EXOCYTOSIS-RELATED GENE-SETS AND RESPONSE TO METHYLPHENIDATE TREATMENT IN ADULTS WITH ADHD

Background Substantial interindividual variability is observed in treatment response to Methylphenidate(MPH), which is considered the first-line pharmacological treatment for adults with ADHD. In addition to its main known mechanism of action involving the blockade of the dopamine transporter, experimental studies have also indicated an ability of MPH to affect vesicle synaptic transmission. Consistently with this hypothesis, genes involved in calcium-triggered vesicle exocytosishave been implicated on pharmacogeneticsof MPH. In genomic approaches, pathways involved in the neurotransmitter release are therefore promising to be investigated in MPH response. The aim of this study was to assess the influence of exocytosis-related gene-sets on response to MPH. Methods The sample with genome-wide data and immediate-release MPH response comprised 189 adults with ADHD. The outcome measure was the change (∆) in severity scores of ADHD symptoms of SNAP-IV from baseline to endpoint (at least 30 days of treatment). Subsets of inattention and hyperactivity/impulsivity symptoms was also evaluated separately. Samples were genotyped on PsychChip array and imputed using the Ricopili pipeline. The resulting dataset consisted of 5,842,472 SNPs after quality control. For SNP annotationto genes, gene locations for build 37 (hg19) and a 2 kb upstream/1 kb downstream window were used. Competitive gene-set analyses were performed in MAGMA v1.06 using the principal components regressionas the gene-based model. Concomitant use of psychiatric medicationand baseline scores of symptoms were included as covariates, as well as the 10 first principal components. Eight annotated gene-sets related to function and regulation of calcium-triggered vesicle exocytosisderived from Gene Ontology (biological process) and collected from Molecular Signatures Database were analyzed. Bonferroni was applied for multiple testing correction. Results Gene-set analysis for the change in severity scores of ADHD resulted in nominal associations for calcium ion regulated exocytosis(GO:0017156; p=0.0189), presynaptic process involved in synaptic transmission (GO:0099531; p=0.0153) and neurotransmitter transport(GO:0006836; p=0.0231) gene-sets. Analyzing specific ADHD dimensions, the same gene-sets were associated to change of inattention symptoms only, where GO:0099531 remained significant after Bonferroni correction(p=0.0012). There was considerable overlap of genes within the testedgene- sets, therefore the gene analysis revealed a shared group of nominally associated genes among the significant sets for both inattention and ADHD, including STX11, STX19, PSEN1, CACNA1A and NRXN1. Discussion Our results suggest an involvement of neurotransmitter release genes in MPH treatment response. The lack of association for hyperactivity/impulsivity symptoms might point out different treatment underlying mechanisms between ADHD dimensions. Despite the evaluation of combined effects of multiple genetic variants grouped into predefined gene-sets is an alternative strategy to GWAS to reach increased statistical power, our small sample size should be considered in the interpretation of the results. Moreover, as the selected gene-sets are not independent, an increased precision in pathway definition would be benefic to these analyses. Notwithstanding, pathways involved in neurotransmitter release emerge as important candidates to be explored in further pharmacogeneticstudies of ADHD.