Sexual dysfunction is a major side effect of selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs). We conducted a genome-wide association study to identify the genetic factors contributing to the risk of SSRI/SNRI-induced sexual dysfunction by testing 186 320 single nucleotide polymorphism (SNP) markers in a cohort of 201 Japanese major depression patients including 36 with sexual dysfunction induced by SSRI (paroxetine or fluvoxamine) or SNRI (milnacipran). The Cochran-Armitage trend test showed that 11 SNPs, tightly clustered in a distinct region on chromosome 14q21.3, were associated with SSRI/SNRI-induced sexual dysfunction at a genome-wide significance level after false discovery rate (FDR) correction, and the strongest SNP association was with rs1160351 (P=3.04 × 10(-7), risk ratio=2.92, 95% confidence interval (CI)=1.79-4.76). These SNPs mapped to the intronic region of the MDGA2 gene. A Manhattan plot showed that the strong association peak remained in MDGA2 after adjustment for sex and age in a multivariable logistic regression analysis although P values increased slightly and became non-significant. Replication studies with larger sample sizes are required to validate this exploratory study, but our findings may provide insights into the genetic basis of sexual dysfunction induced by SSRI/SNRI.

译文

性功能障碍是选择性5-羟色胺再摄取抑制剂 (SSRIs) 和5-羟色胺-去甲肾上腺素再摄取抑制剂 (SNRIs) 的主要副作用。我们进行了一项全基因组关联研究,通过在201名日本重度抑郁症患者队列中测试186 320单核苷酸多态性 (SNP) 标记,确定了导致SSRI/SNRI诱发性功能障碍风险的遗传因素,包括36名由SSRI (帕罗西汀或氟伏沙明) 或SNRI诱发的性功能障碍 (米那西普兰)。Cochran-Armitage趋势测试表明,在错误发现率 (FDR) 校正后,在全基因组显着水平上,紧密聚集在染色体14q21.3的一个不同区域中的11个snp与SSRI/SNRI诱导的性功能障碍相关,SNP关联最强的是rs1160351 (P = 3.04 × 10(-7),风险比 = 2.92,95% 置信区间 (CI)= 1.79-4.76)。这些snp定位到MDGA2基因的内含子区域。曼哈顿图显示,在多变量逻辑回归分析中对性别和年龄进行调整后,MDGA2的强关联峰值仍然存在,尽管p值略有增加并且变得不显着。需要较大样本量的复制研究来验证这项探索性研究,但我们的发现可能为SSRI/SNRI诱发的性功能障碍的遗传基础提供见解。

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