DESCRIPTION (provided by applicant): Attention Deficit Hyperactivity Disorder (ADHD) is a common highly heritable childhood-onset behavioral disorder. We have performed the first coarse genome-wide scans (10 cM spacing) and fine mapping (<2 cM spacing in regions of interest) in ADHD in a total sample of 269 affected sibling pair(ASP) families and identified significant linkage to 16p13 and 17p11. This proposal is to use sequencing based approaches and common SNP genotyping approaches to identify both common variants and multiple rare mutations/polymorphisms in genes within these linked regions that underlie disease susceptibility in ADHD. The availability of a large ADHD Affected Sibling Pair (ASP) sample and the tools of modern genomics now make comprehensive screening of these regions practical using high density SNP typing and large scale resequencing, and a multi-group collaborative approach is taken for testing replication of putative associations in the linked regions. In order to screen these two linked regions for common variants contributing to disease susceptibility, the Research Design is to 1) Screen 12,000 common SNPs for association with ADHD in 310 independent trios from 310 ASP families; 2) Test putative SNP associations in an additional 260 ASP families collected at UCLA; 3) Test SNPs meeting selection criteria on 7 separate ADHD samples consisting in total of 1934 affecteds and 2532 controls. In order to test for association with multiple rare polymorphisms or mutations, direct resequencing of genes on 16p13 and 17p11 will be performed using high density oligo arrays on 90 selected ADHD affecteds from the UCLA cohort of ASP families. Additional ADHD affecteds and controls will be sequenced at genes meeting significance thresholds. These combined approaches have over 80% power to discover and validate common variant contributions to ADHD risk and rare mutations. ADHD is the most commonly diagnosed behavioral disorder of childhood and has a dramatic effect on public health. This work has a significant impact on not only the individual with ADHD but also society, as millions of school aged children are affected with ADHD and affected children impact classroom learning for all, as well continue through their lives with sometimes deleterious behaviors. Identification of the molecular basis of ADHD will enable better diagnostic tools to be developed to diagnose ADHD and its genetic subtypes. Knowledge of risk genes provides an understanding of the disorder that may allow for the development of interventions tailored to the specific genetic factors, as well as enable focused exploration of environmental factors that might impact on expression of the phenotype. Additionally, identification of genes with clear relationships to behavior will provide an improved understanding of basic processes of learning.