Importance Although hypothesis-driven research has identified several factors associated with psychosis, this one-exposure-to-one-outcome approach fails to embrace the multiplicity of exposures. Systematic approaches, similar to agnostic genome-wide analyses, are needed to identify genuine signals. Objective To systematically investigate nongenetic correlates of psychotic experiences through data-driven agnostic analyses and genetically informed approaches to evaluate associations. Design, Setting, Participants This cohort study analyzed data from the UK Biobank Mental Health Survey from January 1 to June 1, 2021. An exposome-wide association study was performed in 2 equal-sized split discovery and replication data sets. Variables associated with psychotic experiences in the exposome-wide analysis were tested in a multivariable model. For the variables associated with psychotic experiences in the final multivariable model, the single-nucleotide variant-based heritability and genetic overlap with psychotic experiences using linkage disequilibrium score regression were estimated, and mendelian randomization (MR) approaches were applied to test potential causality. The significant associations observed in 1-sample MR analyses were further tested in multiple sensitivity tests, including collider-correction MR, 2-sample MR, and multivariable MR analyses. Exposures After quality control based on a priori criteria, 247 environmental, lifestyle, behavioral, and economic variables. Main Outcomes and Measures Psychotic experiences. Results The study included 155 247 participants (87 896 [57%] female; mean [SD] age, 55.94 [7.74] years). In the discovery data set, 162 variables (66%) were associated with psychotic experiences. Of these, 148 (91%) were replicated. The multivariable analysis identified 36 variables that were associated with psychotic experiences. Of these, 28 had significant genetic overlap with psychotic experiences. One-sample MR analyses revealed forward associations with 3 variables and reverse associations with 3. Forward associations with ever having experienced sexual assault and pleiotropy of risk-taking behavior and reverse associations without pleiotropy of experiencing a physically violent crime as well as cannabis use and the reverse association with pleiotropy of worrying too long after embarrassment were confirmed in sensitivity tests. Thus, associations with psychotic experiences were found with both well-studied and unexplored multiple correlated variables. For several variables, the direction of the association was reversed in the final multivariable and MR analyses. Conclusions and Relevance The findings of this study underscore the need for systematic approaches and triangulation of evidence to build a knowledge base from ever-growing observational data to guide population-level prevention strategies for psychosis.

中文翻译：

---

与英国生物银行参与者精神病经历相关的非遗传因素：全暴露分析和孟德尔随机分析。

重要性 尽管假设驱动的研究已经确定了与精神病相关的几个因素，但这种“一次暴露对应一个结果”的方法未能涵盖暴露的多重性。需要类似于不可知的全基因组分析的系统方法来识别真正的信号。目的 通过数据驱动的不可知论分析和遗传信息方法来评估关联，系统地研究精神病经历的非遗传相关性。设计、设置、参与者 这项队列研究分析了 2021 年 1 月 1 日至 6 月 1 日英国生物银行心理健康调查的数据。在 2 个大小相等的分割发现和复制数据集中进行了一项全暴露组关联研究。在多变量模型中测试了与全暴露组分析中的精神病经历相关的变量。对于最终多变量模型中与精神病经历相关的变量，使用连锁不平衡评分回归估计了基于单核苷酸变异的遗传力和与精神病经历的遗传重叠，并应用孟德尔随机化（MR）方法来测试潜在的因果关系。在 1 样本 MR 分析中观察到的显着关联在多项敏感性测试中得到进一步测试，包括碰撞校正 MR、2 样本 MR 和多变量 MR 分析。暴露 在基于先验标准的质量控制后，247 个环境、生活方式、行为和经济变量。主要结果和措施 精神病经历。结果 该研究包括 155 247 名参与者（87 896 [57%] 女性；平均 [SD] 年龄，55.94 [7.74] 岁）。在发现数据集中，162 个变量 (66%) 与精神病经历相关。其中 148 个 (91%) 被重复。多变量分析确定了 36 个与精神病经历相关的变量。其中，28 人与精神病经历有显着的遗传重叠。单样本 MR 分析显示，与 3 个变量呈正向关联，与 3 个变量呈反向关联。 与曾经经历过性侵犯和冒险行为的多效性呈正向关联，与经历过身体暴力犯罪以及吸食大麻和未经历多效性的反向关联。敏感性测试证实，在尴尬之后太久的担忧与多效性存在反向关联。因此，经过充分研究和未经探索的多个相关变量都发现了与精神病经历的关联。对于几个变量，关联的方向在最终的多变量和 MR 分析中发生了逆转。结论和相关性本研究的结果强调需要采用系统方法和证据三角测量，从不断增长的观察数据中建立知识库，以指导人群层面的精神病预防策略。