Poorer performance in tasks testing executive function (EF) is associated with a range of psychopathologies such as schizophrenia, major depressive disorder (MDD) and anxiety, as well as smoking and alcohol consumption. We used two-sample bidirectional Mendelian randomization to examine whether these may reflect causal relationships and the direction of causation. We used genome-wide association study summary data ( N = 17 310 to 848 460) for a common EF factor score (cEF), schizophrenia, MDD, anxiety, smoking initiation, alcohol consumption, alcohol dependence and cannabis use disorder (CUD). We found evidence of increased cEF on reduced schizophrenia liability (OR = 0.10; CI: 0.05 to 0.19; p -value = 3.43 × 10 −12 ), MDD liability (OR = 0.52; CI: 0.38 to 0.72; p -value = 5.23 × 10 −05 ), drinks per week ( β = –0.06; CI: –0.10 to −0.02; p -value = 0.003) and CUD liability (OR = 0.27; CI: 0.12 to 0.61; p -value = 1.58 × 10 −03 ). We also found evidence of increased schizophrenia liability ( β = −0.04; CI: −0.04 to −0.03; p -value = 3.25 × 10 −27 ) and smoking initiation on decreased cEF ( β = −0.06; CI: −0.09 to −0.03; p -value = 6.11 × 10 −05 ). Our results indicate potential causal relationships between cEF and mental health and substance use. Further studies are required to improve our understanding of the underlying mechanisms of these effects, but our results suggest that EF may be a promising intervention target for mental health and substance use.

Background: Executive function consists of several cognitive control processes that are able to regulate lower level processes. Poorer performance in tasks designed to test executive function is associated with a range of psychopathologies such as schizophrenia, major depressive disorder (MDD) and anxiety, as well as with smoking and alcohol consumption. Despite these well-documented associations, whether they reflect causal relationships, and if so in what direction, remains unclear. We aimed to establish whether there is a causal relationship between a latent factor for performance on multiple executive function tasks - which we refer to as common executive function (cEF) - and liability to schizophrenia, MDD, anxiety, smoking initiation, alcohol consumption, alcohol dependence and cannabis use disorder (CUD), and the directionality of any relationship observed. Methods: We used a two-sample bidirectional Mendelian randomisation (MR) approach using genome-wide association study (GWAS) summary data from large cohorts (N=17,310 to 848,460) to examine whether causal relationships exist, and if so in which direction. Results: We found evidence of a causal effect of increased cEF on reduced schizophrenia liability (IVW: OR=0.10; 95% CI 0.05 to 0.19; p-value=3.43x10-12), reduced MDD liability (IVW: OR=0.52; 95% CI 0.38 to 0.72; p-value=5.23x10-05), decreased drinks per week (IVW: β=-0.06; 95% CI -0.10 to -0.02; p-value=0.003), and reduced CUD liability (IVW: OR=0.27; 95% CI 0.12 to 0.61; p-value=1.58x10-03). We also found evidence of a causal effect of increased schizophrenia liability on decreased cEF (IVW: β=-0.04; 95% CI -0.04 to -0.03; p-value=3.25x10-27), as well as smoking initiation on decreased cEF (IVW: β=-0.06; 95%CI -0.09 to -0.03; p-value=6.11x10-05). Conclusion: Our results indicate a potential bidirectional causal relationship between a latent factor measure of executive function (cEF) and schizophrenia liability, a possible causal effect of increased cEF on reduced MDD liability, CUD liability, and alcohol consumption, and a possible causal effect of smoking initiation on decreased cEF. These results suggest that executive function should be considered as a potential risk factor for some mental health and substance use outcomes, and may also be impacted by mental health (particularly schizophrenia). Further studies are required to improve our understanding of the underlying mechanisms of these effects, but our results suggest that executive function may be a promising intervention target. These results may therefore inform the prioritisation of experimental medicine studies (e.g., of executive function interventions), for both mental health and substance use outcomes, to improve the likelihood of successful translation.