Table 1_Brain imaging data and summary data-based Mendelian randomization analysis reveal the impact of multiorgan aging on schizophrenia.xlsx

AimThe 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.
MethodsWe 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.
ResultsWe 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.
ConclusionsThis 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.

研究目的：精神分裂症（schizophrenia, SZ）的不良健康结局主要由其他非神经系统疾病的高患病率所驱动。除脑衰老加速外，精神分裂症患者还表现出全身性衰老的特征。然而，多系统衰老与精神分裂症之间潜在的因果或生物学机制仍未明确。
研究方法：本研究从既往两阶段全基因组关联研究（genome-wide association study, GWAS）、GeneCards数据库以及基因型-组织表达（Genotype-Tissue Expression, GTEx）项目中获取了精神分裂症相关单核苷酸多态性（single-nucleotide polymorphism, SNP）集合、衰老基因数据，以及大脑皮层及其他组织的组织特异性顺式表达数量性状位点（cis-expression quantitative trait locus, cis-eQTL）数据。我们采用组织特异性孟德尔随机化（Mendelian randomization, MR）分析阐明衰老相关基因的组织特异性表达模式，并通过基于汇总数据的孟德尔随机化（summary data-based MR, SMR）方法筛选出与精神分裂症发病风险相关的组织特异性衰老相关基因。通过富集分析，我们明确了这些组织特异性cis-eQTL可能通过衰老通路影响精神分裂症的潜在机制。最后，在临床患者队列中探讨了筛选得到的关键衰老相关基因与大脑预测年龄差（predicted age difference, PAD）之间的关联。
研究结果：本研究发现，包括α-突触核蛋白（synuclein alpha, SNCA）、血管紧张素转换酶（angiotensin I converting enzyme, ACE）、BRCA1 DNA修复相关蛋白（BRCA1 DNA repair-associated, BRCA1）、MutL同源物1（MutL homolog 1, MLH1）、血管内皮生长因子A（vascular endothelial growth factor A, VEGFA）、微管相关蛋白tau（microtubule-associated protein tau, MAPT）以及年龄相关性黄斑变性易感蛋白2（age-related maculopathy susceptibility 2, ARMS2）在内的组织特异性衰老基因的表达，可能与精神分裂症的发生相关。组织特异性cis-eQTL可能通过衰老通路影响精神分裂症的发病风险。BRCA1高表达组的大脑预测年龄差显著高于低表达组。
研究结论：本研究为阐明精神分裂症与多器官系统衰老之间的关联提供了重要线索，并加深了学界对多组织特异性衰老相关基因与精神分裂症关联的认知。