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.

项目摘要 自闭症谱系障碍（ASD）的遗传结构是复杂的，并且正在持续破译它的努力 专注于常见和稀有遗传变异。我们的调查团队大大增加了当前的 了解ASD遗传风险和确定基因的功能影响。尽管我们大规模 遗传分析，仍然存在许多未解决的问题，其中之一是其遗传 建筑在祖先种群之间有所不同。值得注意的是，没有系统的努力来调查这一点 在西班牙裔和拉丁裔人口中，美国最大的少数民族人口（约6000万，18％ 总人口），并迅速增长。在遗传研究中纳入代表性不足的人群是 出于科学原因和均衡，重要的是。因此，该提案概括了2个NIMH优先事项：我们 将调查西班牙裔/拉丁人血统中ASD的遗传风险。进一步我们对ASD的理解 在西班牙裔/拉丁裔人群中，我们提出：1）招募，表型和样品至少1,600个 西班牙裔/拉丁裔ASD三重奏，从而扩展了我们现有的良好特征西班牙裔/拉丁裔ASD的样本集 样品； 2）基因型和序列在队列中的所有样品，并将结果与​​自闭症测序结合 财团和精神病基因组学联盟，对罕见和常见遗传变异的大规模努力， 分别; 3）使用跨疗法全基因组关联分析队列中的常见遗传变异 研究（GWAS），发展为祖先的多基因风险评分，并有助于精细映射和 顶级GWAS发现的共定位； 4）进行遗传关联研究，以实现稀有遗传变异 队列，特别注意祖先，特别是对于罕见的遗传变异。在成功 拟议研究的结论，我们将有四个重要的结果：更深入地了解 常见变化导致​​跨祖先的ASD风险；增强了ASD GWAS基因座的精细映射； 更好，更便携的PR适用于各种祖先；以及更多已知的ASD风险基因。另外，我们 将有助于改善在基因组研究中整合不同血统样本的方法和 在此类研究中，将增强代表性不足人群的招募。