LAUSR

Background The first choice drug for treatment of Attention Deficit Hyperactivity Disorder (ADHD) in Denmark and several other countries is Methylphenidate (MPH). More than 30% of the children treated with MPH have been reported to switch to another drug due to lack of efficacy or adverse reactions. Most likely, a significant fraction of this individual variation in treatment outcome is caused by genetic differences. Previous studies have not identified genes or genetic variants conclusively implicated in the response to MPH. Methods We performed a pharmacogenomics study of the efficacy and adverse reactions of MPH in a sample of 207 Danish children with ADHD, who were drug-naive at baseline and were monitored for 12 weeks. Each week the ADHD symptom severity was scored on the ADHD-RS questionnaire, and any adverse reactions were recorded. We divided the ADHD symptom scores into inattention and hyperactivity/impulsive sub-scores, and performed GWAS on the outcome of MPH treatment defined as the difference in symptom severity from baseline to end of study. This was followed by calculation of pair wise epistatic interaction coefficients on the top SNPs from the GWAS. Moreover, we used functional principal component analysis to derive proxies that describe the longitudinal nature of the data for both the efficacy measurements and the adverse reactions. Subsequently, we performed GWAS using the proxies as phenotypes for the MPH outcome across the entire treatment period. Results None of the GWAS resulted in genome-wide associated hits. However, among the top SNPs for the inattention sub-score were some that fell in: RAS guanyl releasing protein 1 (RASGRP1), sodium/potassium transporting ATPase interacting 2 (NKAIN2) and tetratricopeptide repeat domain 12 (TTC12). For the hyperactivity/impulsive sub-score one of the top SNPs is in the vicinity of gamma-aminobutyric acid type A receptor gamma3 subunit (GABRG3). In the interaction analysis we identified the SNPs with the largest difference in connectivity between the inattention and hyperactivity/impulsive sub-scores and found that some of these were located in or near: myelin transcription factor 1 like (MYT1L), synaptotagmin 17 (SYT17), potassium voltage-gated channel subfamily Q member 5 (KCNQ5) and potassium voltage-gated channel modifier subfamily S member 3 (KCNS3). Discussion Despite the lack of genome-wide significant SNPs, some of the top hits from the GWAS reside in or near genes that could modulate the response to MPH. Some of these genes have previously been implicated in psychiatric disorders (RASGRP1, NKAIN2 and MYT1L), are involved in neurotransmission (GABRG3, KCNQ5, KCNS3 and NKAIN2) or has been implicated in substance abuse, e.g. TTC12 has been implicated in heroin dependence and SYT17 in alcoholism.