Why it matters


Down Syndrome (DS) is the most common form of intellectual disability (ID) in the world, with an incidence of 1 in 1000 births and affects more than 5 million people worldwide. It is characterized by the presence of an extra copy of human chromosome 21 (often shortened to Hsa21 for Homo sapiens chromosome 21), i.e. having 3 copies of chromosome 21 (trisomy 21) is the cause of DS. Within the European population, the prevalence of DS remains high due to increased maternal age and lack of antenatal follow-up in certain at-risk populations, as well as the increasing life expectancy of DS individuals. Mental and physical comorbidities appear at much higher frequency during the lifetime of individuals with DS compared to the typical population. The key to understanding co- and multi-morbidity lies in the elucidation of the common etiological molecular pathways that induce the coexistence of two or more diseases in an individual. Understanding the pathways and mechanisms involved in comorbidities and multi-morbidities is of major importance for the treatment of patients with such conditions.

The hypothesis is that etiological pathways controlling comorbidities could be better identified when diseases cluster in individuals who share a common pattern of influences or if their resilience or vulnerability is altered similarly. This suggests that specific genetic and/or epigenetic mechanisms associated with trisomy 21 predispose to specific disorders. The comorbid phenotypes seen in DS, much like comorbidities seen in the general population, are variable and not fully penetrant. Obesity, a central comorbidity in DS, is diagnosed on individuals presenting a body mass index larger than 30 kg/m2 and affects more than 640 million adults. The average worldwide prevalence is 39% and is expected to rise. Obesity prevalence is higher in ID and particularly increased in DS. Obesity in people with DS increases also the risk of multi-morbidities including obstructive sleep apnea, (which, if left untreated, can lead to hypertension, heart failure, and death), dyslipidemia, hyperinsulinemia, type 2 diabetes and gait disorder. Because people with DS have a longer lifespan nowadays, lead sedentary lifestyles, and remain obese, the incidence of these diseases is likely to increase among them in the future. Despite the complexity, the genetic risk associated with DS is clear and enables us to use DS as a paradigmatic condition to unravel some of the underlying mechanisms of obesity and further comorbid disorders.

In this 5-year-long research project, this unique interdisciplinary consortium of  DS experts consisting of clinicians, pathophysiologists, integrative bioinformaticians and artificial intelligence computer scientists will work together to improve the lives of people with DS (and others affected by obesity and intellectual disabilities).