Abstract

Many psychiatric disorders are associated with impaired executive functioning (EF). The associated EF component varies by psychiatric disorders, and this variation might be due to genetic liability. We explored the genetic association between five psychiatric disorders and EF in clinically-recruited attention deficit hyperactivity disorder (ADHD) children using polygenic risk score (PRS) methodology. Genome-wide association study (GWAS) summary data for ADHD, major depressive disorder (MDD), schizophrenia (SZ), bipolar disorder (BIP) and autism were used to calculate the PRSs. EF was evaluated by the Stroop test for inhibitory control, the trail-making test for cognitive flexibility, and the digital span test for working memory in a Chinese ADHD cohort (n = 1147). Exploratory factor analysis of the three measures identified one principal component for EF (EF-PC). Linear regression models were used to analyze the association between each PRS and the EF measures. The role of EF measures in mediating the effects of the PRSs on ADHD symptoms was also analyzed. The result showed the PRSs for MDD, ADHD and BIP were all significantly associated with the EF-PC. For each EF component, the association results were different for the PRSs of the five psychiatric disorders: the PRSs for ADHD and MDD were associated with inhibitory control (adjusted P = 0.0183 and 0.0313, respectively), the PRS for BIP was associated with working memory (adjusted P = 0.0416), and the PRS for SZ was associated with cognitive flexibility (adjusted P = 0.0335). All three EF measures were significantly correlated with ADHD symptoms. In mediation analyses, the ADHD and MDD PRSs, which were associated with inhibitory control, had significant indirect effects on ADHD symptoms through the mediation of inhibitory control. These findings indicate that the polygenic risks for several psychiatric disorders influence specific executive dysfunction in children with ADHD. The results helped to clarify the relationship between risk genes of each mental disorder and the intermediate cognitive domain, which may further help elucidate the risk genes and motivate efforts to develop EF measures as a diagnostic marker and future treatment target.

Highlights

  • Executive functioning (EF) is a high-order set of cognitive functions that regulate an individual’s capacity to change and adjust his or her behaviors according to the shifting demands of complex environments[1]

  • (se = 0.0391)); and the association of polygenic risk score (PRS) for ASD with all three EF components did not pass the permutation correction. Since both the attention deficit hyperactivity disorder (ADHD) and major depressive disorder (MDD) PRSs were associated with inhibitory control, we constructed a multivariable regression model with standardized ADHD PRS, MDD PRS, their interaction and other covariates

  • The PRSs for MDD, ADHD, and bipolar disorder (BIP) were associated with our overall measure of EF

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Summary

Introduction

Executive functioning (EF) is a high-order set of cognitive functions that regulate an individual’s capacity to change and adjust his or her behaviors according to the shifting demands of complex environments[1]. Chang et al Translational Psychiatry (2020)10:182 psychopathology. Understanding the role of separate EF components in psychiatric disorders is a critical step in gaining a better understanding of disease psychopathology. The specificity of these EF component deficits in different psychiatric disorders is not clear[13]. The heritability of EF was calculated to be approximately 20 to 40%14. The association between EF dysfunction and the psychiatric diseases may, in part, reflect pleiotropy, which is the overlap between the genetic liability of two or more traits, perhaps owing to shared causal pathways[15]. The genes that influence vulnerability to psychiatric disorders may influence EF deficits

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