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Sci Rep. 2018 Jan 30;8(1):1881. doi: 10.1038/s41598-018-20194-7.

Integrative genomic analysis of methylphenidate response in attention-deficit/hyperactivity disorder.

Author information

1
Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
2
Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
3
Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Barcelona, Spain.
4
Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
5
Department of Genetics, Institute of Biosciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
6
Department of Human Genetics and Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands.
7
ADHD Outpatient Program, Adult Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
8
Department of Psychiatry, Faculty of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
9
Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.
10
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain.
11
Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain.
12
Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues de Llobregat, Spain.
13
Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain. marta.ribases@vhir.org.
14
Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain. marta.ribases@vhir.org.
15
Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Barcelona, Spain. marta.ribases@vhir.org.

Abstract

Methylphenidate (MPH) is the most frequently used pharmacological treatment in children with attention-deficit/hyperactivity disorder (ADHD). However, a considerable interindividual variability exists in clinical outcome. Thus, we performed a genome-wide association study of MPH efficacy in 173 ADHD paediatric patients. Although no variant reached genome-wide significance, the set of genes containing single-nucleotide polymorphisms (SNPs) nominally associated with MPH response (P < 0.05) was significantly enriched for candidates previously studied in ADHD or treatment outcome. We prioritised the nominally significant SNPs by functional annotation and expression quantitative trait loci (eQTL) analysis in human brain, and we identified 33 SNPs tagging cis-eQTL in 32 different loci (referred to as eSNPs and eGenes, respectively). Pathway enrichment analyses revealed an over-representation of genes involved in nervous system development and function among the eGenes. Categories related to neurological diseases, psychological disorders and behaviour were also significantly enriched. We subsequently meta-analysed the association with clinical outcome for the 33 eSNPs across the discovery sample and an independent cohort of 189 ADHD adult patients (target sample) and we detected 15 suggestive signals. Following this comprehensive strategy, our results provide a better understanding of the molecular mechanisms implicated in MPH treatment effects and suggest promising candidates that may encourage future studies.

PMID:
29382897
PMCID:
PMC5789875
DOI:
10.1038/s41598-018-20194-7
[Indexed for MEDLINE]
Free PMC Article

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