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

• Published in: Scientific reports Vol. 8; no. 1; pp. 1881 - 11
• Main Authors: Pagerols, Mireia, Richarte, Vanesa, Sánchez-Mora, Cristina, Rovira, Paula, Soler Artigas, María, Garcia-Martínez, Iris, Calvo-Sánchez, Eva, Corrales, Montse, da Silva, Bruna Santos, Mota, Nina Roth, Victor, Marcelo Moraes, Rohde, Luis Augusto, Grevet, Eugenio Horacio, Bau, Claiton Henrique Dotto, Cormand, Bru, Casas, Miguel, Ramos-Quiroga, Josep Antoni, Ribasés, Marta
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 30.01.2018; Nature Publishing Group UK
• Subjects: Adolescent; Attention Deficit Disorder with Hyperactivity - drug therapy; Attention Deficit Disorder with Hyperactivity - genetics; Attention deficit disorder with hyperactivity in children; Attention deficit hyperactivity disorder; Attention-deficit-disordered children; Central Nervous System Stimulants - therapeutic use; Child; Child, Preschool; Children; Drug therapy; Female; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genomic analysis; Genomics - methods; Genètica humana; Human genetics; Humans; Hyperactivity; Male; Methylphenidate; Methylphenidate - therapeutic use; Molecular modelling; Nervous system; Neurological diseases; Polymorphism, Single Nucleotide - drug effects; Polymorphism, Single Nucleotide - genetics; Quantitative trait loci; Single-nucleotide polymorphism; Sistema nerviós; Trastorns per dèficit d'atenció amb hiperactivitat en els infants; Trastorns per dèficit d'atenció en els infants; Treatment Outcome
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-20194-7

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.