NRF1. In nonblood tissues, there were more significantly 2021-01-01T00:00:00Z2021 Mar2026-05-02T11:36:55.744Z2022-02-11T10:06:14.578ZS-EPMC79194483344141510.1101/gr.269381.120