Unraveling the Genetic Etiology of Autism

揭开自闭症的遗传病因学

• 批准号: 7217895
• 负责人: JAMES S SUTCLIFFE
• 金额: $ 49.66万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 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/7217895
• 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); In Vitro; Individual; Integrin beta3; 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; 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); In Vitro; Individual; Integrin beta3; 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

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.

描述（由申请人提供）：自闭症是一种神经精神疾病，表现出复杂的遗传病因，具有显着的临床和基因座异质性。与女性相比，自闭症主要影响男性，从而引起对性偏见在疾病风险或表达中的病因的浓厚兴趣。我们建议进行有希望的初始研究，这涉及一个基因座网络，这对于中枢性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（SLC6A4）和整联蛋白BetA3（ITGB3）位点相关的易感性的性质和程度，它们位于自闭症中赋予明显的男性偏见遗传风险的17q11-21区域内。同样，5-HT-1A受体基因（HTR1A）显示出在男性概率中更明显的等位基因关联。 5-HT转运蛋白（SERT）和5-HT1A受体是CNS中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水平中的Sert和ItGB3的协同作用，许多自动抗体的标志是许多自动抗体的标志。 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）在其他自闭症家族上开发丰富的表型数据集，以更充分地了解该项目中鉴定出的易感性等位基因的基因型 - 表型相关性，（6）探索疾病风险在该网络中与该网络中的其他关键分子相关的程度，通过测试这些蛋白质的蛋白质也存在于这些蛋白质的假设，这些蛋白质也存在于这些蛋白质。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，该蛋白质控制了与自闭症和许多其他疾病的病因有关的重要神经递质系统的发育和互连。