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Sci Rep. 2016 Mar 7;6:22851. doi: 10.1038/srep22851.

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

Author information

1
Inter-institutional Grad Program on Bioinformatics, University of São Paulo, São Paulo, SP, Brazil.
2
Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
3
Department &Institute of Psychiatry, University of São Paulo Medical School, São Paulo, SP, Brazil.
4
National Institute of Developmental Psychiatry for Children and Adolescents (INCT-CNPq), São Paulo, SP, Brazil.
5
Department of Psychiatry, Federal University of São Paulo, São Paulo, SP, Brazil.
6
Department of Psychiatry, Hospital de Clínicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
7
Center of Mathematics, Computation and Cognition. Universidade Federal do ABC, Santo André, Brazil.
8
Hospital Israelita Albert Einstein, Clinical Research, São Paulo, SP, Brazil.
9
Federal Institute of Espírito Santo, Serra, ES, Brazil.
10
Mathematics &Statistics Institute, University of São Paulo, São Paulo, SP, Brazil.
11
Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania Philadelphia, PA, USA.

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.

PMID:
26947246
PMCID:
PMC4780010
DOI:
10.1038/srep22851
[Indexed for MEDLINE]
Free PMC Article

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