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Background <p>Patients with asthma have an increased risk of developing depression, affecting their quality of life. To date, the processes contributing to this comorbidity remain unclear.</p> Methods <p>We integrated two large genome-wide association studies (88,486 patients with asthma and 447,859 controls; 412,024 patients with depression and 1,587,577 controls) with cross-sectional and longitudinal information available from the All of Us Research Program (<i>N</i> = 87,167) through polygenic risk scoring (PRS), Cox proportional-hazards models, one-sample Mendelian randomization (MR), and gene-set and drug-repurposing analyses.</p> Results <p>We observed that depression PRS was associated with increased asthma risk (hazard ratio, <i>HR</i> = 1.13, 95% <i>CI</i> = 1.09–1.17), also when accounting for comorbidity status (<i>HR</i> = 1.08, 95% <i>CI</i> = 1.04–1.12). Conversely, the effect of asthma PRS was null after accounting for comorbidity status. One-sample MR analysis showed an effect of depression genetic liability on asthma, ranging from beta = 0.36 ± 0.03 when considering a linear relationship to beta = 3.21 ± 0.31 when considering possible nonlinear relationships. Conversely, the effect of asthma genetic risk on depression was null after accounting for potential confounders. The gene-set analyses showed that asthma and depression polygenic risks share biological processes, molecular functions, and cellular components related to the immune system and the lung-brain axis.</p> Conclusions <p>Genetic predisposition contributes to asthma-depression comorbidity through direct effects and shared pathogenic processes. These findings highlight the potential to develop targeted interventions to prevent and treat the co-occurrence of respiratory and neuropsychiatric disorders.</p>

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Assessing the comorbidity between asthma and depression through polygenic risk scoring and time-to-event models

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月22日

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  • Xueting Wang,
  • Jun He,
  • Brenda Cabrera-Mendoza,
  • Dan Qiu,
  • Zhongzheng Mao,
  • Wen Gu,
  • Youwen Liu,
  • Jihoon Kim,
  • Renato Polimanti

摘要

Background

Patients with asthma have an increased risk of developing depression, affecting their quality of life. To date, the processes contributing to this comorbidity remain unclear.

Methods

We integrated two large genome-wide association studies (88,486 patients with asthma and 447,859 controls; 412,024 patients with depression and 1,587,577 controls) with cross-sectional and longitudinal information available from the All of Us Research Program (N = 87,167) through polygenic risk scoring (PRS), Cox proportional-hazards models, one-sample Mendelian randomization (MR), and gene-set and drug-repurposing analyses.

Results

We observed that depression PRS was associated with increased asthma risk (hazard ratio, HR = 1.13, 95% CI = 1.09–1.17), also when accounting for comorbidity status (HR = 1.08, 95% CI = 1.04–1.12). Conversely, the effect of asthma PRS was null after accounting for comorbidity status. One-sample MR analysis showed an effect of depression genetic liability on asthma, ranging from beta = 0.36 ± 0.03 when considering a linear relationship to beta = 3.21 ± 0.31 when considering possible nonlinear relationships. Conversely, the effect of asthma genetic risk on depression was null after accounting for potential confounders. The gene-set analyses showed that asthma and depression polygenic risks share biological processes, molecular functions, and cellular components related to the immune system and the lung-brain axis.

Conclusions

Genetic predisposition contributes to asthma-depression comorbidity through direct effects and shared pathogenic processes. These findings highlight the potential to develop targeted interventions to prevent and treat the co-occurrence of respiratory and neuropsychiatric disorders.