43. RARE CODING VARIATION IDENTIFIES NEW GENETIC CONTRIBUTORS TO SCHIZOPHRENIA

Background Schizophrenia (SCZ) is a complex and severe psychiatric disorder characterized by a heterogeneous combination of symptoms, including hallucinations, delusions, and cognitive impairment. Rare variant association studies (RVAS) of coding variants are a powerful way to identify genes associated with schizophrenia. The Schizophrenia Exome Meta-Analysis (SCHEMA) Consortium is a global collaboration dedicated to identifying genes associated with schizophrenia by studying ultra-rare, gene-disrupting mutations. Methods The SCHEMA 2.0 case-control analysis investigated exome-wide, gene set, and individual gene-level rare variant association analysis on 87,959 schizophrenia cases and 150,587 control exomes. We restricted gene-level analyses to protein truncating variants (PTVs) and damaging missense variants identified through integrating multiple missense annotations. We then evaluated the gene expression patterns and cellular functions among the 5% false discovery rate (FDR) significant genes. Finally, we examined the phenotypic outcomes among SCHEMA 2.0 PTV carriers in the All of Us database. Results We identify 16 genes at exome-wide significance: SETD1A, ZMYM2, HERC1, RB1CC1, SCAF1, XPO7, SP4, FYN, PPP3CA, CUL1, HDAC9, JARID2, ATP9A, PTK2, STAG1, and SCN2A, and an additional 24 at an FDR 5%. Notably, we report an FDR 5% association with CHRM4 (cholinergic receptor muscarinic 4), one of the targets of the recently approved antipsychotic xanomeline/trospium (brand name: Cobenfy). Cases carrying ultra-rare, damaging variants, primarily PTVs and deleterious missense mutations, show strong enrichment in constrained genes and with consistent effects across ancestries. Half of the exome-wide significant genes overlap with those implicated in developmental delay, autism, or bipolar disorder, underscoring shared neurodevelopmental risk. All genes identified are highly expressed in excitatory and inhibitory neurons, and their expression patterns span diverse developmental stages. Functionally, the identified genes implicate chromatin regulation, protein degradation, and synaptic function. In a PheWAS of PTV carrier status in the All of Us data, we identified 13 phenome-wide significant associations, including with personality disorders, bipolar, anxiety, and asthma. Discussion This study represents the largest rare coding variant association analysis of schizophrenia to date, nearly tripling the case sample size from prior efforts and yielding a substantial significant increase in discovery. Ultra-rare variants, particularly PTVs, are useful tools for identifying genes with large effect sizes, especially in traits subject to negative selection such as schizophrenia. Our results deepen understanding of the genetic architecture of schizophrenia, and establish a foundation for elucidating disease biology through direct modeling of risk genes in cellular and animal systems, while also providing a framework for future work of biologically informed patient stratification to better understand disease presentation.