GENETICS OF SEROTONIN IN AUTISM: NEUROCHEMICAL AND CLINICAL

神经化学、行为和遗传证据表明自闭症患者存在5-羟色胺能功能障碍 特别是在受限和重复行为(RRB)方面。高血压病患者血小板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中的开创性发现之一。自闭症是 大多数可遗传的复杂神经精神障碍和血小板5-羟色胺水平也是极其可遗传的。 此外，在自闭症和强迫症中，升高的血小板5-羟色胺与复发风险有关。 精神障碍(OCD)。自闭症和强迫症之间的关系被RRB之间的相关性所强调 有自闭症和父母OC症状的先证者。最近发现的5-羟色胺转运体的突变 (SERT)基因(SLC6A4)导致5-羟色胺转运体活性升高的常见模式和表型 患有RRBs或强迫症的自闭症。许多研究试图测试SLC6A4的遗传效应，但该领域已经 受到自闭症患者RRBs和5-羟色胺能关键血小板标志物缺乏可靠测量的限制 功能。坚持相同(IS)的指数现在允许RRB症状包括在基因中 分析。破译自闭症和5-羟色胺之间的关系需要关键的神经化学表型 以阐明其潜在的机制。例如，我们对近交系和自交系中血小板5-羟色胺水平的研究 外交群体认为整合素53基因(ITGB3)是血小板5羟色胺的数量性状基因座。 后续研究表明，ITGB3与自闭症有直接联系。初步数据进一步 表明SERT和ITGB3在血小板中物理上相互作用，而在小鼠脑中缺乏ItgbS 显著降低SERT活性。其他研究发现，血小板减少的5HT2A与 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他们的相似之处减少了约束。我们建议 进一步研究SLC6A4、ITGBS和HTR2A以评估导致A 调节失调的5-羟色胺系统、IS和自闭症。考虑到强有力的证据支持5HT的普遍参与和 具体地说，我们假设5-羟色胺相关基因中的其他变异 可能也会增加患自闭症的风险。我们建议系统地评估5-羟色胺相关基因的作用 在自闭症中，使用关键的神经化学和行为措施提供的表型数据最多 可能会索引与该系统相关的遗传风险

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