Brief association letter 281
Lack of association between the GRM7 gene and attention deficit hyperactivity disorder Glaucia C. Akutagava-Martinsa, Angelica Salatino-Oliveiraa, Estela M. Bruxela, Julia P. Genroa, Nina R. Motaa, Guilherme V. Polanczykb,e, Cristian P. Zenic, Eugênio H. Grevetd, Claiton H.D. Baua,d, Luis A. Rohdeb,c and Mara H. Hutza Psychiatric Genetics 2014, 24:281–282 a
b
Department of Genetics, Universidade Federal do Rio Grande do Sul, Institute for Developmental Psychiatry for Children and Adolescents, cDivision of Child and Adolescent Psychiatry, dAdult ADHD Outpatient Program, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul and eDepartment of Psychiatry, Universidade de São Paulo, São Paulo, Brazil
Attention deficit hyperactivity disorder (ADHD) is a highly heritable and common neurodevelopmental disorder affecting 5% of school-age children. Symptoms persist into adulthood in about 50% of the cases. Molecular genetics studies of ADHD have determined that both common and rare variants of genes related to neurotransmission and neurodevelopment are involved in susceptibility to ADHD (Akutagava-Martins et al., 2013). Among these genes, those encoding glutamate receptors are of particular interest, given their role in neuronal communication, synaptogenesis, and several cellular and cognitive processes. The glutamate receptor, metabotropic 7 gene (GRM7), has emerged as a potential ADHD susceptibility gene. It is expressed in brain areas related to ADHD such as the cerebral cortex, hippocampus, and cerebellum. In a large genome-wide study, the rs7623055 polymorphism showed a nominal association with ADHD (Elia et al., 2011). Recently, Park et al. (2013) reported an association with the rs3792452 polymorphism in a Korean sample. The aim of the present study was to investigate the possible association between these GRM7 gene polymorphisms and ADHD genetic susceptibility in Brazilian patients with ADHD. Two samples were investigated: (a) 512 youths with ADHD and their parents and 132 youths without ADHD as controls; and (b) 389 adults with ADHD and 406 controls. Diagnostic criteria, and clinical and demographic characteristics have been described elsewhere (Salatino-Oliveira et al., 2012; Polina et al., 2014). Both rs3792452 and rs7623055 polymorphisms were genotyped using the TaqMan allelic discrimination system (Applied Biosystems Inc., Foster City, California, USA). The association hypotheses were tested by both familybased (youths) and case–control (youths and adults) approaches using UNPHASED 3.1.7 software (sites.google.com/ site/fdudbridge/software). Power estimation was performed using StatMate 2.0 software (GraphPad Software Inc., La Jolla, California, USA). This study was approved by the Ethics Committee of Hospital de Clínicas de Porto Alegre. Children 0955-8829 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
Correspondence to Mara H. Hutz, PhD, Department of Genetics, Universidade Federal do Rio Grande do Sul, Caixa Postal 15053, CEP 91501-970 Porto Alegre, Rio Grande do Sul, Brazil Tel: + 55 51 3308 6720; fax: + 55 51 3308 7311; e-mail: [email protected] Received 10 July 2014 Accepted 10 September 2014
and adolescents verbally agreed to participate and their parents provided a written informed consent. Adults were invited to participate and provided a written informed consent. Allele frequencies were as follows: (a) ADHD youths: 0.813 (C) and 0.188 (T) for rs3792452; 0.533 (C) and 0.467 (G) for rs7623055; controls: 0.782 (C) and 0.218 (T) for rs3792452; 0.527 (C) and 0.473 (G) for rs7623055. (b) ADHD adults: 0.763 (C) and 0.237 (T) for rs3792452; 0.614 (C) and 0.386 (G) for rs7623055; controls: 0.777 (C) and 0.223 (T) for rs3792452; 0.576 (C) and 0.424 (G) for rs7623055. Genotype frequencies were in Hardy–Weinberg equilibrium in all samples. No evidence of an association was observed in these samples either in the family-based (P = 0.103 and 0.216 for rs3792452 and rs7623055, respectively) or in the case–control approaches (P = 0.309 for rs3792452 and 0.829 for rs7623055 in youths; P = 0.394 for rs3792452 and 0.110 for rs7623055 in adults). The results reported here do not support a role for GRM7 in ADHD even though our sample has over 95% statistical power to detect differences of at least 10% on allele frequencies. These negative results confirm the need for replication in independent samples before any gene can be considered as an ADHD susceptibility gene. However, other members of the GRM family of receptors should be investigated to determine the role of glutamate in ADHD.
Acknowledgements This study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Brazil), and Fundo de Incentivo à Pesquisa e Eventos – Hospital de Clínicas de Porto Alegre (FIPE/HCPA, Brazil). Conflicts of interest
Dr Luis A. Rohde was on the speaker’s bureau and/or has acted as consultant for Eli-Lilly, Janssen-Cilag, Novartis, and Shire in the last 3 years. The ADHD and Juvenile Bipolar Disorder Outpatient Programs chaired by him DOI: 10.1097/YPG.0000000000000059
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
282 Psychiatric Genetics 2014, Vol 24 No 6
received unrestricted educational and research support from the following pharmaceutical companies in the last 3 years: Eli-Lilly, Janssen-Cilag, Novartis, and Shire. He also receives research support from Brazilian government institutions (CNPq, FAPERGS, HCPA, and CAPES) and authorship royalties from Oxford Press and ArtMed. Dr Guilherme V. Polanczyk is on the board membership and speaker’s bureau of Shire and has received travel support from this company. He has developed educational presentations for Shire and Janssen-Cilag. He also receives research support from Brazilian government institutions (CNPq and FAPESP) and authorship royalties from Manole Editors. Dr Cristian P. Zeni has received travel support from Shire. Dr Eugênio H. Grevet was on the speaker’s bureau and received travel support from Shire. Dr Mara H. Hutz receives research support from Brazilian government institutions
(CNPq, FINEP, and CAPES). For the remaining authors there are no conflicts of interest.
References Akutagava-Martins GC, Salatino-Oliveira A, Kieling CC, Rohde LA, Hutz MH (2013). Genetics of attention-deficit/hyperactivity disorder: current findings and future directions. Expert Rev Neurother 13:435–445. Elia J, Glessner JT, Wang K, Takahashi N, Shtir CJ, Hadley D, et al. (2011). Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder. Nat Genet 44:78–84. Park S, Jung SW, Kim BN, Cho SC, Shin MS, Kim JW, et al. (2013). Association between the GRM7 rs3792452 polymorphism and attention deficit hyperactivity disorder in a Korean sample. Behav Brain Funct 9:1. Polina ER, Rovaris DL, de Azeredo LA, Mota NR, Vitola ES, Silva KL, et al. (2014). ADHD diagnosis may influence the association between polymorphisms in nicotinic acetylcholine receptor genes and tobacco smoking. Neuromolecular Med 16:389–397. Salatino-Oliveira A, Genro JP, Chazan R, Zeni C, Schmitz M, Polanczyk G, et al. (2012). Association study of GIT1 gene with attention-deficit hyperactivity disorder in Brazilian children and adolescents. Genes Brain Behav 11:864–868.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Lack of association between the GRM7 gene and attention deficit hyperactivity disorder Glaucia C. Akutagava-Martinsa, Angelica Salatino-Oliveiraa, Estela M. Bruxela, Julia P. Genroa, Nina R. Motaa, Guilherme V. Polanczykb,e, Cristian P. Zenic, Eugênio H. Grevetd, Claiton H.D. Baua,d, Luis A. Rohdeb,c and Mara H. Hutza Psychiatric Genetics 2014, 24:281–282 a
b
Department of Genetics, Universidade Federal do Rio Grande do Sul, Institute for Developmental Psychiatry for Children and Adolescents, cDivision of Child and Adolescent Psychiatry, dAdult ADHD Outpatient Program, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul and eDepartment of Psychiatry, Universidade de São Paulo, São Paulo, Brazil
Attention deficit hyperactivity disorder (ADHD) is a highly heritable and common neurodevelopmental disorder affecting 5% of school-age children. Symptoms persist into adulthood in about 50% of the cases. Molecular genetics studies of ADHD have determined that both common and rare variants of genes related to neurotransmission and neurodevelopment are involved in susceptibility to ADHD (Akutagava-Martins et al., 2013). Among these genes, those encoding glutamate receptors are of particular interest, given their role in neuronal communication, synaptogenesis, and several cellular and cognitive processes. The glutamate receptor, metabotropic 7 gene (GRM7), has emerged as a potential ADHD susceptibility gene. It is expressed in brain areas related to ADHD such as the cerebral cortex, hippocampus, and cerebellum. In a large genome-wide study, the rs7623055 polymorphism showed a nominal association with ADHD (Elia et al., 2011). Recently, Park et al. (2013) reported an association with the rs3792452 polymorphism in a Korean sample. The aim of the present study was to investigate the possible association between these GRM7 gene polymorphisms and ADHD genetic susceptibility in Brazilian patients with ADHD. Two samples were investigated: (a) 512 youths with ADHD and their parents and 132 youths without ADHD as controls; and (b) 389 adults with ADHD and 406 controls. Diagnostic criteria, and clinical and demographic characteristics have been described elsewhere (Salatino-Oliveira et al., 2012; Polina et al., 2014). Both rs3792452 and rs7623055 polymorphisms were genotyped using the TaqMan allelic discrimination system (Applied Biosystems Inc., Foster City, California, USA). The association hypotheses were tested by both familybased (youths) and case–control (youths and adults) approaches using UNPHASED 3.1.7 software (sites.google.com/ site/fdudbridge/software). Power estimation was performed using StatMate 2.0 software (GraphPad Software Inc., La Jolla, California, USA). This study was approved by the Ethics Committee of Hospital de Clínicas de Porto Alegre. Children 0955-8829 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
Correspondence to Mara H. Hutz, PhD, Department of Genetics, Universidade Federal do Rio Grande do Sul, Caixa Postal 15053, CEP 91501-970 Porto Alegre, Rio Grande do Sul, Brazil Tel: + 55 51 3308 6720; fax: + 55 51 3308 7311; e-mail: [email protected] Received 10 July 2014 Accepted 10 September 2014
and adolescents verbally agreed to participate and their parents provided a written informed consent. Adults were invited to participate and provided a written informed consent. Allele frequencies were as follows: (a) ADHD youths: 0.813 (C) and 0.188 (T) for rs3792452; 0.533 (C) and 0.467 (G) for rs7623055; controls: 0.782 (C) and 0.218 (T) for rs3792452; 0.527 (C) and 0.473 (G) for rs7623055. (b) ADHD adults: 0.763 (C) and 0.237 (T) for rs3792452; 0.614 (C) and 0.386 (G) for rs7623055; controls: 0.777 (C) and 0.223 (T) for rs3792452; 0.576 (C) and 0.424 (G) for rs7623055. Genotype frequencies were in Hardy–Weinberg equilibrium in all samples. No evidence of an association was observed in these samples either in the family-based (P = 0.103 and 0.216 for rs3792452 and rs7623055, respectively) or in the case–control approaches (P = 0.309 for rs3792452 and 0.829 for rs7623055 in youths; P = 0.394 for rs3792452 and 0.110 for rs7623055 in adults). The results reported here do not support a role for GRM7 in ADHD even though our sample has over 95% statistical power to detect differences of at least 10% on allele frequencies. These negative results confirm the need for replication in independent samples before any gene can be considered as an ADHD susceptibility gene. However, other members of the GRM family of receptors should be investigated to determine the role of glutamate in ADHD.
Acknowledgements This study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Brazil), and Fundo de Incentivo à Pesquisa e Eventos – Hospital de Clínicas de Porto Alegre (FIPE/HCPA, Brazil). Conflicts of interest
Dr Luis A. Rohde was on the speaker’s bureau and/or has acted as consultant for Eli-Lilly, Janssen-Cilag, Novartis, and Shire in the last 3 years. The ADHD and Juvenile Bipolar Disorder Outpatient Programs chaired by him DOI: 10.1097/YPG.0000000000000059
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
282 Psychiatric Genetics 2014, Vol 24 No 6
received unrestricted educational and research support from the following pharmaceutical companies in the last 3 years: Eli-Lilly, Janssen-Cilag, Novartis, and Shire. He also receives research support from Brazilian government institutions (CNPq, FAPERGS, HCPA, and CAPES) and authorship royalties from Oxford Press and ArtMed. Dr Guilherme V. Polanczyk is on the board membership and speaker’s bureau of Shire and has received travel support from this company. He has developed educational presentations for Shire and Janssen-Cilag. He also receives research support from Brazilian government institutions (CNPq and FAPESP) and authorship royalties from Manole Editors. Dr Cristian P. Zeni has received travel support from Shire. Dr Eugênio H. Grevet was on the speaker’s bureau and received travel support from Shire. Dr Mara H. Hutz receives research support from Brazilian government institutions
(CNPq, FINEP, and CAPES). For the remaining authors there are no conflicts of interest.
References Akutagava-Martins GC, Salatino-Oliveira A, Kieling CC, Rohde LA, Hutz MH (2013). Genetics of attention-deficit/hyperactivity disorder: current findings and future directions. Expert Rev Neurother 13:435–445. Elia J, Glessner JT, Wang K, Takahashi N, Shtir CJ, Hadley D, et al. (2011). Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder. Nat Genet 44:78–84. Park S, Jung SW, Kim BN, Cho SC, Shin MS, Kim JW, et al. (2013). Association between the GRM7 rs3792452 polymorphism and attention deficit hyperactivity disorder in a Korean sample. Behav Brain Funct 9:1. Polina ER, Rovaris DL, de Azeredo LA, Mota NR, Vitola ES, Silva KL, et al. (2014). ADHD diagnosis may influence the association between polymorphisms in nicotinic acetylcholine receptor genes and tobacco smoking. Neuromolecular Med 16:389–397. Salatino-Oliveira A, Genro JP, Chazan R, Zeni C, Schmitz M, Polanczyk G, et al. (2012). Association study of GIT1 gene with attention-deficit hyperactivity disorder in Brazilian children and adolescents. Genes Brain Behav 11:864–868.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
