Abstract
Numerous observational studies have highlighted associations between mitochondrial dysfunction and schizophrenia (SCZ), yet the causal relationship remains elusive. This study aims to elucidate the causal link between mitochondria-associated proteins and SCZ. We used summary data from a genome-wide association study (GWAS) of 66 mitochondria-associated proteins in 3,301 individuals from Europe, as well as a GWAS on the large, multi-ethnic ancestry of SCZ, involving 76,755 cases and 243,649 controls. We conducted bidirectional two-sample Mendelian randomization (MR) analyses, with inverse variance weighting (IVW) as the primary method. To account for multi-directionality and ensure robustness, we included MR-Egger, weighted median (WM), weighted mode, and simple mode methods as supplementary sensitivity analyses. Moreover, we explored the GWAS catalog and the Drug-Gene Interaction Database (DGIdb) to identify and evaluate potential therapeutic targets. MR analysis revealed significant genetically determined causal associations between ETHE1 (OR: 1.06), SOD (OR: 0.97), CALU3 (OR: 1.03), and C1QBP (OR: 1.05) and SCZ. According to the reverse MR analysis, a causal relationship was shown between SCZ and CA5A (OR: 1.09), DLD (OR: 1. 08), AIF1 (OR: 0.93), SerRS (OR: 0.93) and MULA of NFKB1 (OR: 0.77). After conducting the gene-drug analysis, HRG, F12, GPLD1, C1R, BCHE, CFH, PON1, and CA5A were identified as promising therapeutic targets. This present study reveals a significant causal relationship between mitochondria-associated proteins and SCZ, offering valuable insights into the disease's pathogenicity and identifying potential therapeutic targets for drug development.