Genetic Architecture of Schizophrenia Clinical Subtypes

Background Clinical heterogeneity in schizophrenia (SZ) presents a significant challenge to genetic research, as diverse symptom profiles may stem from distinct genetic risk factors. Although previous studies have stratified patients into symptom-based subtypes, and preliminary evidence suggests the presence of distinct architectures, these findings remain limited. This study aimed to identify the clinically defined SZ subtypes and investigate the genetic architecture underlying different subtypes. Methods In a Chinese Han cohort of 2,410 SZ patients, we applied K-means cluster analysis to symptom profiles to identify clinical subtypes. The identified subtype structure was validated in an independent cohort of 480 patients. Subsequently, subtype-specific genome-wide association studies (GWAS) were conducted to identify genetic risk loci associated with individual subtypes. Results Three stable subtypes were identified: Cluster-L (low severity), Cluster-S (severe), and Cluster-N (predominant negative symptoms). Reproducibility of this classification was confirmed in the independent cohort. The three subtypes also exhibited significantly different symptom network structures. In GWAS analysis, A total of four genome-wide significant loci were detected, including a Cluster-N–specific locus within the CNTN2 gene (lead SNP rs3767295, P = 5.30E-10, OR = 0.62). Gene-based analyses revealed additional risk genes unique to particular subtypes. Moreover, subtype-specific patterns emerged in both pathway-specific polygenic risk scores (pPRS) and cell type–specific PRS (ctPRS). Conclusions These findings underscore the value of patient stratification in improving statistical power to detect subtype-specific risk loci. They further demonstrate that SZ patients with distinct symptom profiles harbor differential genetic liabilities involving diverse biological pathways and cell types.