Polygenicity shapes distinct brain patterns and clinical profiles of bipolar disorder
7 affiliations
- 1Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine
- 2Department of Epidemiology, Centre for Global Health, School of Public Health, Key Laboratory of Public Health Safety and Emergency Prevention and Control Technology of Higher Education Institutions in Jiangsu Province, National Vaccine Innovation Platform, Nanjing Medical University
- 3Liangzhu Laboratory, Zhejiang University Medical Center
- 4Huai’an No.3 People’s Hospital
- 5Department of Psychiatry and Psychotherapy, Jena University Hospital
- 6Peking University Sixth Hospital, Peking University Institute of Mental Health
- 7Division of Pediatric Pulmonary Medicine, UPMC Children’s Hospital of Pittsburgh, University of Pittsburgh
Abstract
Background Bipolar disorder (BD) manifests both genetic predispositions and brain imaging abnormalities. Genetic analyses provide a powerful approach to disentangling the associations between BD and brain imaging-derived phenotype (IDP). However, in East Asian (EAS) populations, the genetic basis of these neuroimaging changes and their clinical relevance remains underexplored due to limited integrative evidence. Methods We investigated the genetic architecture and clinical relevance of BD and brain IDPs in East Asian populations using individual-level data from the Chinese Bipolar Disorder (CN-BD) cohort (N = 3,920), summary statistics of BD from the Psychiatric Genomics Consortium (PGC) (N = 16,915) and of IDPs from the CHIMGEN Consortium (N = 7,058), and genotype and clinical data from the Chinese Longitudinal and Systematic Study of Bipolar Disorder cohort (CLASS-BD). We employed genetic correlation (GNOVA), multi-trait meta-analysis (MTAG, CPASSOC), and ancestry-specific fine-mapping (MESuSiE) to identify shared genetic loci. Functional annotation, protein association (SMR, BLISS), and spatiotemporal expression trajectory analyses were conducted. Bidirectional Mendelian Randomization (MR) assessed causal relationships, and polygenic risk score (PRS)-PheWAS explored phenome-level associations with clinical traits. Results Our multi-trait meta-analysis identified 11 pleiotropic single nucleotide variants (SNVs) implicated in BD-IDP pairs, showing convergent enrichment in lipid metabolism and neurotransmitter biosynthesis pathways. Fine-mapping revealed an EAS-specific causal signal (rs7941324 near RPS27P20), which demonstrated high posterior inclusion probability in EAS but not European ancestries, and colocalized with BD and specific brain alterations. MR revealed 27 IDP-to-BD and 35 BD-to-IDP causal relationships, distinguishing structural changes of the parietal and temporal gyri as markers preceding BD onset and the right precuneus area as a state marker that followed BD onset. Clinically, BD-IDP polygenic risk scores were significantly associated with depressive symptoms, anxiety, and suicide risk. Mediation analysis further indicated that depressive and anxiety symptoms statistically mediated the relationship between BD-IDP PRS and suicide risk. Moreover, PRS-PheWAS identified 135 significant associations with metabolic phenotypes, highlighting a psycho-metabolic nexus in BD. Conclusions Our findings reveal associations between polygenicity and distinct BD brain patterns and clinical profiles. We identified ancestry-specific causal variants and bidirectional BD-IDP relationships. PRS associations with depressive symptoms, anxiety, suicide risk, and metabolic phenotypes highlight precision medicine potential for BD.
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BibTeX
@article{feng2026polygenicity,
title = {{Polygenicity shapes distinct brain patterns and clinical profiles of bipolar disorder}},
author = {Yu Feng and Xiaonan Guo and Peng Huang and Ningning Jia and Li Wang and Xiaolong Ji and Zeyu Qin and Meng Li and Jianbo Lai and Xiaofeng Qin and Weihua Yue and Sheng Yang and Shaohua Hu},
journal = {BMC Medicine},
year = {2026},
month = jul,
doi = {10.1186/s12916-026-05096-0},
url = {https://doi.org/10.1186/s12916-026-05096-0},
note = {CC BY},
}
RIS
TY - JOUR
TI - Polygenicity shapes distinct brain patterns and clinical profiles of bipolar disorder
AU - Yu Feng
AU - Xiaonan Guo
AU - Peng Huang
AU - Ningning Jia
AU - Li Wang
AU - Xiaolong Ji
AU - Zeyu Qin
AU - Meng Li
AU - Jianbo Lai
AU - Xiaofeng Qin
AU - Weihua Yue
AU - Sheng Yang
AU - Shaohua Hu
PY - 2026
DA - 2026/07/01
JO - BMC Medicine
DO - 10.1186/s12916-026-05096-0
UR - https://doi.org/10.1186/s12916-026-05096-0
AB - Background Bipolar disorder (BD) manifests both genetic predispositions and brain imaging abnormalities. Genetic analyses provide a powerful approach to disentangling the associations between BD and brain imaging-derived phenotype (IDP). However, in East Asian (EAS) populations, the genetic basis of these neuroimaging changes and their clinical relevance remains underexplored due to limited integrative evidence. Methods We investigated the genetic architecture and clinical relevance of BD and brain IDPs in East Asian populations using individual-level data from the Chinese Bipolar Disorder (CN-BD) cohort (N = 3,920), summary statistics of BD from the Psychiatric Genomics Consortium (PGC) (N = 16,915) and of IDPs from the CHIMGEN Consortium (N = 7,058), and genotype and clinical data from the Chinese Longitudinal and Systematic Study of Bipolar Disorder cohort (CLASS-BD). We employed genetic correlation (GNOVA), multi-trait meta-analysis (MTAG, CPASSOC), and ancestry-specific fine-mapping (MESuSiE) to identify shared genetic loci. Functional annotation, protein association (SMR, BLISS), and spatiotemporal expression trajectory analyses were conducted. Bidirectional Mendelian Randomization (MR) assessed causal relationships, and polygenic risk score (PRS)-PheWAS explored phenome-level associations with clinical traits. Results Our multi-trait meta-analysis identified 11 pleiotropic single nucleotide variants (SNVs) implicated in BD-IDP pairs, showing convergent enrichment in lipid metabolism and neurotransmitter biosynthesis pathways. Fine-mapping revealed an EAS-specific causal signal (rs7941324 near RPS27P20), which demonstrated high posterior inclusion probability in EAS but not European ancestries, and colocalized with BD and specific brain alterations. MR revealed 27 IDP-to-BD and 35 BD-to-IDP causal relationships, distinguishing structural changes of the parietal and temporal gyri as markers preceding BD onset and the right precuneus area as a state marker that followed BD onset. Clinically, BD-IDP polygenic risk scores were significantly associated with depressive symptoms, anxiety, and suicide risk. Mediation analysis further indicated that depressive and anxiety symptoms statistically mediated the relationship between BD-IDP PRS and suicide risk. Moreover, PRS-PheWAS identified 135 significant associations with metabolic phenotypes, highlighting a psycho-metabolic nexus in BD. Conclusions Our findings reveal associations between polygenicity and distinct BD brain patterns and clinical profiles. We identified ancestry-specific causal variants and bidirectional BD-IDP relationships. PRS associations with depressive symptoms, anxiety, suicide risk, and metabolic phenotypes highlight precision medicine potential for BD.
SN - 1741-7015
ER -