The objectives of GO-DS21 will be achieved by a set of matching and interlinked work packages (WP): one WP for clinical evaluation and selection of individuals with DS with and without obesity; four methodological WPs covering multiomics: transcriptomic, epigenetic, metabolomics, proteomic and microbiome; one technological/integrative WP; one for dissemination and exploitation of results as well as guideline design and one WP for project management. Each WP has key intermediate goals, adjustments to maintain a high-risk/high-gain balance, feed-forward, and feed-back mechanisms. We will develop several mouse models and cellular models on which data will be generated that will comply with the multilayer analysis tools. These will be developed and disseminated through patient and scientific associations (T21RS and EDSA) and caregivers.
Overall organization of the work packages in GO-DS21 showing the interconnections
Primary care data from up to 6,000 DS (UK Clinical Practice Research Datalink – CPRD) combined with socio-economic factors will be incorporated into our analyses, including deprivation scores. An in-depth prospective study will assess 300 DS participants from our existing registries/cohorts/clinics in the UK, France and Spain, and link clinical data with standardized samples for cutting-edge high-throughput technologies for the multi-omic profiling (metabolomic, proteomic, metagenomic, transcriptomic, microRNA, epigenomics).
Aims & Objectives: The study of comorbidity patterns in DS will help us understand the development of conditions associated with trisomy 21 during the lifespan. It is an opportunity to explore the mechanisms by which environmental factors such as lifestyle and anxiety or response to stress may account for the variability in the expression of phenotypes between DS individuals. The basic hypothesis is that diseases (and comorbidity) arise from one or more biological networks perturbed by the genetic disorder (trisomy 21) through interaction with environmental risks and epigenetic changes; specific hypotheses have been given in the methodology section.
Specific objectives of WP1 are:
- To describe age-related prevalence and incidence of obesity and its associated comorbidities in DS individuals at population level compared against matched controls to identify unique pattern(s) of comorbidities and related factors in DS individuals
- To obtain in-depth prospective data on associated factors related to BMI/ weight in DS individuals, including cognitive abilities, lifestyle, activity levels, sleep and mental health
- To determine the role of cortisol and hypothalamic pituitary adrenal (HPA) stress response in obesity and related comorbidities in DS individuals
- To obtain biomarker and cellular samples for analysis in other WPs (WPs2 and 5)
WP2 will perform an in-depth characterization of rodent DS models to determine the intrinsic contribution of Hsa21 overdosage and to evaluate the consequence of changes in the environment with enriched diet, stress and exercise. We will benefit from a controlled environment and well-known and established mouse models with robust cognitive impairment to test for comorbidities. Environmental challenges (such as obesogenic diet, stress, exercise and further parameters captured in WP1) and genetic approaches will be applied to identify additional candidate genes that could affect the risk of comorbidities in mice and rats.
Specific objectives of WP2 are:
- To investigate the natural history of increased adiposity/cognitive deficit comorbidity and validate the hypothesis that DS-mice have increased adrenal hyper-responsiveness to ACTH and propensity to obesity and comorbidities
- To determine the impact of obesogenic environments combined with stress or exercise on comorbidities in DS models
- To dissect the specific chromosomal regions involved using DS mice and rat models
- To explore the changes (at molecular/cellular and/or biomarker levels) that are expressed before the onset of physical comorbidity in DS models
WP3 will focus on the investigation of the contribution of three candidate comorbidity genes from the Hsa21 that are overexpressed in Down Syndrome (DS) people and whose functions are at the crossroads of cognition, stress response and metabolism. The overarching hypothesis is that overexpression of several key driver genes induces a novel causative mechanism in the appearance of obesity and cognitive impairment comorbidity. The main aim is to demonstrate the contribution of these key driver genes in isolation or in combination, to the overall phenotype of obesity and cognitive impairment using genetic and pharmacological approaches. In doing so, we provide proof of concept that these genes are critical to the development of co-morbidities which can be targeted to rescue the phenotype. We will also explore HPA function as a common mechanism for obesity and cognitive impairment comorbidity.
Specific objectives of WP3 are:
- To genetically rescue the comorbidity phenotypes of obesity and cognitive impairment in DS trisomic mice by normalization of one of the key driver genes
- To restore normal HPA function in DS-mice following gene dosage normalization of one of the driver genes
- To validate if an additional copy of the driver genes is sufficient to induce HPA dysfunction, obesity and cognition co-morbidities
- Postnatal rescue of obesity and cognitive impairment in DS-mice, targeting the main driver genes
The aim of WP4 is to produce a large panel of OMICS data from a selection of individuals with DS with BMI>35 versus control with normal BMI, and cellular models of the affected human tissues (adipocytes, neurons) derived from iPS cells from selected individuals with extreme phenotypes to perform cellular analyses and test comorbidity associated candidate genes. The same panel of OMICS will be used to analyze samples from the mouse models.
Specific objectives of WP4 are:
- Identification of plasma metabolomic and proteomic changes, and microbiomic features correlated to obesity/ID comorbidity in 60 individuals with DS at the 2 extremes of the comorbidity phenotype
- Identification of metabolomic, plasma proteomic and microbiomic features correlated to diet/exercise/stress and obesity/ID comorbidity in mouse models of DS
- Generation of iPS cells from fibroblasts of 4 women and 4 men with DS from the two extremes of the comorbidity phenotype in the middle-aged adults 35-45 extreme HighIQ-Lean and LowIQ-Obese
- Identification of metabolomic, proteomic features and cellular phenotypes in neurons and adipocytes derived from iPS cells
The aim of WP5 is to decipher the transcriptomic and epigenetic landscapes of representative tissue samples to better categorize mental and physical comorbidities in DS. This will be achieved by comprehensively investigating transcriptomic and epigenomic signatures in DS patients and genetically engineered rodent models of this syndrome. This will also be investigated in response to environmental changes such as diet or stress.
The specific objectives of WP5 are:
- Generate and analyze data for a comparison of epigenetic signatures from blood samples of DS patients with genetically engineered animal models of DS
- Relate epigenetic signatures in the blood to epigenetic signatures in relevant organs of genetic models (mouse and iPS cells) and respective phenotypes
- Generate a comprehensive map of DS and comorbidity related regulatory mechanisms by integration of short and long RNA expression (including single-cell analyses) and DNA methylation data also following intervention and under environmental stress
WP6 will build the “GO-DS21 comorbidity network” from the data gathered in WPs 1 – 5 with multi-omic and clinical data fusion, meta-analysis of high dimensional data, interpretation, discussion and visualization of the results from the molecular to clinical space in context with the aim to generate an integrated gene and comorbidity ontology, and the identification of biomarkers. Mathematical modelling of comorbidity trajectories, personalized comorbidity map and biomarkers will help for better stratification of people with DS to allow a personalized intervention therapy to improve the care and their daily life.
The specific objectives of WP6 are:
- To develop novel or adapt existing white box approaches to integrate multi-omics and clinical data and identify multi-omics and clinical signatures in DS patients
- To develop novel or adapt existing black-box approaches (unsupervised, semi-supervised and supervised) to integrate multi-omics and clinical data and identify multi-omics and clinical signatures in DS patients
- To generate a comprehensive comorbidity map of DS and associated multi-omics regulatory mechanisms by integrative synthesis analyses of complex evidence
- Network science of drivers underlying hallmarks of DS, characterization of the phenotype phase space and the genetic-phenotype relationships across comorbidities. Using a multi-parameter evidence synthesis approach to estimate the disease burden associated with each morbidity, we will derive a computational comorbidity model and develop the better-suited visualization tool for displaying the multi-view medical data
Evidence-based medicine must provide the best evidence available from systematic research to clinician practice. This view, however, is limited and confines it to a purely biomedical approach that does not readily or explicitly incorporate the patients’ perspective. Current developments within the health care system have changed the role of patients from passive recipients of medical services to active partners and co-producers of their own health. Down Syndrome (DS) individuals’ involvement in such activities is a major challenge but we plan to utilize the knowledge and experience of families in order to apply the knowledge gained in GO-DS21 to foster the prevention of obesity comorbidity, improve the health status and the quality of life of individuals with DS.
The objectives of WP7 are twofold:
- The development of a communication strategy and dissemination plan aimed at involving the potential stakeholders of the EU member states, including DS individuals and their families, health care professionals, and regulatory agencies
- To identify what key roles and co-creation tasks are DS individuals and their families able to fulfill within the comorbidity management process
A communication, a co-creation strategy and dissemination plan will be implemented including the following objectives:
- To disseminate the results of GO-DS21 to relevant stakeholders
- To disseminate the results to the scientific, healthcare, pharmaceutical and policy sectors and foster interaction and exchange with DS organizations
- To identify and valorize the intellectual property rights (IPR) generated within Go-DS21
- To incorporate new findings of GO-DS21 into international clinical guidelines, inform patient communities of the benefits for the patients and actively integrate DS individuals and families in the management of obesity comorbidity
Management and coordination of all the issues related to the broad spectrum of methods and tasks performed in the multidisciplinary consortium, with administrative activities needed for effective project management. Effective project management is a central element of successful research, since large research projects entail substantial amounts of administrative work.
The specific objectives of WP8 are:
- To make GO-DS21 achieve its objectives and to deliver in time, budget and quality its milestones and deliverables
- To help the consortium abide by the regulations and contractual obligations according to the grant agreement, its annexes and the consortium agreement
- To look after the project`s finances and to report them properly to the European Commission
- To establish a communication infrastructure which enables the partners to communicate efficiently and to stay connected for the run-time of the project
- To preserve the rights of the partners regarding intellectual property and to act as a mediator in case of disputes
This work package sets out the ‘ethics requirements’ that the project must comply with.