The Metabotropic Glutamate Receptor Subtype 7 rs3792452 Polymorphism Is Associated with the Response to Methylphenidate in Children with Attention-Deficit/Hyperactivity Disorder Subin Park, MD, PhD, 1 Bung-Nyun Kim, MD, PhD, 1 Soo-Churl Cho, MD, PhD, 1 Jae-Won Kim, MD, PhD, 1 Johanna Inhyang Kim, MD, 1 Min-Sup Shin, PhD, 1 Hee-Jeong Yoo, MD, PhD, 1 Doug Hyun Han, MD, PhD, 2 and Jae Hoon Cheong, PhD 3 Abstract Objective: The purpose of this study was to investigate the association between the metabotropic glutamate receptor subtype 7 (mGluR7) gene (GRM7) polymorphism and treatment response to methylphenidate in Korean children with attention-deficit/ hyperactivity disorder (ADHD). Methods: We enrolled 175 medication-naı ¨ve children with ADHD in an open-label 8 week trial of methylphenidate. The participants were genotyped and evaluated using the Clinical Global Impressions (CGI) Scale and the parent version of the ADHD Rating Scale-IV (ADHD-RS) before and after treatment. Results: After the 8 week course of methylphenidate, children with the GRM7 rs37952452 polymorphism G/A genotype had a more pronounced response rate to the treatment than did children with the G/G genotype according to the ADHD-RS scores (72.2% vs. 55.4%, respectively; p = 0.011) and the more stringent standard of combined ADHD-RS and CGI-Improvement (CGI-I) scores (50.0% vs. 35.3%, respectively; p = 0.044). Conclusions: The present study suggests that the GRM7 rs37952452 polymorphism may play a role in the treatment response to methylphenidate in children with ADHD. Further studies to evaluate the association between glutamate genes and treatment response to methylphenidate in children with ADHD, including a replication of our findings using a control or comparative group in a larger sample, are warranted. Introduction A ttention-deficit/hyperactivity disorder (ADHD) is characterized by deficits in selective attention, sustained at- tention, and inhibitory control (Biederman and Faraone 2005). The behavioral and cognitive deficits of ADHD, which have been at- tributed, in part, to dysfunctional neural reinforcement mecha- nisms, have been widely hypothesized to originate in dysfunctions in the dopaminergic system. Abnormal dopamine functioning may be the result of a primary defect in dopamine neurons (neuronal firing, dopamine transport, synthesis, receptor functioning) and/or an indirect result of impaired glutamate and/or noradrenergic reg- ulation of dopamine neurons (Volkow et al. 2007). Psychostimulants, particularly methylphenidate (MPH), con- stitute the first-line pharmacotherapy for patients with ADHD. Several previous studies have investigated the association between genetic factors and response to MPH and have produced mixed results (Stein and McGough 2008; Froehlich et al. 2010). To avoid the pitfalls associated with small candidate-gene studies, Mick et al. (2008) conducted a genome-wide association study (GWAS) of the treatment response to MPH in 187 children with ADHD. Although the authors failed to find a significant association between markers and treatment response, they did find evidence suggestive of an association with Single nucleotide polymorphisms (SNPs), possi- bly implicating some novel genes in the MPH response: An armadillo/beta-catenin-like domain gene (ARMC3), sorting nexin 29 (SNX29), a member of the junctophilin family ( JPH2), growth arrest-specific 7 (GAS7), holocarboxylase synthetase (HLCS), and a metabotropic glutamate receptor subtype 7 (mGluR7) gene (GRM7). Of these, the most intriguing was the GRM7 gene, which 1 Division of Child and Adolescent Psychiatry, Department of Psychiatry, Seoul National University College of Medicine, Seoul, Republic of Korea. 2 Department of Psychiatry, Chung Ang University, College of Medicine, Seoul, Republic of Korea. 3 Uimyung Research Institute for Neuroscience, Sahmyook University, Seoul, Republic of Korea. Funding: This study was supported by a grant from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A120013), and by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education Science and Technology, Republic of Korea (2010-0002283). JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Volume 24, Number 4, 2014 ª Mary Ann Liebert, Inc. Pp. 223–227 DOI: 10.1089/cap.2013.0079 223