bioRxiv : the preprint server for biology · 2026

Analysis of Rare Coding Variation Identifies New Genetic Contributors to Schizophrenia.

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Sealock Julia M, Dowd Connor, Liao Calwing, Ye Robert, Howrigan Daniel, Satterstrom F Kyle, Auwerx Chiara, Kim Soyeon, Huai Cong, He Lin, Alemayehu Melkam, Gichuru Stella, Mwende Rehema M, Newton Charles R J C, Koen Nastassja, Zingela Zukiswa, Kyebuzibwa Joseph, Stevenson Anne, Hassan Arsalan, Wang Kai, Arai Makoto, Horiuchi Yasue, Itokawa Masanari, Serrano Nora Ayola, Bearden Carrie E, Belangero Sintia I, Castor Albuquerque Saulo G, Crossley Nicolas, de Souza Rodrigues Andre L, Diaz-Zuluaga Ana M, Diniz Mateus M, Freitas Thiago H, Gadelha Ary, Gomez-Makhinson Juliana, Holanda Nayana, Kopelowicz Alex, Lorencetti Pedro G, Quarantini Lucas C, Ramirez-Diaz Ana M, Reus Victor I, Santoro Marcos L, Teshiba Terri, Ziebold Carolina, Sotelo-Ramirez Carlo Esteban, Sanabrais-Jiménez Marco Antonio, Hahn Eric, Nguyen Van Phi, Lind Penelope A, Forsyth Jennifer, Okewole Adeniran, Go Rodney C P, Gur Raquel, Gur Ruben, Craddock Nicholas, Palotie Aarno, Hämäläinen Eija, Pietiläinen Olli, Glatt Stephen J, Hultman Christina, López Celso Arango, McQuillin Andrew, Bass Nick, Pulver Ann E, St Clair David, Cohen Bruce, Blackwood Douglas H, McIntosh Andrew, Esko Tõnu, Karlson Elizabeth, Corvin Aiden P, Morris Derek W, Manoach Dara, Landen Mikael, SCHEMA Consortium, Boehnke Michael, Børglum Anders D, Churchhouse Claire, Curtis David, O'Donovan Michael C, Owen Michael J, Rees Elliott, Sullivan Patrick F, Vawter Marquis P, Walters James T R, Scott Laura, Medland Sarah E, Nguyen Van Tuan, Ta Thi Minh Tam, Camarena Beatriz, Freimer Nelson, Lopez-Jaramillo Carlos, Olde Loohuis Loes, Ophoff Roel A, Sawa Akira, Pato Carlos N, Pato Michele T, Ayub Muhammad, Knowles James A, Stroud Rocky, Atwoli Lukoye, Dickens Akena, Kariuki Symon M, Koenen Karestan C, Stein Dan J, Teferra Solomon, Qin Shengying, Daly Mark J, Huang Hailiang, Neale Benjamin M

Аннотация

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.

Analysis of Rare Coding Variation Identifies New Genetic Contributors to Schizophrenia.

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