title: An integrative approach to investigate the respective roles of single-nucleotide variants and copy-number variants in Attention-Deficit/Hyperactivity Disorder.
abstract: 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.
authors.affiliation: Inter-institutional Grad Program on Bioinformatics, University of São Paulo, São Paulo, SP, Brazil.|Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Leandro de Araújo
authors.initials: Lde A
authors.lastname: Lima
authors.affiliation: Department &Institute of Psychiatry, University of São Paulo Medical School, São Paulo, SP, Brazil.
authors.forename: Ana Cecília
authors.initials: AC
authors.lastname: Feio-dos-Santos
authors.affiliation: National Institute of Developmental Psychiatry for Children and Adolescents (INCT-CNPq), São Paulo, SP, Brazil.|Department of Psychiatry, Federal University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Sintia Iole
authors.initials: SI
authors.lastname: Belangero
authors.affiliation: National Institute of Developmental Psychiatry for Children and Adolescents (INCT-CNPq), São Paulo, SP, Brazil.|Department of Psychiatry, Federal University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Ary
authors.initials: A
authors.lastname: Gadelha
authors.affiliation: National Institute of Developmental Psychiatry for Children and Adolescents (INCT-CNPq), São Paulo, SP, Brazil.|Department of Psychiatry, Federal University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Rodrigo Affonseca
authors.initials: RA
authors.lastname: Bressan
authors.affiliation: National Institute of Developmental Psychiatry for Children and Adolescents (INCT-CNPq), São Paulo, SP, Brazil.|Department of Psychiatry, Hospital de Clínicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Giovanni Abrahão
authors.initials: GA
authors.lastname: Salum
authors.affiliation: National Institute of Developmental Psychiatry for Children and Adolescents (INCT-CNPq), São Paulo, SP, Brazil.|Department of Psychiatry, Federal University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Pedro Mario
authors.initials: PM
authors.lastname: Pan
authors.affiliation: Department &Institute of Psychiatry, University of São Paulo Medical School, São Paulo, SP, Brazil.|National Institute of Developmental Psychiatry for Children and Adolescents (INCT-CNPq), São Paulo, SP, Brazil.|Department of Psychiatry, Federal University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Tais Silveira
authors.initials: TS
authors.lastname: Moriyama
authors.affiliation: Department &Institute of Psychiatry, University of São Paulo Medical School, São Paulo, SP, Brazil.|National Institute of Developmental Psychiatry for Children and Adolescents (INCT-CNPq), São Paulo, SP, Brazil.
authors.forename: Ana Soledade
authors.initials: AS
authors.lastname: Graeff-Martins
authors.affiliation: National Institute of Developmental Psychiatry for Children and Adolescents (INCT-CNPq), São Paulo, SP, Brazil.|Department of Psychiatry, Federal University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Ana Carina
authors.initials: AC
authors.lastname: Tamanaha
authors.affiliation: Department &Institute of Psychiatry, University of São Paulo Medical School, São Paulo, SP, Brazil.|National Institute of Developmental Psychiatry for Children and Adolescents (INCT-CNPq), São Paulo, SP, Brazil.
authors.forename: Pedro
authors.initials: P
authors.lastname: Alvarenga
authors.affiliation: Department &Institute of Psychiatry, University of São Paulo Medical School, São Paulo, SP, Brazil.|National Institute of Developmental Psychiatry for Children and Adolescents (INCT-CNPq), São Paulo, SP, Brazil.
authors.forename: Fernanda Valle
authors.initials: FV
authors.lastname: Krieger
authors.affiliation: Department &Institute of Psychiatry, University of São Paulo Medical School, São Paulo, SP, Brazil.|National Institute of Developmental Psychiatry for Children and Adolescents (INCT-CNPq), São Paulo, SP, Brazil.
authors.forename: Bacy
authors.initials: B
authors.lastname: Fleitlich-Bilyk
authors.affiliation: National Institute of Developmental Psychiatry for Children and Adolescents (INCT-CNPq), São Paulo, SP, Brazil.|Department of Psychiatry, Federal University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Andrea Parolin
authors.initials: AP
authors.lastname: Jackowski
authors.affiliation: National Institute of Developmental Psychiatry for Children and Adolescents (INCT-CNPq), São Paulo, SP, Brazil.|Department of Psychiatry, Federal University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Elisa
authors.initials: E
authors.lastname: Brietzke
authors.affiliation: National Institute of Developmental Psychiatry for Children and Adolescents (INCT-CNPq), São Paulo, SP, Brazil.|Center of Mathematics, Computation and Cognition. Universidade Federal do ABC, Santo André, Brazil.
authors.forename: João Ricardo
authors.initials: JR
authors.lastname: Sato
authors.affiliation: Department &Institute of Psychiatry, University of São Paulo Medical School, São Paulo, SP, Brazil.|National Institute of Developmental Psychiatry for Children and Adolescents (INCT-CNPq), São Paulo, SP, Brazil.
authors.forename: Guilherme Vanoni
authors.initials: GV
authors.lastname: Polanczyk
authors.affiliation: National Institute of Developmental Psychiatry for Children and Adolescents (INCT-CNPq), São Paulo, SP, Brazil.|Department of Psychiatry, Federal University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Jair de Jesus
authors.initials: Jde J
authors.lastname: Mari
authors.affiliation: National Institute of Developmental Psychiatry for Children and Adolescents (INCT-CNPq), São Paulo, SP, Brazil.|Department of Psychiatry, Hospital de Clínicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Gisele Gus
authors.initials: GG
authors.lastname: Manfro
authors.affiliation: National Institute of Developmental Psychiatry for Children and Adolescents (INCT-CNPq), São Paulo, SP, Brazil.|Department of Psychiatry, Federal University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Maria Conceição
authors.initials: MC
authors.lastname: do Rosário
authors.affiliation: Department &Institute of Psychiatry, University of São Paulo Medical School, São Paulo, SP, Brazil.|National Institute of Developmental Psychiatry for Children and Adolescents (INCT-CNPq), São Paulo, SP, Brazil.
authors.forename: Eurípedes Constantino
authors.initials: EC
authors.lastname: Miguel
authors.affiliation: Hospital Israelita Albert Einstein, Clinical Research, São Paulo, SP, Brazil.
authors.forename: Renato David
authors.initials: RD
authors.lastname: Puga
authors.affiliation: Department &Institute of Psychiatry, University of São Paulo Medical School, São Paulo, SP, Brazil.
authors.forename: Ana Carolina
authors.initials: AC
authors.lastname: Tahira
authors.affiliation: Department &Institute of Psychiatry, University of São Paulo Medical School, São Paulo, SP, Brazil.
authors.forename: Viviane Neri
authors.initials: VN
authors.lastname: Souza
authors.affiliation: Department &Institute of Psychiatry, University of São Paulo Medical School, São Paulo, SP, Brazil.
authors.forename: Thais
authors.initials: T
authors.lastname: Chile
authors.affiliation: Department &Institute of Psychiatry, University of São Paulo Medical School, São Paulo, SP, Brazil.
authors.forename: Gisele Rodrigues
authors.initials: GR
authors.lastname: Gouveia
authors.affiliation: Inter-institutional Grad Program on Bioinformatics, University of São Paulo, São Paulo, SP, Brazil.|Federal Institute of Espírito Santo, Serra, ES, Brazil.
authors.forename: Sérgio Nery
authors.initials: SN
authors.lastname: Simões
authors.affiliation: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Chang
authors.affiliation: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Renata
authors.initials: R
authors.lastname: Pellegrino
authors.affiliation: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Tian
authors.affiliation: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Glessner
authors.affiliation: Inter-institutional Grad Program on Bioinformatics, University of São Paulo, São Paulo, SP, Brazil.|Mathematics &Statistics Institute, University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Ronaldo Fumio
authors.initials: RF
authors.lastname: Hashimoto
authors.affiliation: Department &Institute of Psychiatry, University of São Paulo Medical School, São Paulo, SP, Brazil.|National Institute of Developmental Psychiatry for Children and Adolescents (INCT-CNPq), São Paulo, SP, Brazil.|Department of Psychiatry, Hospital de Clínicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Luis Augusto
authors.initials: LA
authors.lastname: Rohde
authors.affiliation: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.|Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania Philadelphia, PA, USA.
authors.forename: Patrick M A
authors.initials: PM
authors.lastname: Sleiman
authors.affiliation: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.|Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania Philadelphia, PA, USA.
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.affiliation: Inter-institutional Grad Program on Bioinformatics, University of São Paulo, São Paulo, SP, Brazil.|Department &Institute of Psychiatry, University of São Paulo Medical School, São Paulo, SP, Brazil.|National Institute of Developmental Psychiatry for Children and Adolescents (INCT-CNPq), São Paulo, SP, Brazil.
authors.forename: Helena
authors.initials: H
authors.lastname: Brentani
mesh_terms: D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics* / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D001938:Brazil; D002648:Child; D015331:Cohort Studies; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D056915:DNA Copy Number Variations; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D025941:Protein Interaction Mapping