Genome-Wide Screens for Autism Susceptibility Loci

描述(申请人提供)：自闭症是一种相对常见的神经精神障碍，发病率约为千分之一，遗传遗传率大于80%。尽管遗传因素在自闭症中的作用是毋庸置疑的，但它们的性质仍然难以捉摸，也没有发现与其病因有关的单一基因。事实上，Risch和他的同事最近的一项研究强调，15个或更多的隔离因素可能是家庭内风险增加的原因，而这些因素都不是主要因素。自闭症的病因学很可能是复杂疾病的代表，而不是例外。事实上，人们普遍认为，复杂的疾病遗传模式表现出多个基因、环境和表观遗传因素之间的相互作用。因此，连锁分析虽然成功地被用于识别孟德尔疾病中的疾病基因，但在复杂的疾病家族中基本上失败了。人们还假设，人类疾病中的基因改变通常是点突变或小的插入/缺失。然而，人类基因组序列表明，节段性非整倍体可能是人类疾病的基础。因此，我们建议在自闭症的研究中开发两种新型的全基因组筛查，一种是单核苷酸多态(SNPs)，另一种是基因组节段性非整倍体。这些技术在易感基因鉴定方面应该被证明特别强大，因为它们不会受到目前对基因功能和调控的有限了解的阻碍。

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.