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

Mireia Pagerols,Luis Augusto Rohde,Montse Corrales,Claiton Henrique Dotto Bau,Eugenio Horacio Grevet,Cristina Sánchez-Mora,Marta Ribasés,Miguel Casas,Nina Roth Mota,Eva Calvo-Sánchez,Josep Antoni Ramos-Quiroga,María Soler Artigas,Bru Cormand,Bruna Santos Da Silva,Vanesa Richarte,Marcelo Moraes Victor,Iris Garcia-Martínez,Paula Rovira

doi:10.1038/s41598-018-20194-7

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.

Highlights

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by persistent and age-inappropriate symptoms of inattention, hyperactivity and/or impulsivity[1], which significantly impacts on academic, social, emotional and psychological functioning
The set of 32 eGenes included three candidates previously investigated in attention-deficit/hyperactivity disorder (ADHD), namely ALDH1L134, CDH2335 and CMTM836, and showed over-representation of genes implicated in abnormal morphology of molecular layer of cerebellum (PB-H = 0.012), abnormal morphology of white matter (PB-H = 0.012), morphology of axons (PB-H = 0.012), morphology and length of neurites (PB-H = 0.012 and PB-H = 0.021, respectively), coordination (PB-H = 0.022), and formation of hippocampus (PB-H = 0.033)
15 revealed the same direction of effect, with rs17685420 in the phosphatidylethanolamine binding protein 4 (PEBP4) gene being significant after Bonferroni correction (OR = 3.07 (1.76–5.35), P = 7.90e-05), followed by additional compelling markers such as rs2071421 within ARSA (OR = 2.63 (1.29– 5.37), P = 7.71e-03), rs2886059 in ALDH1L1 (OR = 2.30 (1.14–4.66), P = 0.020), and rs17712523 in CDH23 (OR = 2.13 (1.07–4.24), P = 0.031). This is the first study investigating the genetic basis of MPH response from an integrative perspective that combines genome-wide association studies (GWAS) data, functional annotation, expression quantitative trait loci (eQTL) in relevant tissues to ADHD and pathway enrichment analyses

Summary

Introduction

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by persistent and age-inappropriate symptoms of inattention, hyperactivity and/or impulsivity[1], which significantly impacts on academic, social, emotional and psychological functioning. Most of the pharmacogenetic studies conducted so far in ADHD patients have focused on genes related to the catecholamine neurotransmission, with SLC6A3 and DRD4 being the most extensively investigated, since MPH is thought to exert its therapeutic effects through the inhibition of the dopamine and the norepinephrine transporters[10]. Based on this putative mechanism of action, additional genes such as DRD2, DRD5, COMT, SLC6A2, ADRA2A, TPH2, SLC6A4, HTR1B, HTR2A and MAOA11 have been considered plausible candidates that may influence medication response. Despite the fact that GWAS have been useful to identify genetic risk loci for multiple complex conditions, yet the functional effects of the trait-associated variants and the underlying pathological mechanisms remain mainly elusive

Methods

Results

Conclusion