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<p>Obesity and psychiatric disorders frequently co-occur, yet the heterogeneous genetic mechanisms underlying this comorbidity remain elusive. Here, we stratify the polygenic architecture of body mass index (BMI) into five biologically distinct clusters based on metabolic signatures and construct partitioned polygenic scores (pPGSs) for each. Using individual-level data from the UK Biobank (<i>N</i> = 310,708), we identify cluster-specific psychiatric risk profiles, with amino acid-related clusters showing the strongest associations. These effects are markedly modulated by sex and BMI: underweight individuals and females show amplified psychiatric vulnerability, while obesity attenuates certain associations. Integration of proteomic and metabolomic data reveals key molecular mediators, including TNN, LEP, and ANGPT2, that influence psychiatric outcomes in a BMI- and sex-dependent manner. Mediation analyses demonstrate that pPGSs primarily exert indirect effects on psychiatric disorders through immune and metabolic molecular networks. These findings highlight the functional heterogeneity of BMI genetics, providing a framework for precision psychiatry.</p>

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BMI-driven multi-omics analysis profiles the molecular mechanism of psycho-metabolic nexus and contributes to risk stratification

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月24日

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  • Xiaonan Guo,
  • Yu Feng,
  • Peng Huang,
  • Ningning Jia,
  • Zeyu Qin,
  • Lingzhuo Kong,
  • Yiqing Chen,
  • Shuxiang Yang,
  • Jiayi Zhang,
  • Sheng Yang,
  • Shaohua Hu

摘要

Obesity and psychiatric disorders frequently co-occur, yet the heterogeneous genetic mechanisms underlying this comorbidity remain elusive. Here, we stratify the polygenic architecture of body mass index (BMI) into five biologically distinct clusters based on metabolic signatures and construct partitioned polygenic scores (pPGSs) for each. Using individual-level data from the UK Biobank (N = 310,708), we identify cluster-specific psychiatric risk profiles, with amino acid-related clusters showing the strongest associations. These effects are markedly modulated by sex and BMI: underweight individuals and females show amplified psychiatric vulnerability, while obesity attenuates certain associations. Integration of proteomic and metabolomic data reveals key molecular mediators, including TNN, LEP, and ANGPT2, that influence psychiatric outcomes in a BMI- and sex-dependent manner. Mediation analyses demonstrate that pPGSs primarily exert indirect effects on psychiatric disorders through immune and metabolic molecular networks. These findings highlight the functional heterogeneity of BMI genetics, providing a framework for precision psychiatry.