This is a proposal to identify the chromosomal location of genes responsible for attention deficit hyperactivity disorder (ADHD), an inherited disorder that begins in childhood and is characterized by problems with attention, concentration, and distractibility. This goal will be achieved by studies of families with multiple affected siblings (affected sib pair or ASP families) in the genetically homogeneous population of the Central Valley of Costa Rica (CVCR). ADHD families in this population have likely inherited a susceptibility to ADHD from one or a few common ancestors. ADHD genes will be mapped by searching for genome regions that ADHD patients share identical by descent (IBD), using linkage and association studies. The study sample will consist of families with two or more siblings affected with ADHD and their parents (approximately 300 families total). Diagnostic assessment will include interviews of patients, family members, and teachers, and review of medical records. Final diagnoses will be achieved through a """"""""best estimate"""""""" consensus process conducted by experts in diagnosing ADHD. Genealogies will be obtained for all families, who will be included in the study only if the majority of their ancestors (equal to or >5/8 great-grandparents) are of CVCR origin. The samples will be genoyped for candidate genes thought to play a role in ADHD susceptibility, as well as using markers distributed throughout the genome. Power analyses show a high probability of detecting ADHD susceptibility genes in the proposed study sample, even given etiological heterogeneity. This study is innovative in that it combines the use of linkage and association studies in a genetically isolated population, as well as using cutting edge statistical approaches to increase the power and refine the precision of the sample. Once ADHD genes are localized, fine-mapping studies can begin, ultimately leading to positional cloning efforts. Preliminary studies conducted in the CVCR show the feasibility of the sampling, diagnostic, and genotyping approaches described in this application. The sampling will be facilitated by ongoing collaborations established in the CVCR.
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