Multivariate genomewide linkage scan of neurocognitive traits and ADHD symptoms: Suggestive linkage to 3q13

Abstract

Family and twin studies suggest that a range of neurocognitive traits index the inherited liability to ADHD; however, the utility of such measures as endophenotypes in molecular genetic studies remains largely untested. The current paper examined whether the inclusion of neurocognitive measures in a genomewide linkage analysis of ADHD could aid in identifying QTL linked to the behavioral symptoms of the condition. Data were from an affected sibling pair linkage study of DSM-IV ADHD conducted at Massachusetts General Hospital. The sample included 1,212 individuals from 271 families. ADHD symptoms were assessed with the K-SADS-E. The neurocognitive battery included Wechsler Intelligence Scales subtests, the Stroop, the Wisconsin Card Sorting Test (WCST), the Rey Osterreith Complex Figure, a working memory CPT, the CVLT and WRAT-III subscales. Evidence for linkage was assessed using a simulation-based method that combines information from univariate analyses into the equivalent of a multivariate test. After correction for multiple trait testing, a region on chromosome 3q13 showed suggestive linkage to all neurocognitive traits examined and inattention symptoms of ADHD. The second highest peak occurred on 22q12 but showed linkage to a single subscale of the WCST. In univariate analysis, this region retained criteria for suggestive linkage to this measure after correction for multiple trait testing. Our primary findings raise the possibility that one or more genes on 3q13 influence neurocognitive functions and behavioral symptoms of inattention. Overall, these data support the utility of neurocognitive traits as ADHD endophenotypes, but also highlight their limited genetic overlap with the disorder.

Potential cognitive endophenotypes in multigenerational families: segregating ADHD from a genetic isolate

“…Following this approach, the evaluation of candidate neuropsychological ADHD endophenotypes as quantitative trait loci revealed two significant genome-wide linkage signals on chromosome 2q21.1 (LOD score: 3.944) for motor timing and on 13q12.11 (LOD score: 3.959) for Digit Span (Rommelse et al 2008). Additional suggestive linkage signals have been reported for chromosomes 2p, 2q, 3p, 3q, 4q, 8q, 12p, 12q, 14q, 17q, and 22q (Doyle et al 2008; Rommelse et al 2008). …”

Advances in genetic studies of attention-deficit/hyperactivity disorder

“…These regions had not been reported in previous studies of ADHD [20]. Doyle et al [21] examined whether the inclusion of neurocognitive measures in a genomewide linkage scan of ADHD could aid in identifying areas of the genome linked to behavioral symptoms. The sample included 1212 individuals from 271 families and featured sibling pairs with ADHD.…”

The genetics of reading disability

“…It is located in the chromosome 3p12-q13 DYX5 locus. This locus also has been linked to neurocognition measures and inattention in a family sample with attention-defi cit/hyperactivity disorder [47], which is interesting in light of the comorbidity between RD and attention-defi cit/hyperactivity disorder. The ROBO1 gene was found to be disrupted by a translocation t(3;8)(p12:q11) in a Finnish individual with dyslexia [9].…”