TY - JOUR
T1 - Integrative genomic analysis of methylphenidate response in attention-deficit/hyperactivity disorder
AU - Pagerols, Mireia
AU - Richarte, Vanesa
AU - Sánchez-Mora, Cristina
AU - Rovira, Paula
AU - Soler Artigas, María
AU - Garcia-Martínez, Iris
AU - Calvo-Sánchez, Eva
AU - Corrales, Montse
AU - Da Silva, Bruna Santos
AU - Mota, Nina Roth
AU - Victor, Marcelo Moraes
AU - Rohde, Luis Augusto
AU - Grevet, Eugenio Horacio
AU - Bau, Claiton Henrique Dotto
AU - Cormand, Bru
AU - Casas, Miguel
AU - Ramos-Quiroga, Josep Antoni
AU - Ribasés, Marta
PY - 2018/12/1
Y1 - 2018/12/1
N2 - © 2018 The Author(s). 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.
AB - © 2018 The Author(s). 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.
U2 - https://doi.org/10.1038/s41598-018-20194-7
DO - https://doi.org/10.1038/s41598-018-20194-7
M3 - Article
C2 - 29382897
SN - 2045-2322
VL - 8
JO - Scientific Reports
JF - Scientific Reports
M1 - 1881
ER -
