An integrative approach to investigate the respective roles of single-nucleotide variants and copy-number variants in Attention-Deficit/Hyperactivity Disorder

An integrative approach to investigate the respective roles of single-nucleotide variants and copy-number variants in Attention-Deficit/Hyperactivity Disorder

Scientific Reports, March 2016

26947246

Leandro de Araújo Lima, Ana Cecília Feio-dos-Santos, Sintia Iole Belangero, Ary Gadelha, Rodrigo Affonseca Bressan, Giovanni Abrahão Salum, Pedro Mario Pan, Tais Silveira Moriyama, Ana Soledade Graeff-Martins, Ana Carina Tamanaha, Pedro Alvarenga, Fernanda Valle Krieger, Bacy Fleitlich-Bilyk, Andrea Parolin Jackowski, Elisa Brietzke, João Ricardo Sato, Guilherme Vanoni Polanczyk, Jair de Jesus Mari, Gisele Gus Manfro, Maria Conceição do Rosário, Eurípedes Constantino Miguel, Renato David Puga, Ana Carolina Tahira, Viviane Neri Souza, Thais Chile, Gisele Rodrigues Gouveia, Sérgio Nery Simões, Xiao Chang, Renata Pellegrino, Lifeng Tian, Joseph T. Glessner, Ronaldo Fumio Hashimoto, Luis Augusto Rohde, Patrick M.A. Sleiman, Hakon Hakonarson, Helena Brentani

Many studies have attempted to investigate the genetic susceptibility of Attention-Deficit/Hyperactivity Disorder (ADHD), but without much success. The present study aimed to analyze both single-nucleotide and copy-number variants contributing to the genetic architecture of ADHD. We generated exome data from 30 Brazilian trios with sporadic ADHD. We also analyzed a Brazilian sample of 503 children/adolescent controls from a High Risk Cohort Study for the Development of Childhood Psychiatric Disorders, and also previously published results of five CNV studies and one GWAS meta-analysis of ADHD involving children/adolescents. The results from the Brazilian trios showed that cases with de novo SNVs tend not to have de novo CNVs and vice-versa. Although the sample size is small, we could also see that various comorbidities are more frequent in cases with only inherited variants. Moreover, using only genes expressed in brain, we constructed two "in silico" protein-protein interaction networks, one with genes from any analysis, and other with genes with hits in two analyses. Topological and functional analyses of genes in this network uncovered genes related to synapse, cell adhesion, glutamatergic and serotoninergic pathways, both confirming findings of previous studies and capturing new genes and genetic variants in these pathways.