Gene overdosage and comorbidities during the early lifetime in down syndrome
The aim of the project is to elucidate etiological mechanisms involved in the appearance of obesity, and intellectual disability comorbidities in Down syndrome (DS). With its incidence of 1 in 1000 births, DS offers a great opportunity to uncover common/novel mechanisms because it is associated with a higher risk to develop several obesity, and intellectual disability. The increased risk to develop this combination of comorbidities in DS, suggests that specific genetic or epigenetic mechanisms associated with trisomy 21 (the cause of DS) predispose to this comorbidity.
For this aim, GO-DS21 will have the following objectives: 1) To determine age-related comorbidity patterns observed over the early lifetime (before age 45) in persons with Down syndrome (WP1). 2) To identify specific physiological biomarkers (WP4), and regulatory and epigenetic signatures (WP5) in human, cellular and animal models. 3) To decipher the contribution of environmental factors (stress, diet, exercise) to trisomy 21 obesity/ID comorbidities in preclinical models (WP2, 3). 4) To investigate the effects of overdosage of three Hsa21 candidate genes (DYRK1A, MRAP, NRIP1) to explain comorbid patterns in mouse models (WP3). 5) To integrate multilevel data from human patients, preclinical and cellular models across different spatial and temporal scales of biological complexity using computational biology models and machine learning approaches (WP6). 6) To design new therapeutic interventions to reduce the penetrance of comorbidities in preclinical models (WP3 and WP4). This approach will help to improve diagnosis and understanding of prognostic factors, and will establish recommendations and targeted interventions to prevent or minimise comorbidities in persons with DS (WP7). Beyond the impact for patients with DS we expect that findings of this project will also be beneficial for patients in the general population.