Genetic influences on externalizing psychopathology overlap with cognitive functioning and show developmental variation

Abstract

Background Questions remain regarding whether genetic influences on early life psychopathology overlap with cognition and show developmental variation. Methods Using data from 9,421 individuals aged 8 to 21 from the Philadelphia Neurodevelopmental Cohort, factors of psychopathology were generated using a bifactor model of item-level data from a psychiatric interview. Five orthogonal factors were generated: anxious-misery (mood and anxiety), externalizing (attention deficit hyperactivity and conduct disorder), fear (phobias), psychosis-spectrum, and a general factor. Genetic analyses were conducted on a subsample of 4,662 individuals of European American ancestry. A genetic relatedness matrix was used to estimate heritability of these factors, and genetic correlations with executive function, episodic memory, complex reasoning, social cognition, motor speed, and general cognitive ability. Gene × Age analyses determined whether genetic influences on these factors show developmental variation. ResultsExternalizing was heritable (h 2 =0.46, p=1x10 -6 ), but not anxious-misery (h 2 =0.09, p=0.183), fear (h 2 =0.04, p=0.337), psychosis-spectrum (h 2 =0.00, p=0.494) or general psychopathology (h 2 =0.21, p=0.040). Externalizing showed genetic overlap with face memory (ρ g =-0.412, p=0.004), verbal reasoning (ρ g =-0.485, p=0.001), spatial reasoning (ρ g =-0.426, p=0.010), motor speed (ρ g =0.659, p=1x10 -4 ), verbal knowledge (ρ g =-0.314, p=0.002), and general cognitive ability (g)(ρ g =-0.394, p=0.002). Gene × Age analyses revealed decreasing genetic variance (γ g = -0.146, p = 0.004), and increasing environmental variance (γ e = 0.059, p = 0.009) on externalizing.Conclusions Cognitive impairment may be a useful endophenotype of externalizing psychopathology and, therefore, help elucidate its pathophysiological underpinnings. Decreasing genetic variance suggests that gene discovery efforts may be more fruitful in children than adolescents or young adults.

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“…This general domain explains most of the associations with positive attributes, which suggests this association is not due to a particular set of symptoms, but to overall mental health problems which are shared among all symptomatic domains. After parsing out variance due to this common factor, the conduct score still explained additional variability in positive attributes, which suggests the associations between conducts specific factor and positive attributes might be due to other mechanisms not shared with the common factors such as genetic overlap with poor verbal and spatial reasoning, verbal knowledge, and general cognitive ability [40], for example. Previous research has found bidirectional associations between positive attributes and both internalizing and externalizing disorders, especially the latter [11].…”

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