Autism is a devastating neurodevelopmental condition whose biological basis is still poorly understood. Furthermore, there are no laboratory or radiological tests available to aid in diagnosis, and although early behavioral intervention is considered effective in some cases, there are few proven treatments currently available. Autism has a striking genetic component with first degree relative risk estimated in some studies higher than 50. Therefore, defining the genes with variants contributing to autism risk would theoretically define the key molecular pathways involved. A number of genome-wide linkage scans and association studies performed in the last decade have begun to show promise by identifying a few overlapping regions of interest, but, no clear autism gene has been isolated and confirmed in multiple populations. In Iceland we have recruited most of confirmed autism cases in Iceland and used the genealogy database to connect many of these cases into the extended families. In preliminary analyses, suggestive loci have been found, most of which overlap with previously reported suggestive loci in autism scans, including those from a large subset of the AGRE/UCLA cohort, which consists of mostly nuclear multiplex autism pedigrees. Both the Decode group and the UCLA group have been attempting to increase the power of their respective cohorts by increasing the number of affecteds in their studies through broadening of the autism- related phenotyping to include quantitative measures of autism-related impaired social interaction, using the Social Responsiveness Scale (SRS). The use of this scale also allows for a QTL analysis that may further increase the power to find significant linkage, and takes advantage of the critical dimension of social deficits as a core feature of autism spectrum disorders in genetic studies for the first time. Genome-wide linkage scans in the ACRE and Decode populations have revealed a number of suggestive loci for autism or autism-related endophenotypes. Several of the loci with highest statistical support identified in ACRE and ICELAND cohorts overlap with each other and with loci from other populations, including an AGRE locus enhanced by QTL analysis based on SRS data. We believe that collaborative efforts to isolate genes from the strongest overlapping loci provides an efficient way to leverage these already recruited and genotyped patient cohorts. This grant proposal leverages both of these large cohorts that have already been genotyped in initial genome scans. We propose to phenotype additional relatives both in Iceland and the US, and analyze the US and Decode cohorts in parallel, performing the same multipoint QTL analysis, followed by fine mapping and narrowing regions of shared linkage. We plan to focus on the isolation of genes within loci that are supported in both populations. [unreadable] [unreadable] [unreadable]