Abstract
Background 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 response, which may reflect underlying genetic influences. Methods We performed a Genome-Wide Association Study (GWAS) of MPH efficacy in 173 ADHD pediatric patients, considering the Clinical Global Impression-Improvement scale as the primary outcome measure of treatment success. For subsequent analyses, we prioritized the Single-Nucleotide Polymorphisms (SNPs) with P-values below 0.05 on the GWAS based on functional annotation and expression quantitative trait loci (eQTL) analysis in human brain. Ingenuity Pathway Analysis was used to assess the biological functions and pathways related to genes containing at least one SNP nominally associated with both MPH response and human cortical expression levels (eSNPs), and to test for over-representation of genes previously studied in either ADHD or treatment outcome. We subsequently meta-analyzed the association between clinical response and the eSNPs identified across the discovery sample and an independent cohort of 189 ADHD adult patients. Results Although no variant reached genome-wide significance, the set of genes containing SNPs nominally associated with MPH response was significantly enriched for genes previously studied in ADHD or treatment outcome (Padjusted=1.56e-31). Considering these results, we prioritized the nominally significant markers by functional annotation and eQTL analysis in human brain, and we identified 33 SNPs tagging cis-eQTL in 32 different loci (eGenes). Pathway enrichment analyses revealed an over-representation (Padjusted Discussion To our knowledge, this is the first study investigating the genetic basis of MPH response from an integrative perspective that combines GWAS data, functional annotation, eQTL in relevant tissues to ADHD and pathway enrichment analyses. Our results highlight genes related to nervous system development and function, neurological diseases and psychological disorders. Thus, this comprehensive strategy provides a better understanding of the molecular mechanisms implicated in MPH treatment effects and suggests promising candidates that may contribute to clinical outcome.
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
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
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