{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine",
    "Department 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",
    "Liangzhu Laboratory, Zhejiang University Medical Center",
    "Huai’an No.3 People’s Hospital",
    "Department of Psychiatry and Psychotherapy, Jena University Hospital",
    "Peking University Sixth Hospital, Peking University Institute of Mental Health",
    "Division of Pediatric Pulmonary Medicine, UPMC Children’s Hospital of Pittsburgh, University of Pittsburgh"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 13,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Yu Feng"
    },
    {
      "affs": [
        0
      ],
      "name": "Xiaonan Guo"
    },
    {
      "affs": [
        1
      ],
      "name": "Peng Huang"
    },
    {
      "affs": [
        2
      ],
      "name": "Ningning Jia"
    },
    {
      "affs": [
        3
      ],
      "name": "Li Wang"
    },
    {
      "affs": [
        1
      ],
      "name": "Xiaolong Ji"
    },
    {
      "affs": [
        0
      ],
      "name": "Zeyu Qin"
    },
    {
      "affs": [
        4
      ],
      "name": "Meng Li"
    },
    {
      "affs": [
        0
      ],
      "name": "Jianbo Lai"
    },
    {
      "affs": [
        3
      ],
      "name": "Xiaofeng Qin"
    },
    {
      "affs": [
        5
      ],
      "name": "Weihua Yue"
    },
    {
      "affs": [
        6
      ],
      "name": "Sheng Yang"
    },
    {
      "affs": [
        0
      ],
      "name": "Shaohua Hu"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/6vjd7avcyy38v.bib",
  "cited_by": 0,
  "doi": "10.1186/s12916-026-05096-0",
  "fulltext_url": "https://doi.org/10.1186/s12916-026-05096-0",
  "id": "6vjd7avcyy38v",
  "issns": [
    "1741-7015"
  ],
  "landing_url": "https://doi.org/10.1186/s12916-026-05096-0",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "lcc",
      "R"
    ],
    [
      "openalex",
      "2738|Bipolar Disorder and Treatment"
    ]
  ],
  "openalex": "W7171426014",
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-07-01",
  "publisher": "BMC",
  "ris": "https://research.draconitic.com/paper/6vjd7avcyy38v.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T13:46:06Z",
      "native_id": "ca520afb1caa4561a376daafc5cd1970",
      "source": "doaj",
      "url": "https://doi.org/10.1186/s12916-026-05096-0"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2738|Bipolar Disorder and Treatment",
      "subfield": "psychiatry"
    }
  ],
  "title": "Polygenicity shapes distinct brain patterns and clinical profiles of bipolar disorder",
  "title_text": "Polygenicity shapes distinct brain patterns and clinical profiles of bipolar disorder",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T13:46:06Z",
  "url": "https://research.draconitic.com/paper/6vjd7avcyy38v",
  "venue": "BMC Medicine",
  "versions": []
}