AN INTERNATIONAL, CASE-CASE META-ANALYSIS OF TREATMENT RESISTANT SCHIZOPHRENIA VERSUS NON-TREATMENT RESISTANT SCHIZOPHRENIA

Treatment resistant schizophrenia (TRS) affects up to one-third of individuals diagnosed with schizophrenia and is associated with poorer clinical outcomes and a substantial healthcare burden. Despite its prevalence, the biological mechanisms underlying TRS remain unclear. Here, we present the results of an international case-case genome-wide meta-analysis comparing individuals with TRS to those with non-treatment resistant schizophrenia (non-TRS), conducted as a secondary analysis of the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC). The current analysis includes approximately 41,500 individuals from 35 cohorts worldwide. We report the identification of a genome-wide significant locus associated with TRS, with the lead variant mapping to COL19A1. This represents the first genome-wide significant finding specific to TRS, offering early insights into its potential biological distinctiveness. SNP-heritability for TRS is estimated at approximately 3–4%, supporting the hypothesis that TRS has a partially distinct genetic architecture compared to non-TRS schizophrenia. In collaboration with the Horizon Europe-funded Psych-STRATA grant, we aim to expand the meta-analysis with an additional 5,000–10,000 individuals, further enhancing power for locus discovery and enabling deeper biological interpretation. Planned downstream analyses include gene-set enrichment testing, polygenic risk scoring, and genetic correlation analyses with relevant psychiatric and pharmacological traits. As part of the broader Psych-STRATA program, future work will also include a transdiagnostic meta-analysis of treatment resistance across major psychiatric disorders, as well as extensive comparative analyses of treatment resistance in schizophrenia, bipolar disorder, and major depressive disorder. These efforts aim to uncover both disorder-specific and shared genetic mechanisms underlying treatment resistance, ultimately supporting the development of more targeted and effective interventions.