This project is one of four being proposed as part of the UCSD Autism Center of Excellence. One major goal of this study is to identify, in postmortem brain tissue, distinct gene expression profiles of autism that can implicate risk genes for this highly heritable disorder. A second major goal is to identify, in circulating blood cells, a validated gene expression profile of autism that can be developed as a diagnostic tool to improve its identification and early treatment. Although autism is recognized as having a substantial genetic component, its biological basis remains unknown. Due to its high heritability, much research has focused on identifying candidate genes that influence the disorder; however, progress has been slow. In part, this may be attributable to the "single-marker" approach adopted in most prior efforts, since the etiologic complexity and heterogeneity of autism-spectrum disorders invariably thwart classification schemes relying on a single dimension to differentiate affected and unaffected children. To move beyond this single-marker approach, a major objective of the proposed project is to validate suspected risk genes for autism (e.g., genes in the apoptosis, neurogenesis, and Drosophila wingless homolog [wnf] pathways), but also to find new candidate genes by observing patterns of expression of the entire human transcriptome in eight distinct brain regions. The lack of etiologic understanding of autism has also precluded the development of biologically based diagnostic strategies. As such, the diagnosis relies solely on observable behaviors emerging during the first years of life. Yet, the advantages of a more efficient biologically based diagnostic tool for autism are numerous, and as such, another major objective of this study is to develop biologically based markers for autism. To accomplish these objectives, we will pursue five specific aims as follows: 1) Identify ubiquitous and region-specific disruptions in brain gene expression in autism; 2) Identify blood-based predictive biomarkers of early-onset autism; 3) Identify blood-based predictive biomarkers of autism treatment response; 4) Prioritize and verify the differential expression of top candidate genes in postmortem brain and peripheral blood; and 5) Integrate the results of this project with other projects within the Center. The attainment of the :specific aims outlined above will serve to validate several groups of risk genes for autism, identify a new set of potential risk genes, and validate peripheral blood-based biomarkers of the disorder, all while determining the specificity of these effects relative to other developmental disorders and to normal development. The identification of risk genes for autism should facilitate the development of novel therapeutics, while the eventual development of a biological marker system for autism would greatly enhance the efficiency of current diagnostic methods, and it likely would facilitate the search for additional etiologic factors in the disorder.