Brain imaging data and summary data-based Mendelian randomization analysis reveal the impact of multiorgan aging on schizophrenia.

The adverse health outcomes of schizophrenia (SZ) are largely driven by the high prevalence of other non-neurological diseases. In addition to accelerated brain aging, patients with SZ also exhibit signs of systemic aging. However, the potential causal or biological mechanisms between multisystem aging and schizophrenia remain unknown. We obtained SZ-associated single-nucleotide polymorphism (SNP) sets, aging gene data, and tissue-specific cis-expression quantitative trait locus (cis-eQTL) data of the cerebral cortex and other tissues from a previous two-stage genome-wide association study (GWAS), GeneCards database, and Genotype-Tissue Expression (GTEx) project. We employed tissue-specific Mendelian randomization (MR) analysis to elucidate the tissue-specific expression patterns of aging-related genes, and used the summary data-based MR (SMR) approach to obtain tissue aging-related genes associated with the risk of SZ development. We identified the potential aging-related pathways through which these tissue-specific cis-eQTLs may affect SZ using enrichment analyses. Finally, we explored the relationship between the identified crucial aging-related genes and predicted age difference (PAD) of the brain in our clinical patients. We found that the expression of tissue-specific aging genes, including synuclein alpha (SNCA), angiotensin I converting enzyme (ACE), BRCA1 DNA repair-associated (BRCA1), MutL homolog 1 (MLH1), vascular endothelial growth factor A (VEGFA), microtubule-associated protein tau (MAPT), and age-related maculopathy susceptibility 2 (ARMS2), may affect SZ. The tissue-specific cis-eQTL may influence SZ through aging pathways. The brain PAD was significantly higher in the high-expression group of BRCA1 than in the low-expression group. This study provides valuable clues to understand the link between SZ and multiorgan system aging and improves the current understanding of multiple tissue-specific aging-related genes with SZ.