The Roles of Environmental Risks and GEX in Increasing ASD Prevalence

描述（由申请人提供）：自闭症谱系障碍（ASD）的研究报告了逐步提高的患病率估计，范围从0.07%到我们最近报告的2.64%。虽然有证据表明，大部分的上升是由于公众意识的提高，ASD诊断标准的扩大和更好的病例确定，但ASD患病率的上升仍然可能与ASD发病率的增加有关。反过来，由于纯粹的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易感性的相互作用是ASD风险增加的机制。 检测ASD的病因学底物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（格克斯）、样本量不足以及主要使用可能反映偏倚选择的临床样本。 该提案旨在克服这些障碍，并旨在发现ASD的病因学底物，并确定其与ASD发病率的关系。这一目标将通过以下方法实现：首先使用来自韩国高阳市的5个连续出生队列前瞻性检查7岁以下的累积发病率，使用总人口策略和系统的标准化病例识别程序。在这个过程中，我们将建立一个系统确定的人群为基础的队列ASD儿童，他们的家庭和性别和智商匹配的控制，我们将收集数据，从病史，神经心理学测试和体格检查，沿着血液测量激素和推定的环境毒素。有了这些数据，我们将研究环境风险在ASD发病率和表型中的作用。最后，我们将建立一个血清的生物储存库，以进行进一步的分析，包括毒素和ASD相关的免疫学标记，同时还将创建可用于未来遗传和格克斯研究的细胞系和纯化DNA。虽然这些材料将可用于随后的大规模格克斯研究，在该研究中，我们将完成全基因组基因分型，以提供足够的环境响应基因覆盖率，但在拟议研究的第4年和第5年，我们还将使用正在进行的ASD遗传研究中快速发展的数据和复制的遗传标记来检查格克斯。 当拟定的样本采集完成后，将对其进行独立分析，然后与我们的大规模西蒙斯基金会资助的流行病学样本（N= 10，000）的数据相结合，该样本采集了唾液/血液，并测量了ASD症状的表型。这种组合将极大地增加力量，并提供大量的机会来解决ASD遗传结构，环境因素和格克斯在大规模，统计学上良好的动力，系统确定，基于人群，遗传同质的ASD个体群体中的作用，沿着匹配的对照。

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.