Genome-Wide Screens for Autism Susceptibility Loci

Johns Hopkins University, Baltimore MD

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Abstract

DESCRIPTION (provided by applicant): Autism is a relatively common neuropsychiatric disorder with an incidence of approximately I in 1000 and genetic heritability of greater than 80%. Although the role of hereditary factors in autism is not in doubt their nature remains elusive and no single gene contributing to its etiology has been identified. Indeed, a recent study by Risch and colleagues emphasized that 15 or more segregating factors probably account for the increased intra-familial risk and that none of them are major factors. As opposed to being the exception, the etiology of autism is likely to be representative of complex disease. Indeed, it is commonly assumed that complex disease inheritance patterns manifest the interaction among multiple genes, the environment, and epigenetic factors. Thus, linkage analysis, while successfully employed to identify disease genes in Mendelian disorders, has largely failed in complex disease families. It has also been assumed that genetic alterations in human disease are generally point mutations or small insertions/deletions. However, the human genome sequence suggests that segmental aneuploidy can underlie human disease. Consequently, we propose to develop two novel types of genome wide screens, one for single nucleotide polymorphisms (SNPs) and the other for genomic segmental aneuploidy, in the study of autism. These techniques should prove particularly robust for susceptibility gene identification, as they are not hindered by the current limited understanding of both gene function and regulation.