基于两样本孟德尔随机化研究抑郁症和抗抑郁药物靶基因与睡眠呼吸暂停的关联

doi:10.6040/j.issn.1671-7554.0.2024.1213

摘要/Abstract

摘要： 目的研究抑郁症与阻塞性睡眠呼吸暂停(obstructive sleep apnea, OSA)的因果关系,从抗抑郁药物靶点中寻找治疗OSA合并抑郁症的潜在靶点。方法从全基因组关联分析(genome-wide association studies, GWAS)获取抑郁症和OSA的相关遗传变异数据;从eQTLGen Consortium获得抗抑郁药物靶点的编码基因数据;分别以抑郁症和抗抑郁药物靶点作为暴露,OSA为结局,进行两样本孟德尔随机化方法(two-sample Mendelian randomization, TSMR)分析。将与暴露变量强相关的单核苷酸多态性(single nucleotide poly-morphisms, SNP)作为工具变量,采用逆方差加权法(inverse-variance weighted, IVW)作为分析因果关系的主要方法,MR-Egger、加权中位数法(weighted median, WME)、简易模式法(simple mode, SM)和加权模式法(weighted mode, WM)作为次要方法进行TSMR分析;采用MR-PRESSO和留一法进行敏感度分析,Cochrans Q检验和MR-Egger截距测试检测异质性和水平多效性,漏斗图评估潜在偏倚。结果 IVW分析结果显示,遗传预测的抑郁症与OSA风险增加存在因果关系(OR=1.180,95%CI=1.065~1.306,P=0.001);Cochrans Q检验和MR-Egger截距测试结果显示不存在异质性和水平多效性;MR-PRESSO检验和留一法检验结果显示剔除任何一个SNP对因果关系的影响均不显著;漏斗图显示左右分布大致均匀。抗抑郁药物靶点HTR3A(OR=1.174,95%CI=1.022~1.350,P=0.024)和GRIN3A(OR=1.227,95%CI=1.126~1.338,P<0.001)的表达会使OSA风险增加。结论抑郁症会增加OSA发病风险,抗抑郁药物靶点HTR3A和GRIN3A可能成为治疗抑郁症合并OSA的候选药物靶点。

关键词: 孟德尔随机化, 抑郁症, 阻塞性睡眠呼吸暂停, 抗抑郁药物靶点

Abstract: Objective To explore the causal relationship between obstructive sleep apnea(OSA)and depression and to find potential targets for the treatment of OSA with depression from the targets of antidepressant drugs. Methods Data on genetic variants associated with depression and OSA were obtained from genome-wide association studies(GWAS). The coding gene data of antidepressant drug targets were obtained from eQTLGen Consortium website. TSMR analysis was performed with depression and antidepressant drug targets as exposure and OSA as outcome. Single nucleotide polymorphisms(SNPS)strongly associated with exposure variables were used as instrumental variables, and inverse-variance weighted(IVW)was used as the main analysis method while MR-Egger, weighted median(WME), simple mode(SM)and weighted mode(WM)were used as supplementary evidence for TSMR analysis. Sensitivity analysis was performed with MR-PRESSO and leave-one-out method, excluding each instrumental variable to observe its influence on the overall estimation. Cochrans Q test and MR-Egger intercept test were used to determine heterogeneity and horizontal pleiotropy. Funnel plot was used to assess potential bias. Results IVW analysis showed that there was a causal relationship between genetic prediction of depression and increased risk of OSA(OR=1.180, 95%CI=1.065-1.306, P=0.001). Cochrans Q test and MR-Egger intercept test showed no heterogeneity and horizontal pleiotropy. MR-PRESSO test and leave-one-out test indicated that the effect of excluding any SNP on causality was not significant, and the funnel plot showed that the left and right distribution was roughly uniform. The expression of antidepressant drug targets HTR3A(OR=1.174,95%CI= 1.022-1.350,P=0.024)and GRIN3A(OR=1.227,95%CI= 1.126-1.338,P<0.001)had a causal relationship with increased risk of OSA. Conclusion Depression can increase the risk of OSA, and the antidepressant drug targets HTR3A and GRIN3A may be candidate drug targets for the treatment of depression with OSA.

Key words: Mendelian randomization, Depression, Obstructive sleep apnea, Antidepressant drug targets

中图分类号:

R749

陈婵,李巨章,何稳,吴巧珍. 基于两样本孟德尔随机化研究抑郁症和抗抑郁药物靶基因与睡眠呼吸暂停的关联[J]. 山东大学学报 (医学版), 2026, 64(1): 28-36.

CHEN Chan, LI Juzhang, HE Wen, WU Qiaozhen. Association of depression and antidepressant drug target genes with sleep apnea based on two-sample Mendelian randomization[J]. Journal of Shandong University (Health Sciences), 2026, 64(1): 28-36.

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