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Uncovering how rare genetic changes disrupt brain signaling and structure, this landmark study sheds new light on the roots of schizophrenia and opens doors for future therapies.
Study: Whole-exome sequencing analysis identifies risk genes for schizophrenia. Image Credit: magic pictures / Shutterstock
In a recent study published in the journal Nature Communications, researchers in Cardiff, Wales, identified risk genes for schizophrenia.
Schizophrenia is a severe psychiatric syndrome characterized by cognitive and behavioral symptoms. Studies have established a highly polygenic architecture of schizophrenia, with thousands of alleles contributing to liability. Common variants currently explain 24% of the variance in schizophrenia liability, while rare copy number variants (CNVs) and ultrarare coding variants explain about 5% of the variance.
Rare coding variants (RCVs) that contribute to schizophrenia are concentrated among 3,000 genes under selective constraint against frame-shift, essential splice-site, and stop-gain mutations. Studies by the Schizophrenia Exome-Sequencing Meta-Analysis (SCHEMA) consortium and Psychiatric Genomics Consortium implicate only 12 exome-wide significant genes in schizophrenia. Identifying more genes enriched for RCVs in schizophrenia will help delineate the underlying neurobiology.
The study and findings
In the present study, researchers analyzed exome-wide sequencing data for RCVs in a new sample of 4,650 schizophrenia cases and 5,719 controls drawn partially from Alzheimer’s disease cohorts (though sensitivity analyses confirmed robustness). In this sample, singleton protein-truncating variants (PTVs) and singleton missense variants with MPC >2 scores in constrained genes were enriched in cases relative to controls. Controls had a significantly higher rate of singleton synonymous variants in constrained genes than cases.
However, the rates of damaging missense variants and singleton PTVs in non-constrained genes were similar between cases and controls. Further, a per-gene RCV meta-analysis was performed using data from this new sample and the SCHEMA study, which cumulatively comprised 28,898 cases and 103,041 controls – making this the largest exome-sequencing meta-analysis of schizophrenia to date. Cochran-Mantel-Haenszel tests were used to evaluate genes for RCV enrichment.
The researchers identified two novel, exome-wide significant risk genes: ZNF136 (zinc finger protein 136) and STAG1 (STAG1 cohesin complex component), a regulator of 3D genome organization whose disruption may impair neurodevelopment. These genes were previously implicated in schizophrenia by the SCHEMA study at a false discovery rate (FDR) < 5%. ZNF136 was associated with rare PTVs, whereas STAG1 was associated with rare PTVs and missense variants. STAG1 and KLC1 also showed convergence with fine-mapped common variant schizophrenia signals.
In addition, six additional genes at FDR < 5% were identified: SLC6A1 (solute carrier family 6 member 1, a GABA transporter), PCLO (piccolo presynaptic cytomatrix protein), ZMYND11 (zinc finger MYND-type containing 11), BSCL2 (lipid droplet biogenesis associated, seipin), KLC1 (kinesin light chain 1), and CGREF1 (cell growth regulator with EF-hand domain 1). Among these, KLC1 and SLC6A1 were associated with damaging missense variants defined by MPC>2 scores alone.
Among genes overlapping the critical regions of schizophrenia CNV loci, five showed enrichment for RCVs at nominal significance levels. PTVs in NRXN1 (neurexin 1) showed the most significant RCV association and survived correction. Besides, the most significant RCV association among multigenic schizophrenia CNV loci was observed for PTVs in the chromosome 22 open reading frame 39 (C22orf39) gene, overlapping the 22q11.2 deletion locus, though no multi-gene loci survived correction.
Because RCV-enriched genes overlap between schizophrenia and other developmental and psychiatric disorders, the team investigated whether the novel risk genes identified in this study were associated with RCVs in bipolar disorder (BD), developmental disorder (DD), epilepsy, and autism spectrum disorder (ASD). They found evidence of genic pleiotropic effects for four schizophrenia genes: SLC6A1, STAG1, CGREF1, and ZMYND11, though this does not imply shared disease mechanisms.
Missense variants in SLC6A1 showed broad effects across epilepsy, ASD, DD, and schizophrenia, while PTVs in SLC6A1 were additionally associated with DD. Missense variants and PTVs in STAG1 were associated with DD and schizophrenia. Further, PTVs in ZMYND11 were associated with DD, ASD, and schizophrenia, while missense variants were associated with DD. PTVs in CGREF1 were associated with autism and schizophrenia.
Finally, the team analyzed genes previously implicated in schizophrenia in the new sample alone. The 12 previously implicated genes were enriched for rare PTVs in schizophrenia cases in the new sample compared to controls. Single-gene enrichment tests for these 12 genes in the new sample revealed that eight genes had a greater burden of RCVs in cases than in controls, though CACNA1G showed higher rates in controls.
Conclusions
In sum, the findings implicate ZNF136 and STAG1, a chromatin organization gene, in schizophrenia at exome-wide significance and six other genes (CGREF1, BSCL2, KLC1, PCLO, SLC6A1, a GABA signaling gene, and ZMYND11) at FDR < 5%. Many of these were enriched for RCVs in ASD, DD, and epilepsy, supporting their association with schizophrenia. STAG1 and KLC1 also showed convergence with common variant signals. Key limitations include a lack of deep phenotypic data and the underrepresentation of diverse populations. Overall, these results provide novel mechanistic insights into the complex neurobiology of schizophrenia, particularly implicating disrupted chromatin organization in neurodevelopment and GABAergic signaling.