Genomics of Autism in Latinx Ancestries

拉丁裔血统中自闭症的基因组学

• 批准号: 10582709
• 负责人: Joseph D. Buxbaum
• 金额: $ 78.2万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-03 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582709
• 关键词: Affect; Caring; Clinical; Complex; Copy Number Polymorphism; Data; Encapsulated; Enrollment; Epilepsy; Equity; Etiology; European ancestry; Future; Gene Dosage; Gene Expression; Genes; Genetic; Genetic Risk; Genetic Variation; Genetic study; Genomics; Genotype; Heritability; Hispanic; Hispanic Populations; Individual; Inherited; Intellectual functioning disability; Latin American; Latina; Latino Population; Latinx; Latinx population; Maps; Medical; Methods; Minority Groups; National Institute of Mental Health; Nucleotides; Parents; Phenotype; Population; Prevention; Public Health; Research; Risk; Sampling; Single Nucleotide Polymorphism; Site; Subgroup; Testing; Underrepresented Populations; United States; Variant; autism spectrum disorder; case control; clinical phenotype; cohort; comorbidity; disorder risk; exome sequencing; gene discovery; genetic analysis; genetic architecture; genetic association; genetic variant; genome wide association study; genome-wide; improved; insertion/deletion mutation; non-genetic; parity; polygenic risk score; portability; proband; psychiatric genomics; recruit; risk variant; transmission process

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.

项目概要 自闭症谱系障碍 (ASD) 的遗传结构非常复杂，我们正在努力破译它 专注于常见和罕见的遗传变异。我们的调查团队在目前的基础上已显着增加 了解 ASD 遗传风险以及已识别基因的功能影响。尽管我们规模庞大 遗传分析中，仍有许多未解答的问题，其中之一是其遗传是否 不同祖先群体的建筑风格有所不同。值得注意的是，目前还没有系统性的努力来调查这一问题 西班牙裔和拉丁裔/拉美裔人口是美国最大的少数族裔人口（约 6000 万，占 18%） 的总人口），并且增长迅速。将代表性不足的人群纳入遗传学研究是 出于科学原因和平等性都很重要。因此，该提案概括了 NIMH 的 2 个优先事项：我们 将调查西班牙裔/拉丁裔血统人群患 ASD 的遗传风险。加深我们对自闭症谱系障碍 (ASD) 的了解 在西班牙裔/拉丁裔人群中，我们建议：1) 招募至少 1,600 名额外人员，进行表型分析和抽样调查 西班牙裔/拉丁裔 ASD 三人组，从而扩展了我们现有的具有良好特征的西班牙裔/拉丁裔 ASD 样本集 样品； 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学联盟，对罕见和常见的遗传变异进行了大规模的努力， 分别; 3) 使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），开发基于祖先的多基因风险评分，并有助于精细绘图和 顶级 GWAS 研究结果的共定位； 4) 对罕见遗传变异进行遗传关联研究 队列，特别注意考虑祖先，特别是罕见的遗传变异。在成功的 根据所提出的研究结论，我们将获得四个重要结果： 更深入地了解稀有和稀有程度如何 共同的变异会导致不同血统的自闭症谱系障碍风险；增强 ASD GWAS 位点的精细定位； 更好、更便携的 PRS，适合不同的血统；以及大量已知的 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血统样本的方法， 将在此类研究中增加对代表性不足的人群的招募。