Abstract
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=3.43×10−12), reduced MDD liability (IVW: OR=0.52; 95% CI 0.38 to 0.72; p-value=5.23×10−05), 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=1.58×10−03). 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=3.25×10−27), as well as smoking initiation on decreased cEF (IVW: β=−0.06; 95%CI −0.09 to −0.03; p-value=6.11×10−05).
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.
Competing Interest Statement
The authors have declared no competing interest.
Funding Statement
This work was supported by the UK Medical Research Council Integrative Epidemiology Unit at the University of Bristol (Grant ref: MC_UU_00011/7) and the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. HMS is supported by the European Research Council (Grant ref: 758813 MHINT). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health and Social Care. ASH acknowledges funding from that National Institute on Drug Abuse (Grant ref: T32DA007261).
Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
The data used in this study are publicly-available GWAS data for cEF (available upon request by contacting the authors), schizophrenia (https://www.med.unc.edu/pgc/download-results/scz/), MDD (https://www.med.unc.edu/pgc/download-results/mdd/), anxiety (https://www.med.unc.edu/pgc/download-results/angst/?choice=Other+GWAS+DataAnxiety+Neuro+Genetics+Study+%28ANGST%29), smoking initiation and drinks per week (data with UK Biobank and 23andMe removed can be found here: https://conservancy.umn.edu/handle/11299/201564, and for 23andMe data access needs to be requested (see below), alcohol dependence (https://figshare.com/articles/dataset/sud2018-alc/14672187) and CUD (https://figshare.com/articles/dataset/sud2020-cud/14842692). The full GWAS summary statistics for the 23andMe discovery data set will be made available through 23andMe to qualified researchers under an agreement with 23andMe that protects the privacy of the 23andMe participants. Please visit https://research.23andme.com/collaborate/#dataset-access/ for more information and to apply to access the data.
I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.
Yes
I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).
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I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.
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Data Availability
The data used in this study are publicly-available GWAS data for cEF (available upon request by contacting the authors), schizophrenia (https://www.med.unc.edu/pgc/download-results/scz/), MDD (https://www.med.unc.edu/pgc/download-results/mdd/), anxiety (https://www.med.unc.edu/pgc/download-results/angst/?choice=Other+GWAS+DataAnxiety+Neuro+Genetics+Study+%28ANGST%29), smoking initiation and drinks per week (data with UK Biobank and 23andMe removed can be found here: https://conservancy.umn.edu/handle/11299/201564, and for 23andMe data access needs to be requested (see below), alcohol dependence (https://figshare.com/articles/dataset/sud2018-alc/14672187) and CUD (https://figshare.com/articles/dataset/sud2020-cud/14842692). The full GWAS summary statistics for the 23andMe discovery data set will be made available through 23andMe to qualified researchers under an agreement with 23andMe that protects the privacy of the 23andMe participants. Please visit https://research.23andme.com/collaborate/#dataset-access/ for more information and to apply to access the data.