Year: 2026
Type: preprint
Study design: Observational Study
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.
Authors: Julia M. Sealock, Connor Dowd, Calwing Liao, Robert Ye, Daniel Howrigan, F. Kyle Satterstrom, Chiara Auwerx, Soyeon Kim, Cong Huai, Lin He, Melkam Alemayehu, Stella Gichuru, Rehema M. Mwende, Charles R.J.C. Newton, Nastassja Koen, Zukiswa Zingela, Joseph Kyebuzibwa, Anne Stevenson, Arsalan Hassan, Kai Wang, Makoto Arai, Yasue Horiuchi, Masanari Itokawa, Nora Ayola Serrano, Carrie E. Bearden, Sintia I. Belangero, Saulo G. Castor Albuquerque, Nicolas Crossley, Andre L. de Souza Rodrigues, Ana M. Diaz-Zuluaga, Mateus M. Diniz, Thiago H. Freitas, Ary Gadelha, Juliana Gomez-Makhinson, Nayana Holanda, Alex Kopelowicz, Pedro G. Lorencetti, Lucas C. Quarantini, Ana M. Ramirez-Diaz, Victor I. Reus, Marcos L. Santoro, Terri Teshiba, Carolina Ziebold, Carlo Esteban Sotelo-Ramirez, Marco Antonio Sanabrais-Jiménez, Eric Hahn, Van Phi Nguyen, Penelope A. Lind, Jennifer Forsyth, Adeniran Okewole, Rodney C.P. Go, Raquel Gur, Ruben Gur, Nicholas Craddock, Aarno Palotie, Eija Hämäläinen, Olli Pietiläinen, Stephen J. Glatt, Christina Hultman, Celso Arango López, Andrew McQuillin, Nick Bass, Ann E. Pulver, David St. Clair, Bruce Cohen, Douglas H. Blackwood, Andrew McIntosh, Tõnu Esko, Elizabeth Karlson, Aiden P. Corvin, Derek W. Morris, Dara Manoach, Mikael Landen, Michael Boehnke, Anders D. Børglum, Claire Churchhouse, David Curtis, Michael C. O’Donovan, Michael J. Owen, Elliott Rees, Patrick F. Sullivan, Marquis P. Vawter, James T.R. Walters, Laura Scott, Sarah E. Medland, Van Tuan Nguyen, Thi Minh Tam Ta, Beatriz Camarena, Nelson Freimer, Carlos Lopez-Jaramillo, Loes Olde Loohuis, Roel A. Ophoff, Akira Sawa, Carlos N. Pato, Michele T. Pato, Muhammad Ayub, James A. Knowles, Rocky Stroud, Lukoye Atwoli, Akena Dickens, Symon M. Kariuki, Karestan C. Koenen, Dan J. Stein, Solomon Teferra, Shengying Qin, Mark J. Daly, Hailiang Huang, Benjamin M. Neale
Institutions: Broad Institute, Massachusetts General Hospital, Stanley Center for Psychiatric Research, Harvard University, Kyung Hee University, Kyung Hee University Medical Center, Shanghai Jiao Tong University, Addis Ababa University, Aga Khan University Nairobi, Kenya Medical Research Institute, University of Cape Town, Nelson Mandela University, Makerere University, University of Pennsylvania, Tokyo Metropolitan Institute of Medical Science, Shizuoka Graduate University of Public Health, University of California, Los Angeles, Universidade Federal de São Paulo, Universidad de Antioquia, Universidade do Estado do Pará, Universidade Federal do Pará, Universidade de Fortaleza, Universidade Federal do Ceará, Universidade Federal da Bahia, University of California, San Francisco, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Hanoi Medical University, Charité – Universitätsmedizin Berlin, QIMR Berghofer Medical Research Institute, University of Washington, University of Cambridge, University of Alabama at Birmingham, Cardiff University, University of Helsinki, Institute for Molecular Medicine Finland, HiLIFE – Elämäntieteiden Instituutti, SUNY Upstate Medical University, Karolinska Institutet, Hospital Universitario La Paz, Centro de Investigación Biomédica en Red de Salud Mental, Universidad Autónoma de Madrid, University College London, Johns Hopkins University, University of Aberdeen, McLean Hospital, University of Edinburgh, University of Tartu, Brigham and Women's Hospital, Mass General Brigham, Trinity College Dublin, Ollscoil na Gaillimhe – University of Galway, University of Gothenburg, University of Michigan, Aarhus University, Lundbeck Foundation, University of North Carolina at Chapel Hill, University of California, Irvine, Johns Hopkins Medicine, Rutgers, The State University of New Jersey, Breakthrough Discoveries for thriving with Bipolar Disorder, African Population and Health Research Center, South African Medical Research Council
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: National Science Foundation, UK Research and Innovation, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Vetenskapsrådet, National Institutes of Health, Stanley Center for Psychiatric Research, Broad Institute, Medical Research Council, National Institute of Mental Health, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: Genetics and gene regulation in the inflammatory bowel diseases, G1374662754, 1/2 A Large-Scale Schizophrenia Association Study in Sweden, From Genotypes to Phenotypes in Schizophrenia: A Developmental Functional Genomics Approach, 1/7 Psychiatric Genomics Consortium: Finding actionable variation, G395765120, G4075591208, The South Wales and South West England Mental Health Platform Hub, Molecular Genetic Studies of Schizophrenia, G455107792, Molecular Genetic Studies of Schizophrenia: Understanding Treatment Resistance and Outcomes to Inform Precision Psychiatry., Informing precision psychiatry through developing comprehensive genomic models of mental health disorders, G5517247787, MRC Centre for Neuropsychiatric Genetics and Genomics, G5928719961, The GEN-SCRIP Study (GENetics of SChizophRenia in Pakistan), G6345711408, 1/4 Powering Genetic Discovery for Severe Mental Illness in Latin American and African Ancestries, G7164396267, 2/4 Powering Genetic Discovery for Severe Mental Illness in Latin American and African Ancestries, G8163728846, G8218456548, G8478578813, Statistical methods to localize disease heritability and identify biological mechanisms, Functional and population genetic architectures of complex disease, Identification and characterization of inflammatory bowel disease causal variants, Psychosis Genetics Research in Africa: Building Capacity by Investing in People
OpenAlex ID: W7213934900