Elsevier

Biological Psychiatry

Volume 62, Issue 9, 1 November 2007, Pages 991-998
Biological Psychiatry

Original Article
Testing for Neuropsychological Endophenotypes in Siblings Discordant for Attention-Deficit/Hyperactivity Disorder

https://doi.org/10.1016/j.biopsych.2007.04.003Get rights and content

Background

Neurocognitive deficits associated with attention-deficit/hyperactivity disorder (ADHD) might be useful intermediate endophenotypes for determining specific genetic pathways that contribute to ADHD.

Methods

This study administered 17 measures from prominent neuropsychological theories of ADHD (executive function, processing speed, arousal regulation and, motivation/delay aversion) in dizygotic (DZ) twin pairs discordant for ADHD and control twin pairs (ages 8–18 years) to compare performance between twins affected with ADHD (n = 266), their unaffected co-twins (n = 228), and control children from twin pairs without ADHD or learning difficulties (n = 332).

Results

The ADHD subjects show significant impairment on executive function, processing speed, and response variability measures compared with control subjects. Unaffected co-twins of ADHD subjects are significantly impaired on nearly all the same measures as their ADHD siblings, even when subclinical symptoms of ADHD are controlled.

Conclusions

Executive function, processing speed, and response variability deficits might be useful endophenotypes for genetic studies of ADHD.

Section snippets

The Genetics and Neuropsychology of Attention-Deficit/Hyperactivity Disorder

Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous disorder with a complex, multifactorial etiology (1, 2). Twin studies indicate that ADHD is highly heritable, and molecular genetic studies have identified 8–10 candidate genes that might increase susceptibility to ADHD (3, 4). However, each of these genes accounts for a relatively small proportion of the total variance in ADHD symptoms, and the majority of the genetic variance in ADHD remains unexplained.

The neuropsychology of

Neuropsychological Endophenotypes for ADHD

Owing to the neuropsychological complexity of ADHD, several authors have suggested that neuropsychological measures might be useful endophenotypes for genetic studies of ADHD (e.g., 19, 20). Although there is ongoing debate about the optimal criteria for an endophenotype, virtually all conceptualizations refer to a phenotype that is more proximal to the genetic etiology of the disorder than its behavioral symptoms and is influenced by at least one of the genes that increase susceptibility to

Recruitment

Participants completed the measures described in this paper as part of the Colorado Learning Disabilities Research Center (CLDRC) twin study, an ongoing study of the etiology of learning disabilities and ADHD (27, 28). Parents of all twins between the ages of 8 and 18 years in local school districts were contacted by letter and invited to participate in the initial screening component of the study. If either of the twins met criteria for any DSM-IV ADHD subtype on the basis of parent or teacher

Results

Table 3 provides the unadjusted means of the groups for each neuropsychological measure. Intraclass sibling correlations were significant for nearly all measures (Table 3), suggesting that familial factors contribute to individual differences on many of these tasks. Probands with ADHD are significantly impaired in comparison with the control twins on all EF, processing speed, and response variability measures but none of the motivation or delay aversion measures. The unaffected co-twins of ADHD

Discussion

To test the utility of neuropsychological measures as endophenotypes for ADHD, measures of EF, processing speed, response variability, motivational processes, and delay aversion were administered to a large sample of probands with DSM-IV ADHD and their unaffected co-twins. Consistent with previous research, performance of probands with ADHD is significantly impaired compared with control subjects on all EF, processing speed, and response variability measures. The performance of co-twins without

Conclusions

Unaffected co-twins of probands with ADHD performed worse than control participants on 78% of the measures administered in an extensive battery of neurocognitive tasks. Results were most robust for SSRT, response variability, and measures of perceptual and naming speed, suggesting that these tasks might be useful endophenotypes for molecular genetic studies of ADHD.

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