Abstract
Autism spectrum disorders (ASDs) are described as generalized developmental disorders, with an average age of onset of 36 months. Genetic and environmental factors may contribute to this multifactorial disorder. The present study aimed to investigate the association of three GRIN2B polymorphisms, including rs1019385, rs1024893, and rs3764028, with ASDs. Based on the results, there was a significant difference regarding the genotype frequency of rs3764028 polymorphism between the control and case (ASD) groups (P = 0.027). According to the recessive model, this variant was associated with ASDs (P = 0.23). None of the eight haplotype models with frequencies above 0.5 showed significant differences between the case and control groups in terms of allelic frequency. The present results showed that the rs376028 variant was directly related to the phenotypic symptoms of ASDs.
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Chen, S., Xu, D., Fan, L., et al. (2022). Roles of N-Methyl-D-Aspartate Receptors (NMDARs) in Epilepsy.Front. Mol. Neurosci.14
Cordero, C., Windham, G. C., Schieve, L. A., et al. (2019). Maternal diabetes and hypertensive disorders in association with autism spectrum disorder. Autism Research, 12, 967–975. https://doi.org/10.1002/aur.2105.
Escher, J., Yan, W., Rissman, E. F., et al. (2021). Beyond Genes: Germline Disruption in the Etiology of Autism Spectrum Disorders. J Autism Dev Disord. https://doi.org/10.1007/s10803-021-05304-1
Eshraghi, A. A., Liu, G., Kay, S. I. S., et al. (2018). Epigenetics and Autism Spectrum Disorder: Is There a Correlation? Frontiers In Cellular Neuroscience, 12, 78. https://doi.org/10.3389/fncel.2018.00078.
Foley, D. L., Craig, J. M., Morley, R., et al. (2009). Prospects for Epigenetic Epidemiology. American Journal Of Epidemiology, 169, 389–400. https://doi.org/10.1093/aje/kwn380.
García-Alegría, A. M., Anduro-Corona, I., Pérez-Martínez, C. J., et al. (2020). Quantification of DNA through the NanoDrop Spectrophotometer: Methodological Validation Using Standard Reference Material and Sprague Dawley Rat and Human DNA. Int J Anal Chem 2020:8896738. https://doi.org/10.1155/2020/8896738
Garg, S., Lehtonen, A., Huson, S. M., et al. (2013). Autism and other psychiatric comorbidity in neurofibromatosis type 1: evidence from a population-based study. Dev Med Child Neurol, 55, 139–145. https://doi.org/10.1111/dmcn.12043.
Ghirardi, L., Brikell, I., Kuja-Halkola, R., et al. (2018). The familial co-aggregation of ASD and ADHD: a register-based cohort study. Molecular Psychiatry, 23, 257–262. https://doi.org/10.1038/mp.2017.17.
Hus, V., & Lord, C. (2014). The autism diagnostic observation schedule, module 4: revised algorithm and standardized severity scores. Journal Of Autism And Developmental Disorders, 44, 1996–2012. https://doi.org/10.1007/s10803-014-2080-3.
Jacob, S., Landeros-Weisenberger, A., & Leckman, J. F. (2009). Autism spectrum and obsessive-compulsive disorders: OC behaviors, phenotypes and genetics. Autism Res Off J Int Soc Autism Res, 2, 293–311. https://doi.org/10.1002/aur.108.
Jiang, H., & Jia, J. (2009). Association between NR2B subunit gene (GRIN2B) promoter polymorphisms and sporadic Alzheimer’s disease in the North Chinese population. Neuroscience Letters, 450, 356–360. https://doi.org/10.1016/j.neulet.2008.10.075.
Kim, K. C., Gonzales, E. L., Lazaro, M. T., et al. (2016). Clinical and neurobiological relevance of current animal models of autism spectrum disorders. Biomol Ther (Seoul), 24, 207.
Kohlrausch, F. B., Giori, I. G., Melo-Felippe, F. B., et al. (2016). Association of GRIN2B gene polymorphism and Obsessive Compulsive disorder and symptom dimensions: A pilot study. Psychiatry Research, 243, 152–155. https://doi.org/10.1016/j.psychres.2016.06.027.
Kong, A., Frigge, M. L., Masson, G., et al. (2012). Rate of de novo mutations and the importance of father’s age to disease risk. Nature, 488, 471–475. https://doi.org/10.1038/nature11396.
Kundu, G. K., & Islam, R. (2021). The Genetics of Autism Spectrum Disorder-A Review. J Bangladesh Coll Physicians Surg, 39, 193–199.
Lee, P. Y., Costumbrado, J., Hsu, C. Y., & Kim, Y. H. (2012). Agarose gel electrophoresis for the separation of DNA fragments. Journal Of Visualized Experiments : Jove, 3923. https://doi.org/10.3791/3923.
Lichtenstein, P., Carlström, E., Råstam, M., et al. (2010). The genetics of autism spectrum disorders and related neuropsychiatric disorders in childhood. American Journal Of Psychiatry, 167, 1357–1363.
Lin, C. H., & Lane, H. Y. (2019). The Role of N-Methyl-D-Aspartate Receptor Neurotransmission and Precision Medicine in Behavioral and Psychological Symptoms of Dementia.Front. Pharmacol.10
Maccari, S., Darnaudery, M., Morley-Fletcher, S., et al. (2003). Prenatal stress and long-term consequences: implications of glucocorticoid hormones. Neuroscience And Biobehavioral Reviews, 27, 119–127. https://doi.org/10.1016/s0149-7634(03)00014-9.
Manoli, D. S., & State, M. W. (2021). Autism Spectrum Disorder Genetics and the Search for Pathological Mechanisms. American Journal Of Psychiatry, 178, 30–38. https://doi.org/10.1176/appi.ajp.2020.20111608.
Marcho, C., Oluwayiose, O. A., & Pilsner, J. R. (2020). The preconception environment and sperm epigenetics. Andrology, 8, 924–942. https://doi.org/10.1111/andr.12753.
Miller, D. N., Bryant, J. E., Madsen, E. L., & Ghiorse, W. C. (1999). Evaluation and optimization of DNA extraction and purification procedures for soil and sediment samples. Applied And Environment Microbiology, 65, 4715–4724. https://doi.org/10.1128/aem.65.11.4715-4724.1999.
Miyatake, R., Furukawa, A., & Suwaki, H. (2002). Identification of a novel variant of the human NR2B gene promoter region and its possible association with schizophrenia. Molecular Psychiatry, 7, 1101–1106. https://doi.org/10.1038/sj.mp.4001152.
Montgomery, J. M., Newton, B., & Smith, C. (2008). Test Review: Gilliam, J. (2006). GARS-2: Gilliam Autism Rating Scale’Second Edition. Austin, TX: PRO-ED. J Psychoeduc Assess 26:395–401. https://doi.org/10.1177/0734282908317116
Mori, F., Ribolsi, M., Kusayanagi, H., et al. (2011). Genetic variants of the NMDA receptor influence cortical excitability and plasticity in humans. Journal Of Neurophysiology, 106, 1637–1643. https://doi.org/10.1152/jn.00318.2011.
Morisada, N., Ioroi, T., Taniguchi-Ikeda, M., et al. (2016). A 12p13 GRIN2B deletion is associated with developmental delay and macrocephaly. Hum Genome Var, 3, 16029. https://doi.org/10.1038/hgv.2016.29.
O’Roak, B. J., Vives, L., Girirajan, S., et al. (2012). Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature, 485, 246–250. https://doi.org/10.1038/nature10989.
Ohtsuki, T., Sakurai, K., Dou, H., et al. (2001). Mutation analysis of the NMDAR2B (GRIN2B) gene in schizophrenia. Molecular Psychiatry, 6, 211–216.
Pan, Y., Chen, J., Guo, H., et al. (2015). Association of genetic variants of GRIN2B with autism. Scientific Reports, 5, 1–5.
Rodriguez-Fontenla, C., & Carracedo, A. (2021). UTMOST, a single and cross-tissue TWAS (Transcriptome Wide Association Study), reveals new ASD (Autism Spectrum Disorder) associated genes. Transl Psychiatry, 11, 1–11.
Rylaarsdam, L., & Guemez-Gamboa, A. (2019). Genetic Causes and Modifiers of Autism Spectrum Disorder. Frontiers In Cellular Neuroscience, 13, 385. https://doi.org/10.3389/fncel.2019.00385.
Seripa, D., Matera, M. G., Franceschi, M., et al. (2008). Association analysis of GRIN2B, encoding N-methyl-D-aspartate receptor 2B subunit, and Alzheimer’s disease. Dementia And Geriatric Cognitive Disorders, 25, 287–292. https://doi.org/10.1159/000118634.
Takasaki, Y., Koide, T., Wang, C., et al. (2016). Mutation screening of GRIN2B in schizophrenia and autism spectrum disorder in a Japanese population. Scientific Reports, 6, 33311. https://doi.org/10.1038/srep33311.
Tarabeux, J., Kebir, O., Gauthier, J., et al. (2011). Rare mutations in N-methyl-D-aspartate glutamate receptors in autism spectrum disorders and schizophrenia. Transl Psychiatry, 1, e55. https://doi.org/10.1038/tp.2011.52.
Thapar, A., & Rutter, M. (2015). Using natural experiments and animal models to study causal hypotheses in relation to child mental health problems.Rutter’s Child Adolesc. Psychiatry143–162
Tzang, R. F., Chang, C. H., Chang, Y. C., & Lane, H. Y. (2019). Autism Associated With Anti-NMDAR Encephalitis: Glutamate-Related Therapy. Front psychiatry, 10, 440. https://doi.org/10.3389/fpsyt.2019.00440.
Voineagu, I. (2012). Gene expression studies in autism: moving from the genome to the transcriptome and beyond. Neurobiology Of Diseases, 45, 69–75. https://doi.org/10.1016/j.nbd.2011.07.017.
Wyllie, D. J. A., Livesey, M. R., & Hardingham, G. E. (2013). Influence of GluN2 subunit identity on NMDA receptor function. Neuropharmacology, 74, 4–17. https://doi.org/10.1016/j.neuropharm.2013.01.016.
Yoo, H. J., Cho, I. H., Park, M., et al. (2012). Family based association of GRIN2A and GRIN2B with Korean autism spectrum disorders. Neuroscience Letters, 512, 89–93. https://doi.org/10.1016/j.neulet.2012.01.061.
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We thankfully express our thanks to all those blood donors of the survey subjects for their contribution to the DNA samples.
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Pouyan Mehr, D., Faraji, N., Rezaei, S. et al. Single-locus and Haplotype Associations of GRIN2B Gene with Autism Spectrum Disorders and the Demographic and Clinical Characteristics of Patients in Guilan, Iran. J Autism Dev Disord 54, 607–614 (2024). https://doi.org/10.1007/s10803-022-05818-2
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DOI: https://doi.org/10.1007/s10803-022-05818-2