Rare coding variation implicates thirteen genes in bipolar disorder across 232,536 individuals from global populations
- 1Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA; Program in Medical and Population
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.
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BibTeX
@misc{liao2026rare,
title = {{Rare coding variation implicates thirteen genes in bipolar disorder across 232,536 individuals from global populations}},
author = {C. Liao and R. Ye and J. M. Sealock and T. Boltz and F. Ivankovic and H. Finucane and D. Howrigan and Y. C. Liu and F. K. Satterstrom and A. Hassan and M. Alemayehu and S. Gichuru and R. Mwende and C. Newton and N. Koen and Z. Zingela and A. M. Diaz-Zuluaga and A. M. Ramirez-Diaz and V. I. Reus and T. Teshiba and A. Palotie and E. Hamalainen and O. Pietilainen and P. A. Lind and D. J. Siskind and I. B. Hickie and P. Morales-Cedillo and J. Jimenez-Pavon and M. A. Sanabrais-Jimenez and C. E. Sotelo-Ramirez and E. Hahn and V. P. Nguyen and E. Karlson and C.-E. Chang and H.-C. Chen and M. Alda and M. Landen and J. W. Smoller and N. Craddock and M. P. Vawter and D. Curtis and Mc},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.30.26364416},
url = {https://www.medrxiv.org/content/10.64898/2026.09.30.26364416v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Rare coding variation implicates thirteen genes in bipolar disorder across 232,536 individuals from global populations
AU - C. Liao
AU - R. Ye
AU - J. M. Sealock
AU - T. Boltz
AU - F. Ivankovic
AU - H. Finucane
AU - D. Howrigan
AU - Y. C. Liu
AU - F. K. Satterstrom
AU - A. Hassan
AU - M. Alemayehu
AU - S. Gichuru
AU - R. Mwende
AU - C. Newton
AU - N. Koen
AU - Z. Zingela
AU - A. M. Diaz-Zuluaga
AU - A. M. Ramirez-Diaz
AU - V. I. Reus
AU - T. Teshiba
AU - A. Palotie
AU - E. Hamalainen
AU - O. Pietilainen
AU - P. A. Lind
AU - D. J. Siskind
AU - I. B. Hickie
AU - P. Morales-Cedillo
AU - J. Jimenez-Pavon
AU - M. A. Sanabrais-Jimenez
AU - C. E. Sotelo-Ramirez
AU - E. Hahn
AU - V. P. Nguyen
AU - E. Karlson
AU - C.-E. Chang
AU - H.-C. Chen
AU - M. Alda
AU - M. Landen
AU - J. W. Smoller
AU - N. Craddock
AU - M. P. Vawter
AU - D. Curtis
AU - Mc
PY - 2026
DA - 2026/09/30
PB - medRxiv
DO - 10.64898/2026.09.30.26364416
UR - https://www.medrxiv.org/content/10.64898/2026.09.30.26364416v1
AB - 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.
ER -