基于孟德尔随机化的心理相关表型与胃癌风险因果关联及候选基因优先分析

Causal associations of psychological phenotypes with gastric cancer risk and candidate gene prioritization: a Mendelian randomization study

摘要:

背景与目的 心理相关表型可能通过行为改变、神经内分泌失衡及免疫调节异常等途径影响肿瘤发生，但其与胃癌风险之间的因果关系尚未明确。本研究采用孟德尔随机化（MR）方法评估焦虑、抑郁、神经质及情绪波动与胃癌风险的潜在因果关联，并进一步筛选相关候选基因。方法 采用双样本MR设计，以欧洲人群胃癌全基因组关联研究（GWAS）数据为主要结局，对情绪波动、焦虑、抑郁和神经质四种心理相关表型分别进行单变量MR分析；对阳性结果利用东亚人群胃癌GWAS数据进行外部验证，并进一步开展多变量MR及贝叶斯模型平均MR（MR-BMA）分析。采用PoPS方法进行候选基因优先筛选，并结合GEPIA2平台开展差异表达及预后分析。结果 单变量MR分析显示，仅情绪波动与胃癌风险增加存在统计学关联，逆方差加权法（IVW）分析结果为OR=1.708（95% CI=1.075~2.713，P=0.023）。东亚人群验证结果方向一致，IVW分析OR=1.747（95% CI=0.999~3.056，P=0.050）。多变量MR分析显示，在同时调整焦虑、抑郁及神经质后，情绪波动仍与胃癌风险独立相关（OR=3.296，95% CI=1.089~9.982，P=0.035）。MR-BMA分析显示，情绪波动具有最高边际纳入概率（MIP）（MIP=0.935，调整后P=0.012）。敏感度分析未发现明显异质性、水平多效性及反向因果证据。PoPS分析共筛选出32个候选基因，其中ADAM12和KYNU在胃癌组织中均呈差异表达，且高表达与较差的总生存期相关。结论 遗传学证据提示，情绪波动可能是与胃癌风险升高相关的重要心理相关表型，在多种心理表型中表现出相对独立且稳定的关联。ADAM12和KYNU可能是值得进一步关注的优先候选基因。上述发现为阐释心理相关因素与胃癌发生之间的关系提供了新的遗传学依据，但其潜在生物学机制仍需进一步研究验证。

Abstract:

Background and Aims Psychological phenotypes may influence tumorigenesis through behavioral changes, neuroendocrine dysregulation, and immune modulation. However, their causal relationships with gastric cancer remain unclear. This study aimed to investigate the potential causal associations of anxiety, depression, neuroticism, and mood swings with gastric cancer risk using Mendelian randomization (MR), and to prioritize candidate genes potentially involved in this process.Methods A two-sample MR framework was applied. European gastric cancer genome-wide association study (GWAS) data were used as the primary outcome dataset. Univariable MR analyses were performed for four psychological phenotypes, including mood swings, anxiety, depression, and neuroticism. Positive findings were further evaluated using an East Asian gastric cancer GWAS dataset and subsequently assessed by multivariable MR and Bayesian model averaging MR (MR-BMA). Candidate genes were prioritized using the Polygenic Priority Score (PoPS) method and further evaluated through differential expression and survival analyses using the GEPIA2 platform.Results Univariable MR analysis demonstrated that only mood swings were significantly associated with an increased risk of gastric cancer, with an IVW estimate of OR=1.708 (95% CI=1.075-2.713, P=0.023). External validation in the East Asian dataset showed a consistent effect direction with borderline statistical significance (OR=1.747, 95% CI=0.999-3.056, P=0.050). MVMR analysis indicated that mood swings remained independently associated with gastric cancer risk after adjustment for anxiety, depression, and neuroticism (OR=3.296, 95% CI=1.089-9.982, P=0.035). MR-BMA analysis identified mood swings as the most important exposure (MIP=0.935, adjusted P=0.012). Sensitivity analyses revealed no substantial evidence of heterogeneity, horizontal pleiotropy, or reverse causality. PoPS analysis prioritized 32 candidate genes, among which ADAM12 and KYNU exhibited differential expression in gastric cancer tissues and were significantly associated with overall survival.Conclusion Genetic evidence suggests that mood swings may represent an important psychological phenotype associated with increased gastric cancer risk and retain an independent association among multiple psychological traits. ADAM12 and KYNU may serve as prioritized candidate genes for future mechanistic studies. These findings provide novel genetic insights into the relationship between psychological factors and gastric carcinogenesis, although the underlying biological mechanisms require further validation.