This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The purpose of this project is to search for susceptibility genes for autism using linkage studies of autism and intermediate phenotypes in a sample of unique, large extended pedigrees supplemented by 50 other multiplex pedigrees. In subjects who are found to be part of large extended or multiplex families, detailed assessment will be done on affected subjects, their first degree relatives, and available relatives who connect pedigree branches. DNA will be collected on all multiplex/extended families for linkage analysis, and on the 800 trios to help narrow linkage regions and for immediate candidate gene analysis once pedigree genome scanning is complete. The project has several major strengths. We have unusually large Utah pedigrees (5-6 generations) already identified and partly assessed. We have evidence that phenotyping in these pedigrees and other multiplex families will be feasible. The phenotypes we have chosen to measure on these pedigrees are familial in autism and show evidence of heritable variation. The pedigrees will be used to search for shared DNA haplotypes among distantly related affected cases, and to test for linkage to autism and intermediate phenotypes to identify susceptibility genes. We have phenotypic information from the currently funded Utah Autism Program, part of the NICHD network Collaborative Programs of Excellence in Autism (CPEA). The Leppert and Weiss labs housed in the University of Utah Department of Human Genetics will give us world-class expertise in genetic study design, fine mapping, and interpretation of results. Finally, we have gathered a strong database and analysis team. Ongoing funding provides some ascertainment and phenotyping. This project will provide more phenotyping and genotyping necessary for mapping and sequencing genomic regions of interest.
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