Down Syndrome: A UPDB Discovery Cohort for Translating Genes, Brain and Behaviors to Treatment

摘要 唐氏综合症（DS）或21三体，是影响数百万人的智力残疾（ID）的主要遗传原因 国际吧更令人吃惊的是，DS是自闭症谱系障碍（ASD），阿尔茨海默病的主要风险 (AD)先天性心脏病，以及免疫、内分泌和造血系统缺陷。没有 预防或治疗这些缺陷的DS，部分原因是需要深入注释和深入研究。 表型DS研究和发现队列。为了填补这一空白，本行政补充文件的目标是： 犹他州临床和转化科学奖（CTSA），在朱莉R。科伦伯格，是 协调并扩展NIH INCLUDE（对整个生命周期内共发疾病的研究， 了解唐氏综合征联盟、DS-ConnectTM注册中心、数据管理和门户网站 INCLUDE（DAPI）项目和数据协调中心（DCC）通过完成和集成两个新的 每个DS队列都有现有的深度注释，一个具有深层脑表型和泛组学， 与Crnic研究所的人类三体项目（HTP）重叠。通过此补充，我们将提供： 招募DS-100 B，一个300名参与者的大型队列（200个DS家庭，100个年龄和性别匹配的 控制）覆盖整个寿命，来自独特的多代犹他州人口数据库 （100 B）包括>4000例确诊的DS诊断，以及家庭数据和电子病历 （EMR）。下一阶段将为这个独特的队列建立生物库和泛组学。 深度注释，门户准备人口统计学，临床和家庭数据集为300名参与者在DS-WPB。 使用预先存在的DS脑发现队列建立INCLUDE队列和公共网关， 具有多维链接数据集的独特实时队列：深度注释，深度表型分析， 生物库，具有广泛的预先存在的数据集（认知，行为，MRI，DTI，fMRI，核型，DNA阵列， 甲基化，labs）。 完成DS的泛组学数据集（转录组学、蛋白质组学、细胞因子和代谢组学） 脑发现队列（30例DS，37例父母，14例对照）嵌入较大队列。 ·第一次跨队列合作，使用Brain Discovery将免疫测试与脑成像相结合 队列生物样本库。 这些结果将通过建立一个深度注释的DS来为DS研究合作增加未来的维度 在多代脑卒中患者B和第一个脑DS患者中， 发现队列（也称为cDNAB）对脑成像，基因和泛组学进行了深入的表型分析，作为一个无与伦比的 INCLUDE联盟HTP针对DS-ConnectTM注册中心DAPI的协作数据挖掘资源 和DCC。本建议书是对NOT-OD-20-024的响应，保留了犹他州母公司CTSA的范围， 吸引和培训初级DS研究人员，并将加快翻译为DS治疗的速度。

ABSTRACT Down syndrome (DS) or Trisomy 21, is the major genetic cause of intellectual disabilities (ID) affecting millions worldwide. Even more striking, DS is a major risk for autistic spectrum disorder (ASD), Alzheimer’s disease (AD), congenital heart disease, and deficits of the immune, endocrine and hematopoetic systems. There are no preventatives or treatments of these deficits in DS, due in part to the need for deeply annotated and deeply phenotyped DS study and discovery cohorts. To fill this gap, the goal of this Administrative Supplement to the Utah Clinical and Translational Science Award (CTSA), under the leadership of Julie R. Korenberg, is to harmonize with and expand the NIH INCLUDE (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE) consortium, DS-ConnectTM registry, the Data Management and Portal for INCLUDE (DAPI) Project, and the Data Coordinating Center (DCC) by completing and integrating two novel DS cohorts each with existing deep annotation, and one with deep brain phenotyping and pan-omics that will overlap the Crnic Institute’s Human Trisome Project (HTP). Enabled by this supplement, we will deliver:  Recruitment of DS-UPDB, a large cohort of 300 participants (200 DS families, 100 age and gender-matched controls) covering the entire lifespan, derived from the unique multi-generational Utah Population Database (UPDB) that includes >4000 confirmed DS diagnoses, with family data and the electronic medical record (EMR). The next phase will establish the biobank and pan-omics for this unique cohort.  Deeply annotated, portal-ready demographics, clinical and family datasets for 300 participants in DS-UPDB.  Establishment of an INCLUDE cohort and Public Gateway using the pre-existing DS Brain Discovery Cohort, a unique live cohort with multidimensional linked datasets: deeply annotated, deeply phenotyped and biobanked, with extensive pre-existing datasets (cognition, behavior, MRI, DTI, fMRI, karyotypic, DNA array, methylome, labs).  Completion of Pan-omics datasets (Transcriptomics, Proteomics, Cytokines and Metabolomics) of the DS Brain Discovery Cohort (30 DS, 37 parents, 14 controls) embedded within the larger cohort.  The first inter-cohort collaboration integrating the Immune tests with brain imaging using the Brain Discovery Cohort biobank. The results will add a future dimension to DS research collaboration by establishing a deeply annotated DS cohort enriched for co-occurring conditions, within the multigenerational UPDB, and the first DS Brain Discovery Cohort (also UPDB) deeply phenotyped for brain imaging, genes and pan-omics, as an unparalleled resource for collaborative data mining by the INCLUDE consortia, HTP, for the DS-ConnectTM registry, DAPI, and DCC. This proposal is responsive to NOT-OD-20-024, maintains the scope of the Utah parent CTSA, attracts and trains junior DS investigators, and will accelerate the speed of translation to therapeutics for DS.