Educational attainment reduces the risk of suicide attempt among individuals with and without psychiatric disorders independent of cognition: a bidirectional and multivariable Mendelian randomization study with more than 815,000 participants

Objective Rates of suicidal behavior are increasing in the United States and identifying causal risk factors continues to be a public health priority. Observational literature has shown that educational attainment (EA) and cognitive performance (CP) influence suicide attempt risk; however, the causal nature of these relationships is unknown. Methods Using summary statistics from genome-wide association studies (GWAS) of EA, CP, and suicide attempt risk with > 815,000 combined study participants, we performed multivariable Mendelian randomization (MR) to disentangle the effects of EA and CP on attempted suicide.Results In single-variable MR (SVMR), EA and CP significantly reduced suicide attempt risk (EA odds ratio (OR) per standard deviation (SD) increase in EA (4.2 years), 0.524, 95% CI, 0.412-0.666, P=1.07x10-7; CP OR per SD increase in standardized score, 0.714, 95% CI, 0.577-0.885, P=0.002). Conversely, bidirectional analyses found no effect of suicide attempt on EA or CP. Using various multivariable MR (MVMR) models, EA seems to be the predominant risk factor for suicide attempt risk with the independent effect (OR, 0.342, 95% CI, 0.206-0.342, P=1.61x10-4), while CP had no effect (OR, 1.182, 95% CI, 0.842-1.659, P=0.333). In additional MVMR analyses accounting simultaneously for potential behavioral and psychiatric mediators (tobacco smoking; alcohol consumption; and self-reported nerves, tension, anxiety, or depression), the effect of EA remained significant (OR, 0.541, 95% CI, 0.421-0.696, P=3.33x10 6). Consistency of results across complementary MR methods accommodating different assumptions about genetic pleiotropy strengthened causal inference.Conclusions Our results show that even after accounting for psychiatric disorders and behavioral mediators, EA, but not CP, may causally influence suicide attempt risk, which could have important implications for health policy and programs aimed at reducing the increasing rates of suicide.