PO.PR02.02 · 预防研究
多组学整合揭示晚间昼夜节律偏好通过共享的神经-内分泌-免疫通路成为癌症-抑郁共病的因果风险因素
Multi-omics integration reveals evening circadian preference as a causal risk factor for cancer-depression comorbidity through shared neuro-endocrine-immune pathways
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摘要 Abstract
中文摘要
背景：癌症与抑郁的共病导致预后显著较差，但其共享机制仍不明确。昼夜节律紊乱，尤其是晚间昼夜节律偏好，是一个可能的关联因素，但其在共病中的作用及潜在通路有待进一步研究。
方法：我们开展了一项整合性多组学分析。利用前瞻性UK Biobank数据（N=299155），我们评估了晚间时型与癌症-抑郁共病风险在不同转归路径（基线到共病、癌症到共病、抑郁到共病）中的关联。采用晨型的孟德尔随机化（MR）和多基因风险评分（PRS）进行因果推断和遗传分层。为揭示分子机制，我们整合了基于汇总数据的MR（SMR）和共定位分析，使用GWAS和eQTL数据识别与乳腺癌（BCa）、前列腺癌（PCa）、结直肠癌（CRC）及抑郁一致相关的昼夜节律钟相关基因（CRGs）。此外还开展了通路富集分析和免疫细胞浸润分析以探究共享机制。
结果：晚间时型显著增加了由健康基线状态转归为共病的风险，涉及总体癌症、CRC和BCa（完全校正后HR分别为1.30、1.55和1.43），以及由癌症转归为共病的风险（HR分别为1.29、1.50和1.34）。该效应在女性、吸烟者、受教育程度较高者及社会经济地位较低者等亚组中更为显著。在遗传学上，晨型PRS显示出保护效应，同时具有晚间时型和低PRS的个体构成风险最高的亚组。双样本MR证实了晨型对BCa、CRC和抑郁的因果保护效应。多组学整合识别出五个关键CRGs（GAL、ALAS1、SUCNR1、PTK2、DDIT3），它们对癌症和抑郁均具有一致的因果效应。通路富集分析显示，这些基因显著聚集于神经内分泌调节和代谢通路。GAL和SUCNR1/PTK2分别与肥大细胞和CD8+ T细胞浸润显著相关，揭示了一条从昼夜节律紊乱经由神经-内分泌-免疫失调到共病的通路。
结论：我们的研究阐明晚间时型是癌症-抑郁共病一个重要且可改变的风险因素。我们识别出一个高风险遗传亚组并勾勒出共享的生物学机制，为基于昼夜节律的靶向干预以减轻共病风险提供了基础框架。
查看英文原文 English abstract
Background: The comorbidity of cancer and depression leads to substantially poor prognosis, yet its shared mechanisms remain elusive. Circadian disruption, particularly evening circadian preference, is a plausible link but its role and underlying pathways in comorbidity warrant further investigation.
Methods : We conducted an integrative multi-omics analysis. Utilizing prospective UK Biobank data (N=299155), we assessed the association of evening chronotype with cancer-depression comorbidity risk across distinct transition pathways (baseline to comorbidity, cancer to comorbidity, depression to comorbidity). Mendelian randomization (MR) and polygenic risk scores (PRS) for morning chronotype were performed for causal inference and genetic stratification. To uncover molecular mechanisms, we integrated summary-data-based MR (SMR) and colocalization analyses using GWAS and eQTL data to identify circadian clock-related genes (CRGs) consistently associated with breast (BCa), prostate (PCa), colorectal cancer (CRC), and depression. Pathway enrichment analysis and immune cell infiltration analysis were also conducted to investigate shared mechanisms.
Results: Evening chronotype significantly increased the risk of transitioning from a healthy baseline state to comorbidity for overall cancer, CRC, and BCa (fully adjusted HRs = 1.30, 1.55, and 1.43, respectively), and on the transition from cancer to comorbidity (HRs=1.29, 1.50, and 1.34, respectively). The effect was more pronounced in subgroups such as women, smokers, individuals with higher levels of education, and those with a lower socioeconomic status. Genetically, morning chronotype PRS showed protective effects, and individuals with both evening chronotype and low PRS constituted the highest-risk subgroup. Two-sample MR confirmed a causal protective effect of morning chronotype on BCa, CRC, and depression. Multi-omics integration identified five key CRGs (GAL, ALAS1, SUCNR1, PTK2, DDIT3) with consistent causal effects on both cancer and depression. Pathway enrichment analysis revealed that these genes were significantly clustered in neuroendocrine regulation and metabolic pathways. GAL and SUCNR1/PTK2 were significantly correlated with mast cells and CD8+ T cells infiltration, respectively, revealing a pathway from circadian disruption to comorbidity through neuro-endocrine-immune dysregulation.
Conclusion: Our study elucidates evening chronotype as a significant and modifiable risk factor for cancer-depression comorbidity. We identify a high-risk genetic subgroup and delineate shared biological mechanisms, providing a foundational framework for targeted circadian-based interventions to mitigate comorbidity risk.
利益披露 Disclosure
L. Tang, None..
W. He, None..
H. Hu, None..
J. Wang, None..
J. Liu, None.