Genetic study of Restricted Repetitive Behavior in Autism Spectrum Disorders

描述（由申请人提供）：本研究的目的是确定自闭症谱系障碍（ASD）儿童异常重复行为（如拍打手臂，排队物体，对奇怪物体的特殊迷恋，非常狭窄的限制性兴趣，以及对日常生活变化的不容忍）的遗传因素。作为ASD的核心特征之一，受限重复行为（RRB）经常主导受影响儿童的日常活动，干扰发展功能行为的机会，需要干预和治疗。尽管RRB具有临床意义，但对潜在的遗传机制知之甚少。在这项研究中，我们建议调查GABA和谷氨酸神经传递系统内的遗传变异是否在ASD儿童RRB的发病机制中发挥作用，基于先前的研究，涉及异常的GABA和谷氨酸神经传递在RRB以及ASD的发病机制中。我们将通过一个以社区为基础的支持组织，为有自闭症儿童的学校和家庭确定6至18岁的儿童。将要求确定儿童的主要照顾者完成一系列评定量表，包括社会沟通问卷（SCQ）、社会反应量表（SRS）、重复行为量表修订版（RBS-R）、Vineland适应行为量表-II（父母/照顾者评定表）和药物、家族精神病史和既往病史问卷。将要求患病儿童捐献唾液或口腔拭子样本进行基因分型。将对来自GABA和谷氨酸系统相关基因的总计约750个单核苷酸多态性（SNP）进行基因分型，并分析特定遗传变异与特定形式RRB之间的定量关联。此外，作为次要目标，我们将在GABA和谷氨酸系统相关基因中识别对RRB数量性状有上位性贡献的基因座。如果确定RRB的遗传基础，这将导致对这种慢性和破坏性疾病的早期检测和治疗的新见解。公共卫生相关性：我们的目标是找到自闭症谱系障碍儿童异常重复行为的遗传因素。我们推测GABA和谷氨酸神经传递系统相关基因可能在适应不良重复行为的发生中起关键作用。积极的发现可能会导致一个新的见解，早期发现和治疗这种慢性和致残性疾病。

DESCRIPTION (provided by applicant): The objective of this study is to identify contributing genetic factors for abnormal repetitive behavior (such as flapping arms, lining up objects, peculiar fascination with odd objects, a very narrow restricted interest, and intolerance to changes of routines) among children with autism spectrum disorders (ASDs). As one of the core features of ASDs, restricted repetitive behavior (RRB) frequently dominates the daily activities of affected children, interferes with opportunities to develop functional behaviors, and requires intervention and treatment. Despite the clinical significance of RRB, little is known about underlying genetic mechanisms. In this study, we propose to investigate whether genetic variations within the GABA and glutamate neurotransmission system play a role in the pathogenesis of RRB in children with ASDs, based on prior studies implicating abnormal GABA and glutamate neurotransmission in the pathogeneses of RRB as well as ASDs. We will identify children between ages of 6 and 18 through a community-based support organization for schools and families with children with ASDs. The primary caregivers of the identified children will be asked to complete a battery of rating scales including the social communication questionnaire (SCQ), social responsiveness scale (SRS), the repetitive behavior scale-revised (RBS-R), the Vineland Adaptive Behavior Scale-II (parent/caregiver rating form) and a questionnaire for medication, family psychiatric history and past medical history. Consenting children will be asked to donate either saliva or buccal swab samples for genotyping. A total of ~750 single nucleotide polymorphisms (SNPs) from the GABA and glutamate system related genes will be genotyped and analyzed for quantitative association between specific genetic variants and specific forms of RRB. In addition, we will identify loci contributing epistatically to quantitative traits of RRB among the GABA and glutamate system related genes as a secondary aim. If genetic underpinnings of RRB are identified, this will lead to new insight as to early detection and treatment of this chronic and devastating condition. PUBLIC HEALTH RELEVANCE: Our goal is to find contributing genetic factors for abnormal repetitive behavior among children with autism spectrum disorders. We hypothesize that genes related to the GABA and glutamate neurotransmission system may play a key role in the development of the maladaptive repetitive behavior. Positive findings may lead to a new insight as to early detection and treatment of this chronic and disabling condition.