Genomics of Autism in Latinx Ancestries

项目摘要 自闭症谱系障碍(ASD)的遗传结构是复杂的，正在进行的破译它的努力已经 重点研究了常见和罕见的基因变异。我们的调查团队已经大大增加了目前的 了解ASD的遗传风险和已识别基因的功能影响。尽管我们的大规模 基因分析，仍然有一些悬而未决的问题，其中之一是它的基因 建筑在不同的祖先群体中是不同的。值得注意的是，还没有系统的努力来调查这一点 在西班牙裔和拉丁裔/拉丁裔人口中，美国最大的少数民族人口(约6000万，18% 占总人口的比例)，而且增长迅速。将代表性不足的人群纳入遗传研究是 无论是出于科学原因，还是出于平等性，这都很重要。因此，该提案概括了NIMH的两个优先事项：我们 将调查西班牙裔/拉丁裔祖先患自闭症的遗传风险。加深我们对ASD的认识 在西班牙裔/拉丁裔人群中，我们建议：1)招募、表型和至少额外1600个样本 西班牙裔/拉丁裔ASD三人组，从而扩大了我们现有的具有良好特征的拉美裔/拉丁裔ASD样本集 样本；2)对队列中的所有样本进行基因分型和测序，并将结果与自闭症测序相结合 联盟和精神病学基因组联盟，针对罕见和常见基因变异的大规模努力， 3)利用跨祖先全基因组关联分析队列中常见的遗传变异 研究(GWAS)，制定祖先信息的多基因风险评分，并有助于精细绘图和 共同定位最重要的GWAS发现；以及，4)对 队列，特别注意考虑祖先，特别是罕见的遗传变异。在成功的 总结拟议的研究，我们将有四个重要的结果：更深入地了解如何罕见和 共同的变异增加了ASD跨祖先的风险；增强了ASD基因座的精细定位； 对于不同的祖先，更好、更便携的PR；以及更多已知的ASD风险基因。此外，我们 将有助于改进在基因组研究中整合不同祖先样本的方法 将加强在这类研究中对代表性不足人群的招募。

Project Summary The genetic architecture of autism spectrum disorder (ASD) is complex and ongoing efforts to decipher it have focused on both common and rare genetic variants. Our investigative team has added significantly to current understanding of ASD genetic risk and to the functional impact of identified genes. Despite our large-scale genetic analyses, there remains a number of unanswered questions, one of which is whether its genetic architecture differs across ancestral populations. Notably, there has been no systematic effort to investigate this in Hispanic and Latina/Latino populations, the largest minority population in the United States (~60 million, 18% of the total population), and growing rapidly. Inclusion of under-represented populations in genetic studies is important both for scientific reasons and for parity. This proposal therefore encapsulates 2 NIMH priorities: we will investigate genetic risk for ASD in people of Hispanic/Latinx ancestry. To further our understanding of ASD in Hispanic/Latinx populations, we propose to: 1) recruit, phenotype and sample at least 1,600 additional Hispanic/Latinx ASD trios, thereby expanding our existing sample set of well-characterized Hispanic/Latinx ASD samples; 2) genotype and sequence all samples in the cohort and combine results with the Autism Sequencing Consortium and the Psychiatric Genomics Consortium, large-scale efforts on rare and common genetic variation, respectively; 3) analyze common genetic variation in the cohort using cross-ancestry genome-wide association studies (GWAS), develop ancestry-informed polygenic risk scores, and contribute to fine-mapping and colocalization of top GWAS findings; and, 4) carry out genetic association studies for rare genetic variants in the cohort, taking special care to account for ancestry, especially for rare inherited variation. At the successful conclusion of the proposed studies, we will have four important results: a deeper understanding of how rare and common variation contribute to risk for ASD across ancestries; enhanced fine-mapping of ASD GWAS loci; better, more portable PRS for diverse ancestries; and a larger number of known ASD risk genes. In addition, we will have contributed to improving methods for integrating samples of diverse ancestry in genomic studies and will have enhanced recruitment of under-represented populations in such studies.