Unraveling the Genetic Etiology of Autism

揭开自闭症的遗传病因学

基本信息

批准号：
7387400
负责人：
JAMES S SUTCLIFFE
金额：
$ 48.55万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-04 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7387400
关键词：
17q 17q11 17q11.2 17q21 Affect Alleles Autistic Disorder Behavior Blood Circulation Blood Platelets Brain Cell Adhesion Molecules Chromosomes Clinical Code Complex DNA Sequence Data Data Set Development Diagnostic Dimensions Disease Distal Equilibrium Etiology Exhibits Exons Family Female Genes Genetic Genetic Epistasis Genetic Predisposition to Disease Genetic Risk Genetic Variation Genomics Genotype Haplotypes Heritability Heterogeneity Hippocampus (Brain)ITGB3 gene In Vitro Individual Integrins Language Link Mediating Modeling Nature Neurodevelopmental Disorder Neurotransmitters Obsessive compulsive behavior Oligogenic Traits Pathway interactions Patients Pattern Phenotype Population Predisposition Prevalence Procedures Process Proteins Quantitative Trait Loci Receptor Gene Recurrence Regulation Research Personnel Resistance Risk Risk Factors Screening procedure Serotonin Serotonin Receptor 5-HT1A Sex Bias Siblings Social Interaction Structure Susceptibility Gene System Testing Variant base disorder risk indexing instrument interest male neuropsychiatry novel proband programs protein function raphe nuclei receptor sex synaptogenesis trait trend

项目摘要

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.

自闭症是一种神经精神疾病，表现出复杂的遗传病因，具有重要的临床和基因座异质性。自闭症与女性相比主要影响男性，导致对性别偏见在疾病风险或表达中的病因。我们建议进行有希望的初步研究暗示一个基因座网络对中央血清素能功能的开发和调节至关重要。我们将确定与5-羟色胺（5-HT）转运蛋白相关的敏感性的性质和程度（SLC6A4）和整合素33（ITGB3）基因座，位于17q11-21区域内的染色体内自闭症中有明显的男性偏见遗传风险。同样，5-HT-1A受体基因（HTR1A）显示了等位基因在男性概率中更明显的关联。 5-HT转运蛋白（SERT）和5-HT1A受体是在CMS中控制5-羟色胺浓度和功能的lynchpins，而新兴数据揭示了 SERT和ITGB3在循环中介导升高的5-HT水平的协同作用，一个标志许多自闭症患者。我们建议（1）完全详细阐述一个等位基因异质性框架 SLC6A4的疾病风险，（2）假定SLC6A4风险等位基因的功能性质，（3）遗传特征与ITGB3和HTR1A的功能等位基因显着相关的风险，（4）确定程度涉及该网络的等位基因相互作用或上毒可能导致疾病风险和异常功能，（5）在其他自闭症家庭上开发丰富的表型数据集，以更充分地了解基因型 - 表型相关性可归因于该项目中确定的易感性等位基因，（6）探索通过检验风险的假设，与该网络中其他关键分子有关的疾病风险程度等位基因也存在于编码这些蛋白质的基因座。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以及与自闭症的病因有关的重要神经递质系统的互连其他疾病。