Largest rare-variant study of schizophrenia identifies 16 genes at exome-wide significance
A preprint reporting 87,959 cases implicates 16 genes — including SETD1A, SCN2A, and SP4 — with consistent effects across ancestries and overlap with other neurodevelopmental conditions.
A preprint posted to bioRxiv by researchers who have not yet been named in the available lede presents what they describe as the largest rare coding variant association study of schizophrenia conducted to date, drawing on 87,959 schizophrenia cases and 150,587 controls. The analysis identifies 16 genes reaching exome-wide significance: SETD1A, ZMYM2, HERC1, RB1CC1, SCAF1, XPO7, SP4, FYN, PPP3CA, CUL1, HDAC9, JARID2, ATP9A, PTK2, STAG1, and SCN2A. A further 24 genes reach a 5% false discovery rate threshold.
Cases carrying ultra-rare, damaging variants — predominantly protein-truncating mutations and deleterious missense changes — show strong enrichment in constrained genes, meaning genes where natural selection has historically acted against functional disruption. The authors report that these effects are consistent across ancestries included in the study, which strengthens confidence in the findings relative to single-ancestry analyses.
The preprint notes that half of the 40 genes identified overlap with genes implicated in other neurodevelopmental conditions, echoing a pattern observed in earlier smaller studies. Several of the genes — including SCN2A and SETD1A — have already attracted attention in developmental and epileptic encephalopathy research, suggesting shared rare-variant biology across a range of neurodevelopmental presentations.
As a preprint, these findings have not yet undergone peer review and should be read accordingly. If confirmed, the dataset would substantially expand the catalogue of rare variants contributing to schizophrenia risk and provide a richer framework for understanding its genetic architecture.
Plain-language version
For patients, families, and general readers. Educational only — not medical advice.
Researchers have posted a large study — not yet reviewed by other scientists — examining the genetics of schizophrenia. They analysed genetic data from nearly 88,000 people with schizophrenia and 150,000 people without it, looking specifically for rare changes in protein-coding genes.
The study identified 16 genes where rare, damaging mutations appeared significantly more often in people with schizophrenia than in people without it. Several of these genes are also linked to other conditions affecting brain development in childhood.
Because many people with schizophrenia do not carry any of these rare variants, and because the study is still a preprint and not yet peer-reviewed, these findings are an early step in understanding the biology of schizophrenia rather than a tool for predicting an individual's risk. Researchers say the results could eventually help scientists understand what goes wrong in the brain and potentially point towards new areas of investigation.
This is an educational summary, not medical advice. If anything here raises questions for you, please speak with your GP or a clinical professional.
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Primary sourcePreprint bioRxiv (Cold Spring Harbor Laboratory) · 2026-09-21Analysis of Rare Coding Variation Identifies New Genetic Contributors to Schizophrenia