Rare coding variation implicates thirteen genes in bipolar disorder across 232,536 individuals from global populations
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Bipolar disorder (BD) is highly heritable, yet the contribution of rare coding variation remains incompletely characterized. We analyzed sequencing data from 64,435 individuals with BD and 168,101 controls spanning multiple ancestries and 22 countries, representing the largest and most global sequencing resource with a 6.7-fold increase in effective sample size over the previous study iteration. We observe enrichment of protein-truncating and damaging missense variants in constrained genes and curated neuropsychiatric gene sets, with no enrichment of synonymous variation. These enrichment signals were consistent across ancestry groups, suggesting that genetic risk factors for BD are consistent worldwide. Gene-level analyses identified 13 exome-wide significant genes and an additional 20 genes at FDR < 0.05. These genes showed convergence with common and rare variant risk across other neuropsychiatric disorders. Expression analyses also showed preferential brain expression and increased developmental expression during early childhood. Modelling 3D protein structures further highlighted clustering of ultra-rare missense variants at a predicted interaction interfaces in two Bonferroni-significant genes, DOP1A and ATP9A ; a potential mechanism linking membrane trafficking to BD risk. Together, these results implicate a constellation of rare variants that map onto neuronal biology and demonstrate that diverse global populations converge on shared genetic signals underlying BD risk.
Source: medRxiv
Authors: Calwing Liao, Robert Ye, Julia M. Sealock, Toni Boltz, Franjo Ivankovic, Hilary Finucane, Daniel Howrigan, Yijia Christiana Liu, F. Kyle Satterstrom, Arsalan Hassan, Melkam Alemayehu, Stella Gichuru, Rehema M. Mwende, Charles R.J.C. Newton, Nastassja Koen, Zukiswa Zingela, Ana M. Diaz-Zuluaga, Ana M. Ramirez-Diaz, Victor I. Reus, Terri Teshiba, Aarno Palotie, Eija Hämäläinen, Olli Pietiläinen, Penelope A. Lind, Dan J. Siskind, Ian B. Hickie, Pamela Morales-Cedillo, Joanna Jiménez-Pavón, Marco Antonio Sanabrais-Jiménez, Carlo Esteban Sotelo-Ramírez, Eric Hahn, Van Phi Nguyen, Elizabeth Karlson, Chiao-Erh Chang, Hsi-Chung Chen, Martin Alda, Mikael Landén, Jordan W. Smoller, Nicholas Craddock, Marquis P. Vawter, David Curtis, Andrew McQuillin, René S. Kahn, Roel A. Ophoff, Annabel Vreeker, Christina Hultman, Patrick F. Sullivan, Michael E. Talkowski, Douglas H. Blackwood, Andrew McIntosh, Ann E. Pulver, Bruce Cohen, Rolf Adolfsson, Andreas Reif, Fernando Goes, Robert Yolken, Aiden P. Corvin, Derek W. Morris, BIPEX Collection Scientists, Felecia Cerrato, Sinéad B. Chapman, Caroline Cusick, Zhenglin Guo, Ana Maria Olivares, Guy A. Rouleau, Biju Viswanath, Po-Hsiu Kuo, Van Tuan Nguyen, Thi Minh Tam Ta, Beatriz Camarena, Carlos N. Pato, Michele T. Pato, Sarah E. Medland, Nelson Freimer, Loes Olde Loohuis, Carlos Lopez-Jaramillo, Rocky Stroud, Lukoye Atwoli, Akena Dickens, Karestan C. Koenen, Symon M. Kariuki, Solomon Teferra, Dan J. Stein, Muhammad Ayub, James A. Knowles, Mark J. Daly, Hailiang Huang, Benjamin M. Neale
Institutions: Broad Institute, Massachusetts General Hospital, Stanley Center for Psychiatric Research, Addis Ababa University, Aga Khan University Nairobi, Kenya Medical Research Institute, University of Cape Town, Nelson Mandela University, University of California, Los Angeles, Universidade Federal da Bahia, University of California, San Francisco, University of Helsinki, Institute for Molecular Medicine Finland, HiLIFE – Elämäntieteiden Instituutti, QIMR Berghofer Medical Research Institute, The University of Queensland, Metro South Health, Queensland Centre for Mental Health Research, Addiction and Mental Health Services - MSH, The University of Sydney, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Universidad Nacional Autónoma de México, Hanoi Medical University, Charité – Universitätsmedizin Berlin, Brigham and Women's Hospital, Harvard University, Mass General Brigham, National Taiwan University, National Taiwan University Hospital, Dalhousie University, Karolinska Institutet, Cardiff University, University of California, Irvine, University College London, Icahn School of Medicine at Mount Sinai, Erasmus MC, Erasmus University Rotterdam, University of North Carolina at Chapel Hill, University of Edinburgh, Johns Hopkins University, McLean Hospital, Umeå University, University Hospital Frankfurt, Trinity College Dublin, Ollscoil na Gaillimhe – University of Galway, Breakthrough Discoveries for thriving with Bipolar Disorder, McGill University, National Institute of Mental Health and Neurosciences, Rutgers, The State University of New Jersey, Universidad de Antioquia, Makerere University, 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: Broad Institute, Stiftelsen för Strategisk Forskning, Vetenskapsrådet, National Science and Technology Council, Stanley Center for Psychiatric Research, Broad Institute, National Health and 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, G1626468546, Skräddarsy psykiatrisk behandling med genomvid kartläggning, G4918867262, 1/4 Powering Genetic Discovery for Severe Mental Illness in Latin American and African Ancestries, G7164396267, 1/4 Asian Bipolar Genetics Network (A-BIG-NET), Statistical methods to localize disease heritability and identify biological mechanisms, Functional and population genetic architectures of complex disease, Psychosis Genetics Research in Africa: Building Capacity by Investing in People
OpenAlex ID: W7220473572