GENETICS OF SEROTONIN IN AUTISM: NEUROCHEMICAL AND CLINICAL

自闭症患者血清素的遗传学：神经化学和临床

• 批准号: 7718519
• 负责人: Edwin H Cook
• 金额: $ 37.71万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7718519
• 关键词: Agonist; Alleles; Autistic Disorder; Behavior; Behavioral; Behavioral Genetics; Binding; Blood; Blood Platelet Disorders; Blood Platelets; Brain; Candidate Disease Gene; Clinical; Complex; Data; Development; Diagnosis; Exons; Fathers; Follow-Up Studies; Functional disorder; Genes; Genetic; Genetic Heterogeneity; Genetic Polymorphism; Genetic screening method; Genotype; Goals; HTR2A gene; Haplotypes; Heterogeneity; ITGB3 gene; Individual; Integrins; Investigation; Measures; Modeling; Molecular; Mus; Mutation; Numbers; Obsessive-Compulsive Disorder; Pattern; Phenotype; Population; Predisposition; Proteins; Quantitative Trait Loci; Recurrence; Research; Risk; Risk Factors; Role; Seminal; Serotonin; Source; Specificity; Symptoms; System; Testing; Tryptophan; Variant; autism spectrum disorder; behavior measurement; boys; concept; design; endophenotype; genetic analysis; indexing; inhibitor/antagonist; insertion/deletion mutation; neurochemistry; neuroimaging; neuropsychiatry; novel; proband; promoter; receptor binding; serotonin transporter; sex; social; trait; transmission process; uptake

Neurochemical, behavioral, and genetic evidence implicate serotonergic dysfunction in autism, and specifically in restricted and repetitive behaviors (RRBs). Discovery of elevated platelet serotonin (5HT) in ~25-30% of individuals with autism is one of the seminal findings in neuropsychiatric research. Autism is the most heritable complex neuropsychiatric disorder, and platelet 5HT levels are also extremely heritable. Further, elevated platelet 5HT is associated with recurrence risk, both in autism and in obsessive compulsive disorder (OCD). The relationship between autism and OCD is underscored by correlations between RRBs in probands with autism and parental OC symptoms. Recently described mutations in the serotonin transporter (SERT) gene (SLC6A4) result in a common pattern of elevated 5HT transporter activity and a phenotype of autism with RRBs or OCD. Many studies have sought to test for genetic effects at SLC6A4, but the field has been limited by the lack of robust measures of RRBs in autism and key platelet markers of serotonergic function. Indices of Insistence on Sameness (IS) now allow RRB symptoms to be included in genetic analysis. Deciphering the relationships between autism and 5HT requires critical neurochemical phenotypes for elucidation of the underlying mechanisms. For example, our studies of platelet 5HT levels in inbred and outbred populations point to the integrin (53 gene (ITGB3) as a quantitative trait locus for platelet 5HT. Follow-up studies demonstrate association between ITGB3 and autism directly. Preliminary data further show that SERT and ITGB3 physically interact in platelets, and that absence of ItgbS in mouse brain significantly diminishes SERT activity. Other studies find that decreased platelet 5HT2A correlates between boys with autism and their fathers and parallels decreased binding in recent brain studies. We propose further study of SLC6A4, ITGBS and HTR2A to evaluate common and rare variation contributing to a dysregulated 5HT system, IS, and autism. Given strong evidence supporting 5HT involvement generally and these three components specifically, we hypothesize that other variation within 5HT-related genes is very likely to contribute to autism risk as well. We propose to systematically assess the role of 5HT-related genes in autism by using the critical neurochemical and behavioral measures to provide the phenotype data most likely to index genetic liability related to this system

神经化学、行为和遗传学证据表明自闭症患者存在多巴胺能功能障碍， 特别是在限制和重复行为（RRB）中。发现血小板5-羟色胺（5-HT）升高， 约25-30%的自闭症患者是神经精神病学研究的开创性发现之一。自闭症是 大多数遗传性复杂神经精神障碍和血小板5 HT水平也是非常遗传的。 此外，血小板5 HT升高与自闭症和强迫症复发风险相关。 强迫症（OCD）自闭症和强迫症之间的关系通过RRB之间的相关性来强调， 自闭症先证者和父母的强迫症症状。最近描述的5-羟色胺转运蛋白突变 （SERT）基因（SLC 6A 4）导致5 HT转运蛋白活性升高的共同模式和 患有RRB的自闭症或强迫症许多研究试图测试SLC 6A 4的遗传效应，但该领域 由于缺乏对自闭症RRB的可靠测量和对血小板的关键标志物的限制， 功能一致性指数（IS）现在允许RRB症状包括在遗传学中。 分析.解读自闭症和5 HT之间的关系需要关键的神经化学表型 以阐明潜在的机制。例如，我们对近交系和近交系小鼠血小板5-HT水平的研究， 远交群体指出整联蛋白β 3基因（ITGB 3）是血小板β HT的数量性状基因座。 后续研究表明ITGB 3与自闭症之间存在直接联系。初步数据进一步 显示SERT和ITGB 3在血小板中物理相互作用，且在小鼠脑中不存在ItGB 显著降低SERT活性。其他研究发现，血小板5 HT 2A减少与以下因素相关： 在最近的大脑研究中，患有自闭症的男孩和他们的父亲以及类似的人减少了结合。我们提出 进一步研究SLC 6A 4、ITGBS和HTR 2A，以评估导致 失调的5 HT系统，IS和自闭症。鉴于有强有力的证据普遍支持5 HT参与， 特别是这三个组成部分，我们假设5 HT相关基因中的其他变异非常重要。 也可能导致自闭症风险。我们建议系统地评估5 HT相关基因的作用 通过使用关键的神经化学和行为测量来提供最多的表型数据， 可能会索引与该系统相关的遗传责任