Unraveling the Genetic Etiology of Autism

孤独症是一种神经精神疾病，具有复杂的遗传病因， 异质性与女性相比，自闭症主要影响男性，导致对自闭症的极大兴趣。 疾病风险或表达中的性别偏见的病因学。我们建议进行有希望的初步研究， 暗示了对中枢神经系统功能的发展和调节至关重要的位点网络。我们 将确定与5-羟色胺（5-HT）转运蛋白相关的易感性的性质和程度 （SLC 6A 4）和整合素33（ITGB 3）基因座，其位于染色体17 q11 -21区域内，赋予 孤独症的男性遗传风险。类似地，5-HT-1A受体基因（HTR 1A）显示等位基因， 这种关联在男性先证者中更为明显。5-HT转运蛋白（SERT）和5-HT 1A受体 是控制CMS中5-羟色胺浓度和功能的关键，新的数据显示， SERT和ITGB 3在介导循环中5-HT水平升高中的协同作用， 自闭症患者的症状。我们建议（1）充分阐述等位基因异质性框架， SLC 6A 4的疾病风险，（2）推定的SLC 6A 4风险等位基因的功能性质，（3）表征遗传 风险指数与ITGB 3和HTR 1A的功能等位基因显著相关，（4）确定程度 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）开发一个关于其他自闭症家庭的丰富的表型数据集，以更全面地了解 本项目中鉴定的易感等位基因的基因型-表型相关性，（6）探索 疾病风险与该网络中其他关键分子相关的程度，通过测试风险 在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，我们将大大提高我们的 了解遗传变异如何影响控制发育的蛋白质的表达和功能 和互联的重要神经递质系统，这是牵连在自闭症的病因和许多 其他疾病。

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.