- Largest rare coding variant study: 87,959 cases, 150,587 controls; 16 exome-wide significant genes and 24 additional genes at 5% FDR (40 total).
- Ultra-rare damaging variants, mainly protein-truncating and deleterious missense, are enriched in constrained genes with consistent effects across ancestries.
- Identified genes implicate chromatin regulation, protein degradation and synaptic function; overlap half with developmental delay, autism or bipolar disorder.
bioRxiv [Preprint]. 2026 Sep 21:2026.09.18.752670. doi: 10.64898/2026.09.18.752670.
ABSTRACT
In this study, we present the largest rare coding variant association study of schizophrenia to date, with 87,959 schizophrenia cases and 150,587 controls. 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 a 5% false discovery rate. Cases carrying ultra-rare, damaging variants, primarily protein-truncating and deleterious missense mutations, show strong enrichment in constrained genes with consistent effects across ancestries. Half of the 40 identified genes overlap with those implicated in developmental delay, autism, or bipolar disorder, underscoring shared neurodevelopmental risk. All 40 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. Overall, our results advance understanding of the genetic architecture of schizophrenia, provide a foundation for modeling risk genes in cellular and animal systems, and offer a framework for future work toward biologically informed patient stratification.
PMID:42818077 | PMC:PMC13622030 | DOI:10.64898/2026.09.18.752670
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