BACKGROUND The heterogeneity of genetic effects on major depressive disorder (MDD) may be partly attributable to moderation of genetic effects by environment, such as exposure to childhood trauma (CT). Indeed, previous findings in two independent cohorts showed evidence for interaction between polygenic risk scores (PRSs) and CT, albeit in opposing directions. This study aims to meta-analyze MDD-PRS × CT interaction results across these two and other cohorts, while applying more accurate PRSs based on a larger discovery sample. METHODS Data were combined from 3024 MDD cases and 2741 control subjects from nine cohorts contributing to the MDD Working Group of the Psychiatric Genomics Consortium. MDD-PRS were based on a discovery sample of ∼110,000 independent individuals. CT was assessed as exposure to sexual or physical abuse during childhood. In a subset of 1957 cases and 2002 control subjects, a more detailed five-domain measure additionally included emotional abuse, physical neglect, and emotional neglect. RESULTS MDD was associated with the MDD-PRS (odds ratio [OR] = 1.24, p = 3.6 × 10-5, R2 = 1.18%) and with CT (OR = 2.63, p = 3.5 × 10-18 and OR = 2.62, p = 1.4 ×10-5 for the two- and five-domain measures, respectively). No interaction was found between MDD-PRS and the two-domain and five-domain CT measure (OR = 1.00, p = .89 and OR = 1.05, p = .66). CONCLUSIONS No meta-analytic evidence for interaction between MDD-PRS and CT was found. This suggests that the previously reported interaction effects, although both statistically significant, can best be interpreted as chance findings. Further research is required, but this study suggests that the genetic heterogeneity of MDD is not attributable to genome-wide moderation of genetic effects by CT.

中文翻译：

---

童年创伤是否会降低抑郁症的多基因风险？对精神病学基因组学联盟 5,765 名受试者的荟萃分析


背景遗传对重度抑郁症（MDD）影响的异质性可能部分归因于环境对遗传影响的调节，例如暴露于童年创伤（CT）。事实上，之前两个独立队列的研究结果表明，多基因风险评分 (PRS) 和 CT 之间存在相互作用，尽管方向相反。本研究旨在对这两个队列和其他队列的 MDD-PRS × CT 相互作用结果进行荟萃分析，同时基于更大的发现样本应用更准确的 PRS。方法 数据来自 3024 名 MDD 病例和 2741 名对照受试者，这些受试者来自 9 个队列，为精神病学基因组学联盟 MDD 工作组做出贡献。 MDD-PRS 基于约 110,000 名独立个体的发现样本。 CT 被评估为童年时期遭受性虐待或身体虐待的情况。在 1957 个案例和 2002 个对照受试者的子集中，更详细的五领域测量还包括情感虐待、身体忽视和情感忽视。结果 MDD 与 MDD-PRS（比值比 [OR] = 1.24，p = 3.6 × 10-5，R2 = 1.18%）和 CT 相关（OR = 2.63，p = 3.5 × 10-18 和 OR = 2.62 ，p = 1.4 × 10-5 分别用于二域和五域测量）。 MDD-PRS 与二域和五域 CT 测量之间没有发现交互作用（OR = 1.00，p = .89 和 OR = 1.05，p = .66）。结论 没有发现 MDD-PRS 和 CT 之间相互作用的荟萃分析证据。这表明先前报告的相互作用效应虽然在统计上都很显着，但最好将其解释为偶然发现。还需要进一步的研究，但这项研究表明 MDD 的遗传异质性不能归因于 CT 对全基因组遗传效应的调节。