Abstract Objectives To investigate the genetic overlap and causal relationship between posttraumatic stress disorder (PTSD) and traits related to educational attainment. Design Genetic correlation, polygenic risk scoring, and causal inference via multivariable Mendelian randomization (MR). Setting Psychiatric Genomics Consortium for PTSD, UK Biobank, 23andMe, and Social Science Genetic Association Consortium. Participants 23,185 PTSD cases and 151,309 controls; up to 1,131,881 individuals assessed for educational attainment and related traits. Main outcome measures Genetic correlation obtained from linkage disequilibrium score regression, phenotypic variance explained by polygenic risk scores, and casual effects (beta values) estimated with MR Results PTSD showed strong negative genetic correlations with educational attainment (EdAtt; r g =−0.26, p=4.6×10 −8 ). PRS based on genome-wide significant variants associated with EdAtt significantly predicted PTSD (p=6.16×10 −4 ), but PRS based on variants associated with PTSD did not predict EdAtt (p&gt;0.05). MR analysis indicated that EdAtt has negative causal effects on PTSD (beta=−0.23, p=0.004). Investigating potential mediators of the EdAtt-PTSD relationship, we observed that propensity for trauma exposure and risk-taking behaviors are risk factors for PTSD independently from EdAtt (beta = 0.36, p = 2.57×10 −5 and beta = 0.76, p = 6.75×10 −4 , respectively), while income fully mediates the causal effect of EdAtt on PSTD (MR: Income – beta = −0.18, p =0.001; EdAtt – beta =−0.23, p=0.004; multivariable MR: Income – beta = −0.32, p = 0.017; EdAtt – beta = −0.04, p = 0.786). Conclusions We report novel findings based on large-scale datasets regarding the relationship between educational attainment and PTSD, supporting the role of economic status as the key mediator in the causal relationship observed. What is already known on this topic There is a well-established negative association of educational attainment and other traits related to cognitive ability with posttraumatic stress disorders (PTSD). However, the findings of these previous studies support various possible causal explanations: 1) individuals with high educational attainment are more resilient with respect to developing PTSD, 2) PTSD negatively impacts cognitive ability, or 3) PTSD and educational attainment share some underlying determinants, including relevant molecular mechanisms. A key obstacle to disentangling the complex association between educational attainment and PTSD is reverse causation, i.e. the situation in which the outcome precedes and causes the exposure instead of the other way around. What this study adds We conducted a causal-inference investigation based on large-scale information from the investigation of more than one million individuals. Our main assumption is that genetic information can strongly minimize the bias of reverse causation, because genetic variants are determined at conception and do not change throughout life. Our findings indicate 1) the effect of traits related to educational attainment on PTSD, 2) no reverse effect of PTSD on educational attainment, and 3) economic status mediates the relationship between educational attainment and PTSD, independently from the brain mechanisms related to educational attainment.

Economic status mediates the relationship between educational attainment and posttraumatic stress disorder: a multivariable Mendelian randomization study