Autism Genetics Phase II: Increasing representation of human diversity

摘要 自闭症谱系障碍(ASD)是一种常见的神经精神疾病，目前尚不清楚 病理生理学，但有很大的遗传贡献。在过去的8.5年里，这起案件的调查人员 非常成功的网络在我们对ASD的理解方面做出了重大贡献，并增强了 通过NIMH遗传学倡议和 Agre资源。在我们的上一次更新中，我们采取了一个重要的新方向来填补ASD研究的关键空白，方法是 招募自我报告的非洲血统的受试者(非洲裔美国人；AA)，这是一个以前没有代表的群体 在ASD遗传学研究中。我们在目标上取得了实质性进展，该项目正处于关键时期 阶段：通过继续招聘获得更大的队列，我们将有足够的能力进行第一次 通过全基因组测序(WGS)对编码和非编码基因组进行全面评估。这 提案涉及六个研究地点和AGRE DCC，将系统地研究ASD的遗传学，以 识别罕见的单核苷酸变异(SNV)、结构变异(SV)和常见变异 ASD在这一人群中的易感性。具体地说，我们将通过招聘至少700名机管局来丰富现有资源 先证者和其他家庭成员将使我们的队列达到1300名AA先证者。我们已经成功地 实施了一个健康差异项目，该项目确认了重大的诊断延迟，尽管阐述得很清楚 父母的顾虑。在下一阶段，我们建议通过应用 新的可遗传的、定量的生物标记物，我们假设它将改善获得护理的机会。我们将利用 通过其他资金来源收购所有家庭成员的WGS，不承担本提案的成本，以确定 再生障碍性贫血患者ASD的遗传风险的贡献，包括ASD的新的罕见风险变异，这将 通过改进ASD中罕见变异的分类，也有利于该群体以外的遗传学研究 欧洲(欧盟)和其他民族。我们将用创新的方法来定义当地的祖先，以确定 易感等位基因发生的背景。我们将对罕见的从头开始和传播的 变异，并进行基于基因的负荷测试，这在这个队列中很有能力。基因表达 将使用概况分析、eQTL和网络分析来确定变异的优先顺序。队列中确定的遗传风险因素 到目前为止被研究的(欧盟)将在AA样本中进行关联性测试，以确定这些队列是否 相同的遗传风险因素，使用样本大小提供复制以前的关联和 鉴别罕见的、复发的CNV和SNV。我们将对ASD相关的内表型或 协变量，比如性和社会反应。对新形式或不同人群的观察 此样本中与ASD相关的变异的频率，或与其他人分享最大变异的频率 这两个结果都将对未来的研究和临床护理具有重要意义。就像我们的 在实践中，所有数据将在滚动的基础上共享，进一步增强社区的这一遗传资源。 。

ABSTRACT Autism Spectrum Disorder (ASD) is a common neuropsychiatric condition with largely unknown pathophysiology, but with a substantial genetic contribution. Over the last 8.5 years, the investigators in this highly successful Network have contributed significant advances in our understanding of ASD and enhanced open data and biomaterials resources for the research community via the NIMH Genetics Initiative and the AGRE resource. In our last renewal, we took an important new direction to fill a critical gap in ASD research by recruiting subjects of self-reported African ancestry (African-American; AA), a group not previously represented in ASD genetics research. We have made substantial progress on our aims and the project is in a critical phase: by obtaining a larger cohort via continued recruiting, we will be well powered to conduct the first comprehensive assessment of the coding and non-coding genome via whole genome sequencing (WGS). This proposal involving six research sites and the AGRE DCC, will systematically investigate the genetics of ASD to identify rare single nucleotide variation (SNV), structural variation (SV), and common variation contributing to ASD susceptibility in this population. Specifically, we will enrich existing resources by recruiting at least 700 AA probands and additional family members to bring our cohort to 1300 AA probands. We have successfully conducted a health disparities project that that confirms significant diagnostic delays despite well-articulated parental concerns. In the next phase, we propose to improve early diagnosis, facilitated by the application of a novel heritable, quantitative biomarker, which we hypothesize will improve access to care. We will leverage acquisition of WGS of all family members via other funding sources, at no cost to this proposal, to characterize the contributions of genetic risk for ASD in AA individuals, including novel rare risk variants for ASD, which will also benefit genetic studies outside of this population by improving classification of rare variation in ASD in European (EU) and other ethnicities. We will use innovative methods to define local ancestry to ascertain the background on which susceptibility alleles occur. We will perform analysis of rare de novo and transmitted variants, and perform gene-based burden tests, which are well powered in this cohort. Gene expression profiling, eQTL, and network analysis will be used to prioritize variants. Genetic risk factors identified in cohorts studied to date (EU) will be tested for association in the AA sample to determine whether these cohorts share the same genetic risk factors, using a sample size that provides power to replicate previous associations and identify rare, recurrent CNV and SNV. We will perform follow up GWA on ASD-related endophenotypes or covariates, such as sex and social responsiveness. The observation of new forms or different population frequencies of ASD-related variation in this sample, or alternatively, the sharing of most variation with other cohorts are both outcomes that will have great significance for future studies and clinical care. As has been our practice, all data will be shared on a rolling basis, further enhancing this genetic resource for the community. .