This application requests five years of support to establish a Center for Genomic and Phenomic Studies in Autism involving the University of Southern California (USC), Autism Genetic Resource Exchange (AGRE), MIND Institute/University of California (UC) - Davis, University of Michigan, Children's Hospital Los Angeles (CHLA), and E.K. Shriver Center/University of Massachusetts Medical School. The Center brings together a distinguished multidisciplinary team of investigators with considerable expertise in the genomics and phenomics of autism in multiplex pedigrees, including nationwide family ascertainment and screening, high throughput diagnostics, state-of-the-art clinical evaluation and structural interviewing, cognitive and behavioral evaluations, 3D craniofacial morphology, cytogenetics, DMA microarrays, immunology, structural brain imaging, electrophysiology, and environmental risk assessment. Our research team also has considerable experience in coordinating and widely distributing to the scientific community phenomic and genomic information in autism. We have identified over 1,400 pedigrees with two or more affected children, for which comprehensive clinical data, DMA and cell lines are currently distributed through AGRE and the NIMH Human Genetics Initiative. The Center will utilize a nationwide ascertainment strategy with a demonstrated record of success and collect state-of-the-art high-throughput phenotypic information and blood from a new ethnically diverse sample of 1,500 multiplex autism pedigrees that will be shared with the National Database for Autism Research (NDAR) and the NIMH Human Genetics Initiative. High-throughput phenomics conducted on affected children will include state-of-the-art clinical instrumentation and structural interviews to assess behavioral, social, cognitive/intellectual, language/communicative and adaptive functioning. Cytogenetic and baseline environmental risk assessments also will be made. Pilot studies in a subset of 625 autistic children in California will be conducted to identify robust endophenotypes using state of- the-art technologies for 3D craniofacial morphology, structural brain imaging, DNA microarrays, immunological assays, auditory evoked potentials and other psychophysiological measures, and air quality assessments. Unique strengths of our proposal include: (1) the inclusion of established programs at AGRE and the MIND Institute/UC - Davis that will utilize pre-existing infrastructure, including USC/CHLA's General Clinical Research Center; (2) AGRE's considerable experience in establishing a nationwide collection of phenomic and genomic resources for autism research; and (3) the availability of highly efficient bioinformatics algorithms and a web-based data management system. The ultimate goal of our Center will be to facilitate genetic and environmental studies on autism, thereby improving diagnosis, accelerating our understanding of its etiology and pathophysiology, and facilitating discovery of new therapeutics. ? ? ? ?
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