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，行为和遗传学证据暗示着血清素能功能障碍，并且 特别是限制和重复行为（RRB）。发现升高的血小板5-羟色胺（5HT） 〜25-30％的自闭症患者是神经精神研究中的开创性发现之一。自闭症是 最可遗传的复杂神经精神疾病和血小板5HT水平也是极其可遗传的。 此外，升高的血小板5HT与自闭症和强迫性的复发风险有关 疾病（OCD）。自闭症与强迫症之间的关系由RRB之间的相关性强调 患有自闭症和父母OC症状的概率。最近描述了5-羟色胺转运蛋白中的突变 （SERT）基因（SLC6A4）导致5HT转运蛋白活性和表型的常见模式 使用RRB或强迫症的自闭症。许多研究试图测试SLC6A4的遗传作用，但是该领域的 由于缺乏自闭症中RRB的强大度量和血清素能的关键血小板标记的限制 功能。现在坚持相同性的指标（IS）现在允许将RRB症状包括在遗传中 分析。解密自闭症与5HT之间的关系需要关键的神经化学表型 用于阐明基本机制。例如，我们对近交和血小板5HT水平的研究和 种群群体指向整联蛋白（53基因（ITGB3）作为血小板5HT的定量性状基因座。 后续研究表明，ITGB3与自闭症之间的关联直接。进一步的数据 证明SERT和ITGB3在血小板中物理相互作用，而ITGB在小鼠大脑中的缺失 大大减少了SERT活性。其他研究发现，血小板5HT2A的降低与 在最近的大脑研究中，患有自闭症的男孩及其父亲和相似之处降低了结合。我们建议 进一步研究SLC6A4，ITGB和HTR2A，以评估有助于A的常见和罕见变化 失调的5HT系统，IS和自闭症。有大量证据支持5HT的参与，并且 这三个组成部分特别，我们假设5HT相关基因内的其他变化非常 也可能导致自闭症风险。我们建议系统地评估5HT相关基因的作用 在自闭症中，通过使用关键的神经化学和行为措施来提供表型数据最多 可能与该系统有关