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异质性。与女性相比，自闭症主要影响男性，导致人们对疾病风险或表现中的性别偏见的病因学产生了浓厚的兴趣。我们建议继续进行有希望的初步研究，以发现对中枢5-羟色胺能功能的发展和调节至关重要的基因座网络。我们将确定与5-羟色胺(5-HT)转运体(SLC6A4)和整合素Beta3(ITGB3)基因座相关的易感性的性质和程度，这两个基因座位于染色体17q11-21区域，赋予自闭症显著的男性偏向遗传风险。同样，5-羟色胺-1A受体基因(HTR1A)表现出等位基因关联，在男性先证者中更为明显。5-羟色胺转运体(SERT)和5-HT1A受体是控制中枢5-羟色胺浓度和功能的关键，新的数据显示SERT和ITGB3在调节循环中升高的5-羟色胺水平方面具有协同作用，这是许多自闭症患者的标志。我们建议(1)充分阐述SLC6A4的疾病风险的等位基因异质性框架，(2)推定的SLC6A4风险等位基因的功能性质，(3)通过与ITGB3和HTR1A的功能等位基因的显著关联来表征遗传风险指数，(4)确定涉及该网络的等位基因交互作用或上位性可能在多大程度上促进疾病风险和异常功能，(5)开发关于其他自闭症家系的丰富的表型数据集，以更充分地理解本项目中确定的易感等位基因的基因型-表型相关性，(6)通过检验编码这些蛋白质的基因座上也存在风险等位基因的假设，探索疾病风险与这个网络中其他关键分子的关系。通过这个项目，我们将大大提高我们对遗传变异如何影响蛋白质的表达和功能的理解，这些蛋白质控制着一个关键的神经递质系统的发育和相互连接，该系统与自闭症和许多其他疾病的病因有关。

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.