The Roles of Environmental Risks and GEX in Increasing ASD Prevalence

描述(由申请人提供)：对自闭症谱系障碍(ASD)的研究报告了越来越高的患病率估计，从0.07%到我们最近报告的2.64%。虽然证据表明，ASD发病率的上升主要归因于公众意识的提高、ASD诊断标准的扩大和病例确定的改善，但ASD患病率的上升仍有可能与ASD发病率的增加有关。反过来，由于纯遗传因素不太可能在如此短的时间内产生影响，ASD发病率的增加表明环境因素及其与遗传脆弱性的相互作用是增加ASD风险的机制。检测ASD的病因已被证明是具有挑战性的。这些困难可能源于ASD遗传学的复杂性，包括基因-环境相互作用(GEX)、样本大小不足以及主要使用可能反映偏向选择的临床样本。这项建议旨在克服这些障碍，旨在发现ASD的病因并确定它们与ASD发病率的关系。为实现这一目标，将首先使用韩国高阳市连续出生的5个队列，采用总体人口战略和系统、标准化的病例识别程序，首先前瞻性地检查7岁以下的累积发病率。在这个过程中，我们将建立一个以系统确定的人群为基础的自闭症儿童、他们的家庭以及性别和智商匹配的对照组，我们将从病史、神经心理测试和体检以及血液中收集数据，用于测量荷尔蒙和可能的环境毒素。有了这些数据，我们将检验环境风险在ASD发病率和表型中的作用。最后，我们将建立一个用于进一步分析的血清生物储存库，包括毒素和ASD相关免疫标志物，同时还将创建细胞系和纯化的DNA，可用于未来的遗传学和性别研究。虽然这些材料将用于随后的大规模Gex研究，在该研究中，我们将完成全基因组基因分型，为环境响应基因提供足够的覆盖范围，但在拟议研究的第4年和第5年，我们也将使用快速演变的数据和正在进行的ASD基因研究的复制遗传标记来检查Gex。当拟议的样本收集完成后，将进行独立分析，然后与我们由西蒙斯基金会资助的大规模流行病学样本(N=10,000)的数据结合起来，这些样本的唾液/血液被收集并测量了ASD症状的表型。这一组合将极大地增加ASD的力量并提供大量机会，以解决ASD遗传结构、环境因素的作用和Gex在大规模、统计上强大的、系统确定的、基于人群的、遗传同质的ASD个体群体中的作用，以及匹配的对照。

DESCRIPTION (provided by applicant): Studies of Autism Spectrum Disorder (ASD) have reported progressively higher prevalence estimates, ranging from 0.07 to our recent report of 2.64%. While the evidence suggests that most of the rise is attributable to greater public awareness, a broadening of the ASD diagnostic criteria and better case ascertainment, it still remains possible that the rising ASD prevalence is associated with increases in ASD incidence. In turn, since purely genetic factors are unlikely to have an impact in such a short period of time increases in ASD incidence suggest that environmental factors and their interactions with genetic vulnerability are mechanisms for increasing risk for ASD. Detecting the etiological substrates of ASD has proven to be challenging. These difficulties likely arise from the complexity of ASD genetics, including gene-environmental interaction (GEX), insufficient sample sizes and the use of mainly clinical samples that may reflect biased selection. This proposal is designed to overcome these obstacles, and aims to discover etiologic substrates of ASD and determine their relationship to ASD incidence. This goal will be achieved by first prospectively examining cumulative incidence up to age 7 using 5 successive birth cohorts from Goyang City, South Korea, using a total population strategy and systematic, standardized case identification procedures. In this process, we will establish a systematically-ascertained population-based cohort of children with ASD, their families and sex and IQ matched controls from which we will collect data from medical histories, neuropsychological testing and physical examinations, along with blood for measurement of hormones and putative environmental toxins. With these data, we will examine the role of environmental risks in ASD incidence and phenotype. Finally, we will establish a biorepository of serum for further analyses, including toxins and ASD-related immunological markers, while also creating cell lines and purified DNA that can be used for future genetic and GEX studies. While these materials will be available for a subsequent large scale GEX study in which we will complete whole genome genotyping to provide sufficient coverage for environmentally responsive genes, in years 4 and 5 of the proposed study, we will also examine GEX using rapidly evolving data and replicated genetic markers from ongoing ASD genetic studies. When the proposed sample collection is completed, it will be analyzed independently and then combined with the data from our large-scale, Simons Foundation-funded epidemiological sample (N=10,000) whose saliva/blood were collected and phenotype was measured for ASD symptoms. This combination will dramatically increase the power and provide substantial opportunities to address ASD genetic architecture, the role of environmental factors and GEX in a large-scale, statistically well-powered, systematically-ascertained, population-based, genetically homogenous group of distinct individuals with ASD, along with matched controls.