Heritability of Neuropsychological Subtypes in ADHD

• In Event: 3-202 - What variation in executive functioning tells us about ADHD: Insights from twin and longitudinal studies

Integrative Statement

Introduction.
Attention deficit hyperactivity disorder (ADHD) is associated with a heterogeneous phenotype and etiology. Neuropsychological deficits are frequently proposed as endophenotypes of ADHD; however, no single deficit has been sufficient or necessary to explain variance in ADHD severity. A recent study identified six neuropsychological profiles associated with ADHD (Fair et al., 2012), suggesting homogenous cognitive subtypes that may explain phenotypic variance in the disorder. Given that heritability in ADHD symptom severity is high (~.70), estimation of the heritability of cognitive profiles could offer insight into unique etiological mechanisms associated with homogenous subtypes of ADHD.

Methods.
1,319 twin pairs (34% monozygotic) and 227 siblings (total N=2,866; age range = 7-19 years) were recruited through the Colorado Learning Disabilities Research Center. The sample included youth affected by ADHD (24%) and neurotypical controls (76%). Participants completed a comprehensive neuropsychological battery including tests of verbal and spatial working memory, processing speed, inhibition and arousal. A research diagnosis of ADHD was assigned to youth if caregiver and teacher ratings on a DSM-IV-TR ADHD checklist indicated at least six symptoms of inattention or hyperactivity/impulsivity.

Results.
Latent class analysis of the full sample identified four distinct neuropsychological profiles characterized by 1) Above average cognition, 2) Average cognition, 3) Broad Cognitive Deficits, and 4) Cognitive Deficits with Variable Response Time (RT) (see Figure 2). These subtypes were similar to those identified by Fair and colleagues (2012). Youth with ADHD were more likely to show one of the latter two profiles (odds ratios = 2.62 and 1.74, respectively) although diagnostic groups were represented across all four subtypes. Heritability of neuropsychological profiles was moderate at h2=.44, with the contribution of non-shared environment at .56 and no significant contribution of shared environment. Heritability of neuropsychological profiles did not differ systematically by diagnosis (p=.689). However, the heritability of individual cognitive factors was highly variable within and across subtypes. Likewise, the degree of ADHD symptom variance accounted for by cognitive factors varied across subtypes. Relative to the Average group, the Broad Cognitive Deficits group had lower parental education (p = .012), while parental education in the Cognitive Deficits with Variable RT group was comparable (p = .405).

Conclusions.
Altogether, results suggest neuropsychological profiles, rather than universal cognitive deficits, may increase risk for ADHD in youth and reflect homogenous subtypes of ADHD. Heritability of cognitive factors within subtypes is variable, suggesting neuropsychological profiles may constitute endophenotypes marking distinct genetic risk. Classification of neuropsychological subtypes of ADHD has potential to facilitate precision medicine approaches to treatment of ADHD in youth.

Authors

• Anne Bernard Arnett, University of Washington
  Presenting Author

• Lauren McGrath, University of Denver
  Non-Presenting Author

• Erik Willcutt, University of Colorado, Boulder
  Non-Presenting Author