Comprehensive and integrative analyses identify TYW5 as a schizophrenia risk gene

Background Identifying the causal genes at the risk loci and elucidating their roles in schizophrenia (SCZ) pathogenesis remain significant challenges. To explore risk variants associated with gene expression in the human brain and to identify genes whose expression change may contribute to the susceptibility of SCZ, here we report a comprehensive integrative study on SCZ. Methods We systematically integrated the genetic associations from a large-scale SCZ GWAS (N = 56,418) and brain expression quantitative trait loci (eQTL) data (N = 175) using a Bayesian statistical framework (Sherlock) and Summary data-based Mendelian Randomization (SMR). We also measured brain structure of 86 first-episode antipsychotic-naive schizophrenia patients and 152 healthy controls with the structural MRI. Results Both Sherlock (P = 3. 38 x 10(-6)) and SMR (P = 1. 90 x 10(-8)) analyses showed that TYW5 mRNA expression was significantly associated with risk of SCZ. Brain-based studies also identified a significant association between TYW5 protein abundance and SCZ. The single-nucleotide polymorphism rs203772 showed significant association with SCZ and the risk allele is associated with higher transcriptional level of TYW5 in the prefrontal cortex. We further found that TYW5 was significantly upregulated in the brain tissues of SCZ cases compared with controls. In addition, TYW5 expression was also significantly higher in neurons induced from pluripotent stem cells of schizophrenia cases compared with controls. Finally, combining analysis of genotyping and MRI data showed that rs203772 was significantly associated with gray matter volume of the right middle frontal gyrus and left precuneus. Conclusions We confirmed that TYW5 is a risk gene for SCZ. Our results provide useful information toward a better understanding of the genetic mechanism of TYW5 in risk of SCZ.

Automated summary

This study identified TYW5 as a risk gene for schizophrenia (SCZ) through a comprehensive analysis of genetic associations and brain expression data. TYW5 mRNA expression was significantly associated with SCZ risk, and TYW5 protein abundance in the brain was also linked to SCZ. Further analysis revealed elevated TYW5 expression in the brain tissues and neurons of SCZ cases compared to controls. Additionally, a genetic variant associated with higher TYW5 expression was found to be associated with specific brain structural changes. These findings provide valuable insights into the genetic mechanism of TYW5 in SCZ risk.