Genetic insights into the role of mitochondria-related genes in mental disorders: An integrative multi-omics analysis

Background: Mitochondrial dysfunction has been implicated in the development of mental disorders, yet the underlying mechanisms remain unclear. In this study, we employed summary-data-based Mendelian randomization (SMR) analysis to explore the associations between mitochondrial-related genes and seven common mental disorders across gene expression, DNA methylation, and protein levels. Method: Summary statistics from genome-wide association studies were used for seven mental disorders, including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, anxiety, bipolar disorder, major depressive disorder, post-traumatic stress disorder, and schizophrenia (SCZ). Instrumental variables associated with 1136 mitochondria-related genes were derived from summary statistics for DNA methylation, gene expression, and protein quantitative trait loci. SMR analyses and colocalization analyses were then conducted across these three biological levels to explore the associations with each of the seven mental disorders. Results: We identified mitochondria-related genes associated with mental disorders with multi-omics evidence: RMDN1 for ADHD, and ACADVL, ETFA, MMAB, and PPA2 for SCZ. Specifically, an increase of one standard deviation in the level of RMDN1 was linked to a 12 % decrease in the risk of developing ADHD (OR = 0.88, 95 % CI: 0.83-0.94). Increased levels of ETFA (OR = 1.79, 95 % CI: 1.24-2.60) and MMAB (OR = 1.10, 95 % CI: 1.05-1.16) were significantly associated with increased risk of SCZ. Conversely, high levels of ACADVL (OR = 0.50, 95 % CI: 0.33-0.77) and PPA2 (OR = 0.68, 95 % CI: 0.55-0.85) were associated with a reduced risk of SCZ. Conclusions: These findings suggested that dysfunction in mitochondria-related genes may underlie the molecular mechanisms of ADHD and SCZ, providing novel biomarkers for diagnosis and therapeutic interventions.