孟德尔随机化研究首次性行为年龄与双相障碍的关系

The relationship between age at first sexual intercourse and bipolar disorder:a bidirectional two-sample Mendelian randomization analysis

目的通过孟德尔随机化(Mendelian randomization,MR)方法探索首次性行为年龄(age at first sexual intercourse,AFS)与双相障碍发病风险之间的潜在因果关系。方法利用来自欧洲血统人群的大规模全基因组关联研究(Genome-Wide Association Studies,GWAS)汇总数据,选择与AFS和双相障碍相关、相互独立的遗传位点作为暴露和结局的工具变量。AFS的数据来源包括医学研究委员会整合流行病学单位(Medical Research Council Integrative Epidemiology Unit,MRC-IEU)的406457名个体(AFS1数据)和英国生物库(UK Biobank,UKB)的397338名个体(AFS2数据)。双相障碍的GWAS数据来源于精神病基因组学联盟(Psychiatric Genomics Consortium,PGC)2019年和2021年的研究,分别包括20352例患者与31358名对照者(BD1数据)和41917例患者与371549名对照者(BD2数据)。通过逆方差加权法(inverse variance weighting,IVW)评估AFS与BD的因果效应,此外采用MR-Egger回归、加权中位数法(weighted median,WM)、基于众数的简单估计和基于众数的加权估计法检验结果稳定性,以优势比(odds ratio,OR)和效应系数(beta coefficient,β)作为效应大小的评价指标。结果正向MR分析显示,AFS与双相障碍发病风险存在因果关系(IVW:OR=0.69,95%CI=0.57~0.82,P<0.001)。反向MR分析显示,双相障碍与AFS未见因果关系(IVW:β=0.01,95%CI=-0.01~0.03,P=0.159)。结论AFS与双相障碍发病风险之间有因果关系,而双相障碍对AFS的影响不显著。

Objective This study aims to explore the potential causal relationship between the age at first sexual intercourse(AFS)and the risk of developing bipolar disorder(BD)using the Mendelian Randomization(MR)approach.Methods This study leverages Genome-Wide Association Studies(GWAS)data from European ancestries,identifying independent genetic loci associated with AFS and BD as instrumental variables.AFS data came from the Medical Research Council Integrative Epidemiology Unit(MRC-IEU),covering 406457 individuals(AFS1),and the UK Biobank(UKB),with 397338 individuals(AFS2).Bipolar disorder GWAS data were sourced from the Psychiatric Genomics Consortium(PGC),featuring 20352 cases and 31358 controls in 2019(BD1),and 41917 cases with 371549 controls in 2021(BD2).The causal effects between AFS and BD were assessed using inverse variance weighting(IVW),supplemented by MR-Egger regression,weighted median(WM),Simple Mode and Weighted Mode to ensure result stability.Effect sizes were determined using odds ratio(OR)and beta coefficient(β).Results The forward MR analysis revealed a significant causal relationship between earlier AFS and an increased risk of developing BD(IVW:OR=0.69,95%CI=0.57-0.82,P<0.001).However,the reverse MR analysis did not find a significant effect of BD on the timing of AFS(IVW:β=0.01,95%CI=-0.01-0.03,P=0.159).Conclusion There is a causal relationship between the AFS and the risk of developing BD,while the impact of BD on AFS is not significant.