Subtyping Schizophrenia Using Psychiatric Polygenic Scores

BackgroundSubtyping schizophrenia can disentangle heterogeneity and help with treatment decision- making. However, current schizophrenia subtypes have not demonstrated adequate clinical utility, limited by sample size, suboptimal clustering methods, and choice of clustering input. Polygenic scores (PGS) reflect the genetic risk of phenotypes including comorbidities and are available before treatment, making them candidate clustering input. MethodsWe derived PGS for schizophrenia, autism spectrum disorder, bipolar disorder type-1, depression, and intelligence in 4,915 schizophrenia cases with register linkage. We randomly divided the sample into discovery and replication partitions and applied a novel clustering workflow on both: preprocessing PGS, feature extraction with uniform manifold approximation and projection (UMAP), and clustering with density-based spatial clustering of applications with noise (DBSCAN). After replication, we re-performed clustering on the entire sample and evaluated treatment-relevant variables of medication and hospitalization (extracted from registers) across clusters. OutcomesWe identified five well-replicated PGS clusters. Cluster 1 (26% of entire sample) with generally lower PGS, had the least use of antipsychotics (including clozapine), and fewer outpatient visits. Cluster 2 (48%) with generally higher PGS, especially schizophrenia PGS, had more prescriptions of antipsychotics including clozapine and longer treatment with clozapine. Each featured by specific PGS, clusters 3 (high IQ-PGS, 11%), 4 (high ASD-PGS, 8%), 5 (high BIP-PGS, 7%) showed sub-threshold level significance in the corresponding phenotypic measures but did not differ significantly in the treatment-relevant variables. Solely categorizing the patients with SCZ-PGS did not generate any significant patterns in the phenotypic and treatment-relevant variables. InterpretationThe results suggest that combinations of PGS of brain disorders and traits can provide clinically relevant clusters, offering a direction for future research on schizophrenia subtyping. Future replications in independent samples are required. The workflow can be generalized to other disorders and with mechanism-informed PGS.