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

Josephine Mollon, Emma E.M. Knowles, Samuel R. Mathias, Amanda Rodrigue, Tyler M. Moore, Monica E. Calkins, Ruben C. Gur, Juan Manuel Peralta, Daniel J. Weiner, Elise B. Robinson, Raquel E. Gur, John Blangero, Laura Almasy, David C. Glahn

Research output: Contribution to journalArticlepeer-review


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 8-21 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. RESULTS: Externalizing was heritable (h2 = 0.46, p = 1 × 10-6), but not anxious-misery (h2 = 0.09, p = 0.183), fear (h2 = 0.04, p = 0.337), psychosis-spectrum (h2 = 0.00, p = 0.494), or general psychopathology (h2 = 0.21, p = 0.040). Externalizing showed genetic overlap with face memory (ρg = -0.412, p = 0.004), verbal reasoning (ρg = -0.485, p = 0.001), spatial reasoning (ρg = -0.426, p = 0.010), motor speed (ρg = 0.659, p = 1x10-4), verbal knowledge (ρg = -0.314, p = 0.002), and general cognitive ability (g)(ρg = -0.394, p = 0.002). Gene × Age analyses revealed decreasing genetic variance (γg = -0.146, p = 0.004) and increasing environmental variance (γe = 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.

Original languageEnglish (US)
Pages (from-to)e29
JournalPsychiatrie et Psychobiologie
Issue number1
StatePublished - Mar 31 2021
Externally publishedYes


  • Cognition
  • Gene × Age
  • development
  • externalizing
  • heritability
  • pleiotropy
  • psychopathology

ASJC Scopus subject areas

  • Psychiatry and Mental health


Dive into the research topics of 'Genetic influences on externalizing psychopathology overlap with cognitive functioning and show developmental variation'. Together they form a unique fingerprint.

Cite this