Analysis of Rare Coding Variation Identifies New Genetic Contributors to Schizophrenia
- 1Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.; Stanley Center for Psychiatric Re
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.
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BibTeX
@misc{sealock2026analysis,
title = {{Analysis of Rare Coding Variation Identifies New Genetic Contributors to Schizophrenia}},
author = {J. M. Sealock and C. Dowd and C. Liao and R. Ye and D. Howrigan and F. K. Satterstrom and C. Auwerx and S. Kim and C. Huai and L. He and M. Alemayehu and S. Gichuru and R. M. Mwende and C. R. J. C. Newton and N. Koen and Z. Zingela and J. Kyebuzibwa and A. Stevenson and A. Hassan and K. Wang and M. Arai and Y. Horiuchi and M. Itokawa and N. A. Serrano and C. E. Bearden and S. I. Belangero and S. G. Castor Albuquerque and N. Crossley and A. L. de Souza Rodrigues and A. M. Diaz-Zuluaga and M. M. Diniz and T. H. Freitas and A. Gadelha and J. Gomez-Makhinson and N. Holanda and A. Kopelowicz and P. G. Lorencetti and L. C. Quarantini and A. M. Ramirez-Diaz and V. I. Reus and Sa},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.18.752670},
url = {https://www.biorxiv.org/content/10.64898/2026.09.18.752670v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Analysis of Rare Coding Variation Identifies New Genetic Contributors to Schizophrenia
AU - J. M. Sealock
AU - C. Dowd
AU - C. Liao
AU - R. Ye
AU - D. Howrigan
AU - F. K. Satterstrom
AU - C. Auwerx
AU - S. Kim
AU - C. Huai
AU - L. He
AU - M. Alemayehu
AU - S. Gichuru
AU - R. M. Mwende
AU - C. R. J. C. Newton
AU - N. Koen
AU - Z. Zingela
AU - J. Kyebuzibwa
AU - A. Stevenson
AU - A. Hassan
AU - K. Wang
AU - M. Arai
AU - Y. Horiuchi
AU - M. Itokawa
AU - N. A. Serrano
AU - C. E. Bearden
AU - S. I. Belangero
AU - S. G. Castor Albuquerque
AU - N. Crossley
AU - A. L. de Souza Rodrigues
AU - A. M. Diaz-Zuluaga
AU - M. M. Diniz
AU - T. H. Freitas
AU - A. Gadelha
AU - J. Gomez-Makhinson
AU - N. Holanda
AU - A. Kopelowicz
AU - P. G. Lorencetti
AU - L. C. Quarantini
AU - A. M. Ramirez-Diaz
AU - V. I. Reus
AU - Sa
PY - 2026
DA - 2026/09/18
PB - bioRxiv
DO - 10.64898/2026.09.18.752670
UR - https://www.biorxiv.org/content/10.64898/2026.09.18.752670v1
AB - 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.
ER -