Powering the mind: deciphering the shared genetic architecture between mitochondrial DNA copy number and major...

Mitochondrial DNA copy number (mtDNA-CN) reflects mitochondrial function and has been associated with several psychiatric disorders. However, the shared genetic architecture between mtDNA-CN and psychiatric conditions remains largely unexplored. Utilizing the largest available genome-wide association study (GWAS) summary statistics from individuals of European ancestry, we systematically investigated the shared genetic architecture between mtDNA-CN and five major psychiatric disorders, including attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ). Specifically, we assessed genetic overlap at the global, regional, and variant levels. In addition, gene expression analyses were performed to identify genes whose predicted expression was associated with both mtDNA-CN and psychiatric traits. Functional enrichment analyses were conducted to characterize the biological functions underlying the shared genes. Significant global-level genetic overlap was observed between mtDNA-CN and all five psychiatric disorders. Regional analyses identified four genomic regions with high pleiotropic probability shared between mtDNA-CN and ADHD, BD, and SCZ. At the variant level, 30 lead variants were detected, corresponding to 30 independent loci jointly associated with mtDNA-CN and psychiatric traits. These loci were mapped to 305 unique genes, among which 87 genes exhibited significant associations between their predicted expression levels and both mtDNA-CN and psychiatric disorders. Functional enrichment highlighted neurodevelopmental and ubiquitin-related pathways, with significant downregulation of shared genes in key brain regions. These findings provide comprehensive evidence for shared genetic mechanisms linking mitochondrial function and psychiatric disorders, highlighting mitochondrial dysfunction as a promising target for future therapy.