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Quantitative evaluation of common and rare genetic variations in dopamine system related to attention deficit/hyperactivity disorder and its intermediate phenotypes

Grant number: 11/06594-4
Support type:Regular Research Grants
Duration: September 01, 2011 - February 28, 2014
Field of knowledge:Biological Sciences - Genetics
Principal Investigator:Helena Paula Brentani
Grantee:Helena Paula Brentani
Home Institution: A C Camargo Cancer Center. Fundação Antonio Prudente (FAP). São Paulo , SP, Brazil
Assoc. researchers:Dirce Maria Carraro ; Eurípedes Constantino Miguel Filho ; Guilherme Vanoni Polanczyk


Attention-deficit /hyperactivity disorder (ADHD) is one of the most common mental disorders of childhood and is associated with an important individual and social impact. Most affected individuals persist with symptoms or significant functional impairment into adulthood, which characterizes it as a chronic medical condition. In this mental disorder, genetic factors play an important role, but its complex nature, i.e., many genes of small effect may be involved, making it a multifactorial polygenic disease. So it becomes important to determine not only the environmental risk factors involved, but also the genetic factors of susceptibility or predisposition. Several studies point to the involvement of the dopaminergic system in the pathophysiology of ADHD. Although the studies of candidate genes related to this system have some positive outcomes, their replication is low and none can explain more than 5% of the phenotypic variation in ADHD. The latest techniques of molecular biology that allowed large-scale studies of complete genome (GWAS) to analyze thousands of single basic common variants (SNPs) are a promising tool when compared with association studies of gene variations unique. However, GWAS studies found no statistically significant associations for common variants, besides the fact that the paradigm "common disease, common gene" seems to be not true for most cases of complex diseases such as ADHA. Recent studies of copy number variations (CNV) showed some rare CNV associated with ADHD, but replication is needed. The sequencing of high coverage and next-generation allows a significant increase in the ability to examine the contribution of rare variants and common, as of CNVs in the development of ADHA. The aim of this study is to investigate the relationship between ADHD and intermediate phenotypes related to this disorder and all polymorphisms, VNTRs and CNVs of major genes of the dopaminergic pathway, using sequencing of high performance. (AU)