Pharmacogenomics of Methylphenidate Treatment of Danish Children With ADHD

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-naïve 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. 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). 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.