Bipolar disorder (BD) and schizophrenia (SZ) are associated with higher odds of suicide attempt (SA). In this study, we aimed to explore the effect of BD and SZ genetic liabilities on SA, also considering the contribution of behavioral traits, socioeconomic factors, and substance use disorders. Leveraging large-scale genome-wide association data from the Psychiatric Genomics Consortium (PGC) and the UK Biobank (UKB), we conducted a two-sample Mendelian randomization (MR) analysis to evaluate the putative causal effect of BD (41,917 cases, 371,549 controls) and SZ (53,386 cases, 77,258 controls) on SA (26,590 cases, 492,022 controls). Then, we assessed the putative causal effect of BD and SZ on behavioral traits, socioeconomic factors, and substance use disorders. Considering the associations identified, we evaluated the direct causal effect of behavioral traits, socioeconomic factors, and substance use disorders on SA using a multivariable MR approach. The genetic liabilities to BD and SZ were associated with higher odds of SA (BD odds ratio (OR) = 1.24, p = 3.88 × 10⁻¹²; SZ OR = 1.09, p = 2.44 × 10^-20). However, while the effect of mental distress (OR = 1.17, p = 1.02 × 10^-4) and risk-taking (OR = 1.52, p = 0.028) on SA was independent of SZ genetic liability, the BD-SA relationship appeared to account for the effect of these risk factors. Similarly, the association with loneliness on SA was null after accounting for the effect of SZ genetic liability. These findings highlight the complex interplay between genetic risk of psychiatric disorders and behavioral traits in the context of SA, suggesting the need for a comprehensive mental health assessment for high-risk individuals.

双相情感障碍 (BD) 和精神分裂症 (SZ) 与较高的自杀企图 (SA) 几率相关。在本研究中，我们旨在探讨 BD 和 SZ 遗传倾向对 SA 的影响，同时考虑行为特征、社会经济因素和物质使用障碍的影响。利用来自精神病学基因组学联盟 (PGC) 和英国生物银行 (UKB) 的大规模全基因组关联数据，我们进行了两个样本孟德尔随机化 (MR) 分析，以评估 BD 的假定因果效应（41,917 例，371,549 例）对照）和 SZ（53,386 例病例，77,258 例对照）SA（26,590 例病例，492,022 例对照）。然后，我们评估了 BD 和 SZ 对行为特征、社会经济因素和物质使用障碍的假定因果影响。考虑到所确定的关联，我们使用多变量 MR 方法评估了行为特征、社会经济因素和物质使用障碍对 SA 的直接因果影响。BD 和 SZ 的遗传倾向与较高的 SA 几率相关（BD 比值比 (OR) = 1.24，p  = 3.88 × 10 ^-12；SZ OR = 1.09，p  = 2.44 × 10 ^-20）。然而，虽然精神困扰（OR = 1.17，p  = 1.02 × 10 ^-4）和冒险（OR = 1.52，p  = 0.028）对SA的影响与SZ遗传倾向无关，但BD-SA关系似乎考虑这些风险因素的影响。同样，在考虑了 SZ 遗传责任的影响后，SA 与孤独感的关联也为零。这些发现强调了精神疾病遗传风险与 SA 背景下行为特征之间复杂的相互作用，表明需要对高风险个体进行全面的心理健康评估。