GENETICS OF SEROTONIN IN AUTISM: NEUROCHEMICAL AND CLINICAL ENDOPHENOTYPES

自闭症患者血清素的遗传学：神经化学和临床内表型

• 批准号: 7292304
• 负责人: Edwin H Cook
• 金额: $ 51.52万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-06 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7292304
• 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、行为和遗传证据表明自闭症存在血清素功能障碍， 特别是在限制性和重复性行为（RRB）方面。发现血小板血清素 (5HT) 升高 大约 25-30% 的人患有自闭症，这是神经精神病学研究的开创性发现之一。自闭症是 大多数遗传性复杂的神经精神疾病，血小板 5HT 水平也具有极强的遗传性。 此外，血小板 5HT 升高与自闭症和强迫症复发风险相关。 障碍（强迫症）。自闭症和强迫症之间的关系通过 RRB 之间的相关性得到强调。 患有自闭症和父母 OC 症状的先证者。最近描述的血清素转运蛋白突变 (SERT) 基因 (SLC6A4) 导致 5HT 转运蛋白活性升高的常见模式和表型 患有 RRB 或强迫症的自闭症。许多研究试图测试 SLC6A4 的遗传效应，但该领域还没有 由于缺乏对自闭症 RRB 和血清素能关键血小板标志物的强有力测量而受到限制 功能。坚持同一性指数 (IS) 现在允许将 RRB 症状包含在遗传中 分析。解读自闭症和 5HT 之间的关系需要关键的神经化学表型 用于阐明根本机制。例如，我们对近交系和近交系血小板 5HT 水平的研究 近交群体指出整合素（53）基因（ITGB3）是血小板 5HT 的数量性状基因座。 后续研究证明 ITGB3 与自闭症之间存在直接关联。初步数据进一步 表明 SERT 和 ITGB3 在血小板中发生物理相互作用，并且小鼠大脑中缺乏 ItgbS 显着降低 SERT 活性。其他研究发现，血小板 5HT2A 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的联系减少了。我们建议 进一步研究 SLC6A4、ITGBS 和 HTR2A，以评估导致 5HT 系统失调、IS 和自闭症。鉴于支持 5HT 普遍参与的有力证据， 具体来说，这三个组成部分，我们假设 5HT 相关基因内的其他变异非常重要。 也可能导致自闭症风险。我们建议系统评估5HT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重要的表型数据来治疗自闭症 可能会索引与该系统相关的遗传责任