Unraveling the Genetic Etiology of Autism

描述（由申请人提供）：自闭症是一种神经精神障碍，表现出复杂的遗传病因，具有显著的临床和基因座异质性。与女性相比，自闭症主要影响男性，导致对疾病风险或表达的性别偏见的病因学产生了重大兴趣。我们建议进行有希望的初步研究，涉及一个网络的位点的发展和调节中枢神经系统的功能至关重要。我们将确定与5-羟色胺（5-HT）转运蛋白（SLC 6A 4）和整合素β 3（ITGB 3）基因座相关的易感性的性质和程度，这些基因座位于染色体17 q11 -21区域内，赋予自闭症显著的男性偏好遗传风险。类似地，5-HT-1A受体基因（HTR 1A）显示等位基因关联在男性先证者中更明显。5-HT转运蛋白（SERT）和5-HT 1A受体是控制CNS中5-羟色胺浓度和功能的关键，新出现的数据揭示了SERT和ITGB 3在介导循环中5-HT水平升高中的协同作用，这是许多自闭症患者的标志。我们建议（1）充分阐述SLC 6A 4疾病风险的等位基因异质性框架，（2）推定的SLC 6A 4风险等位基因的功能性质，（3）通过与ITGB 3和HTR 1A功能等位基因的显著关联来表征遗传风险，（4）确定涉及该网络的等位基因相互作用或上位性可能导致疾病风险和异常功能的程度，（5）开发关于其他自闭症家庭的丰富表型数据集，以更全面地了解归因于本项目中鉴定的易感性等位基因的基因型-表型相关性，（6）通过测试风险等位基因也存在于编码这些蛋白质的基因座的假设，探索与该网络中其他关键分子相关的疾病风险程度。通过这个项目，我们将大大推进我们对遗传变异如何影响蛋白质的表达和功能的理解，这些蛋白质控制着自闭症和许多其他疾病病因中所涉及的重要神经递质系统的发育和相互连接。

DESCRIPTION (provided by applicant): Autism is a neuropsychiatric disorder exhibiting a complex genetic etiology with significant clinical and locus heterogeneity. Autism predominantly affects males compared to females, leading to significant interest into the etiology of sex bias in disease risk or expression. We propose to pursue promising initial studies implicating a network of loci critical for the development and regulation of central serotonergic function. We will determine the nature and extent of susceptibility associated with the serotonin (5-HT) transporter (SLC6A4) and integrin beta3 (ITGB3) loci, which lie within a chromosome 17q11-21 region conferring significant male-biased genetic risk in autism. Similarly, the 5-HT-1A receptor gene (HTR1A) shows allelic association that is more pronounced in male probands. The 5-HT transporter (SERT) and 5-HT1A receptor are lynchpins in the control of serotonin concentration and function in the CNS, and emerging data reveals the synergistic actions of SERT and ITGB3 in mediating elevated 5-HT levels in the circulation, a hallmark of many patients with autism. We propose to (1) fully elaborate an allelic heterogeneity framework for disease risk at SLC6A4, (2) the functional nature of putative SLC6A4 risk alleles, (3) characterize genetic risk indexed by significant association with functional alleles at ITGB3 and HTR1A, (4) determine the degree to which allelic interaction or epistasis involving this network may contribute to disease risk and abnormal function, (5) develop a rich phenotypic dataset on additional autism families to more fully understand the genotype-phenotype correlations attributable to susceptibility alleles identified in this project, (6) explore the extent of disease risk in relation to other key molecules in this network by testing the hypothesis that risk alleles also exist at loci encoding these proteins. Through this project, we will substantially advance our understanding of how genetic variation affects expression and function of proteins controlling development and interconnection of a vital neurotransmitter system that is implicated in the etiologies of autism and many other disorders.