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

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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.