Journal Article Preprint Epublish
PubMed: 42926592 DOI: 10.64898/2026.09.30.26364416
Rare coding variation implicates thirteen genes in bipolar disorder across 232,536 individuals from global populations.
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 … and 37 other authors
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.
MeSH
Genes, Bipolar Disorder