基于多基因风险评分与生存分析的哮喘-抑郁症共病遗传关联研究
2026/02/06
背景：哮喘患者患抑郁症的风险增加，这影响了他们的生活质量。然而，导致这种共病的机制目前尚不清楚。
方法：通过多基因风险评分（PRS）、Cox比例风险模型、单样本孟德尔随机化（MR）以及基因集和药物重利用分析，我们将两项大型全基因组关联研究（88486名哮喘患者和447859名对照；412024名抑郁症患者和1587577名对照）与来自“All of Us”研究计划（N = 87167）的横断面和纵向信息进行了整合。
结果：结果显示抑郁症PRS与哮喘风险增加相关（风险比[HR] = 1.13，95% CI 1.09–1.17），即使在校正共病状态后（HR = 1.08，95% CI 1.04–1.12）依然如此。相反，在校正共病状态后，哮喘PRS的效应不显著。单样本MR分析显示，抑郁症遗传易感性对哮喘有影响，在考虑线性关系时beta = 0.36 ± 0.03，而在考虑可能的非线性关系时beta = 3.21 ± 0.31。相反，在校正潜在混杂因素后，哮喘遗传风险对抑郁症的效应不显著。基因集分析表明，哮喘和抑郁症的多基因风险共享与免疫系统和肺－脑轴相关的生物过程、分子功能和细胞组分。
结论：研究发现，抑郁症的遗传易感性可增加哮喘风险，而反向关联不显著，提示抑郁对哮喘的影响可能存在主导性。两种疾病共享免疫系统及肺－脑轴相关通路，表明其共病涉及直接遗传效应与共同生物学机制。研究结果为早期预防与针对性干预呼吸-精神共病提供了依据。
关键词：孟德尔随机化；精神疾病；呼吸系统疾病；电子健康档案；时间关联
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.
Conclusion：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.
Key words: Mendelian randomization; mental illness; respiratory disease; electronic health records; temporal associations.
方法：通过多基因风险评分（PRS）、Cox比例风险模型、单样本孟德尔随机化（MR）以及基因集和药物重利用分析，我们将两项大型全基因组关联研究（88486名哮喘患者和447859名对照；412024名抑郁症患者和1587577名对照）与来自“All of Us”研究计划（N = 87167）的横断面和纵向信息进行了整合。
结果：结果显示抑郁症PRS与哮喘风险增加相关（风险比[HR] = 1.13，95% CI 1.09–1.17），即使在校正共病状态后（HR = 1.08，95% CI 1.04–1.12）依然如此。相反，在校正共病状态后，哮喘PRS的效应不显著。单样本MR分析显示，抑郁症遗传易感性对哮喘有影响，在考虑线性关系时beta = 0.36 ± 0.03，而在考虑可能的非线性关系时beta = 3.21 ± 0.31。相反，在校正潜在混杂因素后，哮喘遗传风险对抑郁症的效应不显著。基因集分析表明，哮喘和抑郁症的多基因风险共享与免疫系统和肺－脑轴相关的生物过程、分子功能和细胞组分。
结论：研究发现，抑郁症的遗传易感性可增加哮喘风险，而反向关联不显著，提示抑郁对哮喘的影响可能存在主导性。两种疾病共享免疫系统及肺－脑轴相关通路，表明其共病涉及直接遗传效应与共同生物学机制。研究结果为早期预防与针对性干预呼吸-精神共病提供了依据。
关键词：孟德尔随机化；精神疾病；呼吸系统疾病；电子健康档案；时间关联
（南方医科大学南方医院 黄海伦 龚钊乾 赵海金 ）
(Wang X, He J, Cabrera-Mendoza B, et al. Assessing the comorbidity between asthma and depression through polygenic risk scoring and time-to-event models[J]. BMC Medicine, 2026. DOI: 10.1186/s12916-026-04646-w.)
Abstract(Wang X, He J, Cabrera-Mendoza B, et al. Assessing the comorbidity between asthma and depression through polygenic risk scoring and time-to-event models[J]. BMC Medicine, 2026. DOI: 10.1186/s12916-026-04646-w.)
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.
Conclusion：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.
Key words: Mendelian randomization; mental illness; respiratory disease; electronic health records; temporal associations.
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