Unraveling the Genetic Etiology of Autism

自闭症是一种神经精神障碍，表现出复杂的遗传病因，具有重要的临床和基因定位。 异质性。与女性相比，自闭症主要影响男性，导致人们对 在疾病风险或表现上的性别偏见的病因。我们建议继续进行有前途的初步研究 暗示着一个对中枢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-羟色胺)转运体相关的易感性的性质和程度 (SLC6A4)和整合素33(ITGB3)基因座，位于染色体17q11-21区域 自闭症患者存在明显的男性偏向遗传风险。同样，5-羟色胺-1A受体基因(HTR1A)显示为等位基因 这种联系在男性先证者中更为明显。5-羟色胺转运体(SERT)和5-HT1a受体 Lynchins是否控制CMS中5-羟色胺的浓度和功能，新出现的数据显示 SERT和ITGB3在调节循环中升高的5-羟色胺水平中的协同作用 许多自闭症患者。我们建议(1)充分阐述一个等位基因异质性框架 SLC6A4的疾病风险，(2)推定的SLC6A4风险等位基因的功能性质，(3)表征遗传 通过与ITGB3和HTR1A上功能等位基因的显著关联来索引风险，(4)决定程度 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，(5)开发更多自闭症家庭的丰富表型数据集，以更全面地了解 本项目中确定的易感等位基因可归因于基因型-表型相关性，(6)探索 通过检验风险与该网络中其他关键分子相关的疾病风险程度 编码这些蛋白质的基因座上也存在等位基因。通过这个项目，我们将大大推进我们的 了解遗传变异如何影响控制发育的蛋白质的表达和功能 以及与自闭症和许多疾病的病因有关的重要神经递质系统的相互连接 其他障碍。

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 33 (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 CMS, 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.