Molecular Epidemiology of Inattentive ADHD

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DESCRIPTION (provided by applicant): This application is a request for 5 years of funding to identify genetic elements which predispose to the development and course of attention deficit/hyperactivity disorder (ADHD). Previously we have used a birth records-based twin design to investigate what elements of the ADHD phenotype are heritable and to determine whether the nature of the underlying heritability represents a continuum of dysfunction or the presence of discrete clinical entities. We have identified a highly heritable form of inattentive ADHD associated with marked academic and social problems which is common in both boys and girls and which is underrepresented in clinic-based populations and ongoing genetic linkage studies of ADHD. This finding suggests that new sampling strategies will be necessary to identify genes contributing to the etiology of this common form of attention disorders. We propose to focus on ascertaining affected and discordant sibling pairs from large families with specific types of parent identified attention problems using a birth records-based sample of families with 4 or more siblings. Using this newly recruited sample and our existing sample of twin-based families we will apply state-of-the-art laboratory and analytic methods to complete a genomic survey for linkage of particular chromosomal loci to inattention problems. Our goal is to recruit a total of 450 affected sibling pairs which both have a severe form of pure attention problems and 1,000 sibling pairs who are discordant. Using non-parametric linkage methods we will complete a genomic survey of microsatellite repeat markers with an average spacing of 10 cM to identify chromosomal regions associated with this phenotype. We will try to further refine the location of putative linkage locations using quantitative and multivariate linkage approaches. The unique features of this application include a fully tested 2-stage population sampling approach for family identification, a focus on a highly heritable inattentive subtype of ADHD common in boys and girls which is underrepresented in clinical and current genotyping samples and the ability to test the generalizability of any findings by the use of population samples of inattentive ADHD. We note that this affected sib-pair sample would also be ideal to conduct more focused studies of neuroimaging, neuropsychological performance, and neurophysiological functioning in future studies.