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Investigation of genetic modifiers in individuals with the 22q11.2 deletion syndrome and its relationship with the disease phenotype

Grant number: 20/14411-6
Support Opportunities:Scholarships abroad - Research Internship - Doctorate (Direct)
Effective date (Start): February 15, 2021
Effective date (End): February 14, 2022
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Maria Isabel de Souza Aranha Melaragno
Grantee:Natália Rodrigues Nunes Nishimoto
Supervisor: Fatima Ferreira-Briza
Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Research place: University of Salzburg, Austria  
Associated to the scholarship:20/04414-8 - Investigation of genetic variants in individuals with 22q11.2 Deletion Syndrome and its effect on phenotype, BP.DD


Several studies have associated specific genes to phenotypes observed in the 22q11.2 deletion syndrome (22q11.2DS), yet much of the etiology for its clinical heterogeneity remains unknown. In addition to genes within the deleted region, several additional genetic factors have been associated with the penetrance of clinical signs in 22q11.2DS. Taking into account that the relationship between immunological alterations and other clinical signs of the syndrome has already been seen, we hypothesize that SNVs associated with non-syndromic immune disorders may predict the risk for scoliosis in patients with 22q11.2DS. Robust statistic models to associate complex traits with genetic variants have been increasingly applied in population genetics. However, the sample size of rare genetic diseases limits the application of these models to genetic syndromes such as 22q11.1DS. To overcome this limitation, the current project leverages public datasets of isolated scoliosis and immunological disorders to verify if variants associated with these conditions can predict the presence of scoliosis in 22q11.2DS. To our knowledge, this is the first study that investigate the genetic association of non-syndromic scoliosis and immunological diseases related to the context of 22q11.2DS. To this end, we propose to perform a genetic correlation study, using association studies from non-syndromic scoliosis and immune disorders, followed by the application of polygenic risk scores of immunological disorders to predict the presence of scoliosis in patients with 22q11.2DS. Also, we will apply machine learning models using SNVs associated with non-syndromic immunological disorders to classify the presence of scoliosis in patients with 22q11.2DS. Together, these results will provide the first in-depth analysis of genetic correlation of idiopathic scoliosis and non-syndromic immune disorders in humans. By assessing the role of common variants in risk prediction of developing scoliosis in patients with 22q11.2DS, a greater understanding of immunological genetic associations involved in idiopathic scoliosis present in the general population will be achieved. (AU)

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