Is there a causal relationship between executive function and liability to mental health and substance use? A Mendelian randomization approach

Abstract

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.

Cognitive impairment as a predictor of long-term psychological distress in patients with polysubstance use disorders: a prospective longitudinal cohort study

“…Moreover, the BRIEF-A has shown questionable criterion-related validity pertaining to performance on objective tests of executive functioning [ 108 , 113 – 115 ] and clinically relevant SUD treatment outcomes [ 82 ]. BRIEF-A may be particularly sensitive to latent executive deficits shared by SUD and psychiatric disorders, e.g., working memory impairments [ 14 , 22 , 116 – 122 ]. Conversely, the BRIEF-A may gauge self-reported functional debilitation associated with psychological distress or mental disorders among patients with SUD rather than impaired executive functioning as defined from psychometric tests.…”

“…The relationship between SUDs, mental health and cognitive functioning is intricately intertwined [ 12 – 14 ]. Epidemiological and clinical studies link SUD to a host of mental illnesses, such as mood and anxiety disorders, attention-deficit hyperactivity disorder, psychosis, personality disorders, suicidality and general psychological distress [ 13 , 15 – 21 ].…”

Alcohol and psychoactive substance use in a cohort of children followed by child protection in France

“…However, when the analysis accounted for gender and externalized symptoms, no bidirectional association was found. Despite these contradictory results, the bidirectional relationship between SUD and psychological symptoms has been documented in the general population (12,(39)(40)(41), further studies should further investigate populations exposed to adversity, especially in child protection settings.…”

The genetic landscape of substance use disorders

“…One study indicated that PAU liability, which combined AUD and problematic drinking, may also causally decrease educational attainment [9], however other studies have failed to replicate this finding [97]. There is no evidence for causal effects in either direction between AUD and executive functioning [98], nor is there evidence for causal effects of alcohol dependence on late-onset Alzheimer's disease risk [99].…”