Insights in the genetic architecture of impulsivity in mice

Impulsivity as observed in tasks of inhibitory response control is a heritable endophenotype of attention deficit hyperactivity disorder (ADHD). To identify genes underlying this variety of impulsivity we assessed inhibitory control of 43 BXD recombinant inbred strains in a five-choice serial reaction time task (5-CSRTT). QTL analysis indicated that impulsivity significantly mapped to a locus on chromosome 14. Candidate genes within QTL interval were identified by the presence of non-synonymous mutations (Ppyr1, Mmrn2, Wapal and 4930474N05Rik) and analysis of the genetic association of syntenic human genes with ADHD diagnosis (Nrg3). Impulsivity in the BXD strains did not correlate with response variability, which is a novel measure of lapses of attention and a well-replicated ADHD endophenotype. This was in line with the hypothesis that separate molecular pathways contribute to attention deficit and hyperactivity-impulsivity in this heterogeneous disorder. Future studies that identify the causative genes within the impulsivity QTL will help to understand the pathway contributing to symptoms of hyperactivity-impulsivity in ADHD.