Glutamate receptor, metabotropic 7 (GRM7) gene variations and susceptibility to autism: A case–control study
Rezvan Noroozi
From the Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Search for more papers by this authorMohammad Taheri
From the Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Search for more papers by this authorCorresponding Author
Abolfazl Movafagh
From the Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Address for correspondence and reprints: Abolfazl Movafagh, Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. E-mail: [email protected]Search for more papers by this authorReza Mirfakhraie
From the Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Search for more papers by this authorGhasem Solgi
Department of Immunology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
Search for more papers by this authorArezou Sayad
From the Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Search for more papers by this authorMehrdokht Mazdeh
Department of Neurology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
Search for more papers by this authorHossein Darvish
From the Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Search for more papers by this authorRezvan Noroozi
From the Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Search for more papers by this authorMohammad Taheri
From the Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Search for more papers by this authorCorresponding Author
Abolfazl Movafagh
From the Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Address for correspondence and reprints: Abolfazl Movafagh, Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. E-mail: [email protected]Search for more papers by this authorReza Mirfakhraie
From the Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Search for more papers by this authorGhasem Solgi
Department of Immunology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
Search for more papers by this authorArezou Sayad
From the Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Search for more papers by this authorMehrdokht Mazdeh
Department of Neurology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
Search for more papers by this authorHossein Darvish
From the Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Search for more papers by this authorAbstract
Autism spectrum disorder (ASD) as a synaptopathy is revealed to be pertained to aberrant glutamatergic neurotransmission. Glutamate receptor, metabotropic 7 (GRM7), a receptor coding gene of this pathway, is a new candidate gene for autism. The aim of this study was to examine if there is a relationship between genetic variants rs779867 and rs6782011 of GRM7 with ASD. The present research was designed as a population-based, case–control study including 518 ASD patients versus 472 control individuals. The results showed that the frequency of rs779867 G/G genotype was significantly higher in ASD patients compared to healthy controls (P = 0.0001). Also, the G allele of this SNP was found to be significantly more frequent in the patients than control group (P = 0.0001). Haplotype analysis exhibited significant association of two estimated block of rs6782011/rs779867 in ASD patients versus control group. We found higher significant frequency of GT haplotype and lower frequencies of AT and AC haplotypes in the patients group compared to healthy controls (P = 0.001, P = 0.006, and P = 0.05, respectively). Our study indicated that the rs779867 polymorphism is associated with ASD; thus, results of this study provide supportive evidence of association of the GRM7 gene with ASD. Autism Res 2016, 9: 1161–1168. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.
References
- American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: American Psychiatric Publishing.
- Andrew Collins. (2001). PRIMER1: Primer design for tetra-primer ARMS-PCR – 2015. Retrieved from http://primer1.soton.ac.uk/primer1.html
- Bahi, A., Fizia, K., Dietz, M., Gasparini, F., & Flor, P.J. (2012). Pharmacological modulation of mGluR7 with AMN082 and MMPIP exerts specific influences on alcohol consumption and preference in rats. Addiction Biology, 17, 235–247.
- Bailey, A., Le Couteur, A., Gottesman, I., Bolton, P., Simonoff, E., Yuzda, E., & Rutter, M. (1995). Autism as a strongly genetic disorder: Evidence from a British twin study. Psychological Medicine, 25, 63–77.
- Bailey, C.H., Kandel, E.R., & Harris, K.M. (2015). Structural components of synaptic plasticity and memory consolidation. Cold Spring Harbor Perspectives in Biology, 7, a021758.
- Bernier, R., Golzio, C., Xiong, B., Stessman, H.A., Coe, B.P., Penn, O., … Vulto-van Silfhout, A.T. (2014). Disruptive CHD8 mutations define a subtype of autism early in development. Cell, 158, 263–276.
- Bourgeron, T. (2015). From the genetic architecture to synaptic plasticity in autism spectrum disorder. Nature Reviews Neuroscience, 16, 551–563.
- Bushell, T.J., Sansig, G., Collett, V.J., van der Putten, H., & Collingridge, G.L. (2002). Altered short-term synaptic plasticity in mice lacking the metabotropic glutamate receptor mGlu7. The Scientific World Journal, 2, 730–737.
- Callaerts-Vegh, Z., Beckers, T., Ball, S.M., Baeyens, F., Callaerts, P.F., Cryan, J.F., … D'Hooge. R. (2006). Concomitant deficits in working memory and fear extinction are functionally dissociated from reduced anxiety in metabotropic glutamate receptor 7-deficient mice. Journal of Neuroscience 26, 6573–6582.
- Chen, J.A., Peñagarikano, O., Belgard, T.G., Swarup, V., & Geschwind, D.H. (2015). The emerging picture of autism spectrum disorder: Genetics and pathology. Annual Review of Pathology: Mechanisms of Disease, 10, 111–144.
- Choudhury, P.R., Lahiri, S., & Rajamma, U. (2012). Glutamate mediated signaling in the pathophysiology of autism spectrum disorders. Pharmacology Biochemistry and Behavior, 100, 841–849.
- Davis, L., Meyer, K., Rudd, D., Librant, A., Epping, E., Sheffield, V., & Wassink, T. (2009). Novel copy number variants in children with autism and additional developmental anomalies. Journal of Neurodevelopmental Disorders, 1, 292–301.
- De Rubeis, S., He, X., Goldberg, A.P., Poultney, C.S., Samocha, K., Cicek, A.E., … Walker, S. (2014). Synaptic, transcriptional and chromatin genes disrupted in autism. Nature, 515, 209–215.
- Dean, A., Sullivan, K., & Soe, M. (2009). Open source epidemiologic statistics for public health. Retrieved from http://www.openepi.com
- DiCicco-Bloom, E., Lord, C., Zwaigenbaum, L., Courchesne, E., Dager, S.R., Schmitz, C., … Young, L.J. (2006). The developmental neurobiology of autism spectrum disorder. Journal of Neuroscience 26, 6897–6906.
- Elia, J., Glessner, J.T., Wang, K., Takahashi, N., Shtir, C.J., Hadley, D., … Robison, R. (2012). Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder. Nature Genetics, 44, 78–84.
- Flor, P., Van Der Putten, H., Rüegg, D., Lukic, S., Leonhardt, T., Bence, M., … Kuhn, R. (1997). A novel splice variant of a metabotropic glutamate receptor, human mGluR7b. Neuropharmacology, 36, 153–159.
- Gai, X., Xie, H., Perin, J., Takahashi, N., Murphy, K., Wenocur, A., & Grice, D. (2012). Rare structural variation of synapse and neurotransmission genes in autism. Molecular Psychiatry, 17, 402–411.
- Ganda, C., Schwab, S.G., Amir, N., Heriani, H., Irmansyah, I., Kusumawardhani, A., … Wildenauer, D.B. (2009). A family-based association study of DNA sequence variants in GRM7 with schizophrenia in an Indonesian population. International Journal of Neuropsychopharmacology, 12, 1283–1289.
- Gee, C.E., Peterlik, D., Neuhäuser, C., Bouhelal, R., Kaupmann, K., Laue, G., … Ofner, S. (2014). Blocking metabotropic glutamate receptor subtype 7 (mGlu7) via the venus flytrap domain (VFTD) inhibits amygdala plasticity, stress, and anxiety-related behavior. Journal of Biological Chemistry, 289, 10975–10987.
- Hadley, D., Wu, Z.-L., Kao, C., Kini, A., Mohamed-Hadley, A., Thomas, K., … Pellegrino, R. (2014). The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism. Nature Communications, 5, 4074. doi: 10.1038/ncomms5074.
- Egebjerg, J., et al. (2001). Glutamate and GABA receptors and transporters: structure, function and pharmacology, CRC Press.
- Jung, N.H., Janzarik, W.G., Delvendahl, I., Muenchau, A., Biscaldi, M., Mainberger, F., … Mall, V. (2013). Impaired induction of long-term potentiation-like plasticity in patients with high-functioning autism and Asperger syndrome. Developmental Medicine & Child Neurology, 55, 83–89.
- Kandaswamy, R., McQuillin, A., Curtis, D., & Gurling, H. (2014). Allelic association, DNA resequencing and copy number variation at the metabotropic glutamate receptor GRM7 gene locus in bipolar disorder. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 165, 365–372.
-
Kinoshita, A.,
Shigemoto, R.,
Ohishi, H.,
van der Putten, H., &
Mizuno, N. (1998). Immunohistochemical localization of metabotropic glutamate receptors, mGluR7a and mGluR7b, in the central nervous system of the adult rat and mouse: A light and electron microscopic study. Journal of Comparative Neurology, 393, 332–352.
10.1002/(SICI)1096-9861(19980413)393:3<332::AID-CNE6>3.0.CO;2-2 CAS PubMed Web of Science® Google Scholar
- Li, W., Ju, K., Li, Z., He, K., Chen, J., Wang, Q., Yang, B., An, L., Feng, G., & Sun, W. (2016). Significant association of GRM7 and GRM8 genes with schizophrenia and major depressive disorder in the Han Chinese population. European Neuropsychopharmacology, 26, 136–146.
- Liu, Y., Zhang, Y., Zhao, D., Dong, R., Yang, X., Tammimies, K., … Gai, Z. (2015). Rare de novo deletion of metabotropic glutamate receptor 7 (GRM7) gene in a patient with autism spectrum disorder. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 168, 258–264.
- Malgaroli, A., & Tsien, R.W. (1992). Glutamate-induced long-term potentiation of the frequency of miniature synaptic currents in cultured hippocampal neurons. Nature, 357, 134–139.
- Nicoletti, F., Bruno, V., Ngomba, R.T., Gradini, R., & Battaglia, G. (2015). Metabotropic glutamate receptors as drug targets: What's new? Current Opinion in Pharmacology, 20, 89–94.
- Ohtsuki, T., Koga, M., Ishiguro, H., Horiuchi, Y., Arai, M., Niizato, K., … Iritani, S. (2008). A polymorphism of the metabotropic glutamate receptor mGluR7 (GRM7) gene is associated with schizophrenia. Schizophrenia Research, 101, 9–16.
- Pagani, F., & Baralle, F.E. (2004). Genomic variants in exons and introns: Identifying the splicing spoilers. Nature Reviews Genetics, 5, 389–396.
- Park, S., Jung, S.-W., Kim, B.-N., Cho, S.-C., Shin, M.-S., Kim, J.-W., … & Son, J.-W. (2013). Association between the GRM7 rs3792452 polymorphism and attention deficit hyperacitiveity disorder in a Korean sample. Behavioral and Brain Functions, 9, 1.
- Pinto, D., Delaby, E., Merico, D., Barbosa, M., Merikangas, A., Klei, L., … Scherer, S.W. (2014) Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. American Journal of Human Genetics, 94, 677–694.
- Ritvo, E.R., Freeman, B.J., Mason-Brothers, A., Mo, A., & Ritvo, A.M. (1985). Concordance for the syndrome of autism in 40 pairs of afflicted twins. American Journal of Psychiatry, 142, 74–77.
- Rosahl, T.W., Geppert, M., Spillane, D., Herz, J., Hammer, R.E., Malenka, R.C., & Südhof, T.C. (1993). Short-term synaptic plasticity is altered in mice lacking synapsin I. Cell, 75, 661–670.
- Rutter, M., Le Couteur, A., Lord, C., & Faggioli, R. (2005). ADI-R: Autism diagnostic interview – Revised: Manual, OS, Organizzazioni Speciali publisher.
- Sansig, G., Bushell, T.J., Clarke, V.R., Rozov, A., Burnashev, N., Portet, C., … Shigemoto, R. (2001). Increased seizure susceptibility in mice lacking metabotropic glutamate receptor 7. Journal of Neuroscience, 21, 8734–8745.
- Sanyal, S., Sandstrom, D.J., Hoeffer, C.A., & Ramaswami, M. (2002). AP-1 functions upstream of CREB to control synaptic plasticity in Drosophila. Nature, 416, 870–874.
- Schwarzschild, M.A., Cole, R.L., & Hyman, S.E. (1997). Glutamate, but not dopamine, stimulates stress-activated protein kinase and AP-1-mediated transcription in striatal neurons. Journal of Neuroscience, 17, 3455–3466.
- Shibata, H., Tani, A., Chikuhara, T., Kikuta, R., Sakai, M., Ninomiya, H., … Fukumaki, Y. (2009). Association study of polymorphisms in the group III metabotropic glutamate receptor genes, GRM4 and GRM7, with schizophrenia. Psychiatry Research, 167, 88–96.
- Shimizu, E., Tang, Y.-P., Rampon, C., & Tsien, J.Z. (2000). NMDA receptor-dependent synaptic reinforcement as a crucial process for memory consolidation. Science, 290, 1170–1174.
- Steffenburg, S., Gillberg, C., Hellgren, L., Andersson, L., Gillberg, I.C., Jakobsson, G., & Bohman, M. (1989). A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden. Journal of Child Psychology and Psychiatry, 30, 405–416.
- Van Bon, B., Coe, B., Bernier, R., Green, C., Gerdts, J., Witherspoon, K., … Bosco, P. (2016). Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID. Molecular Psychiatry 21, 126–132.
- Vanhoutte, P., Barnier, J.-V., Guibert, B., Pagès, C., Besson, M.-J., Hipskind, R.A., & Caboche, J. (1999). Glutamate induces phosphorylation of Elk-1 and CREB, along with c-fos activation, via an extracellular signal-regulated kinase-dependent pathway in brain slices. Molecular and Cellular Biology, 19, 136–146.
- Wang, S.S.-H., Kloth, A.D., & Badura, A. (2014). The cerebellum, sensitive periods, and autism. Neuron, 83, 518–532.
- Ward, L.D., & Kellis, M. (2012). HaploReg: A resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Research, 40, D930–D934.
- Xavier Sole. (2006). SNPStats: A web tool for the analysis of association studies - 2015. Retrieved from http://bioinfo.iconcologia.net/en/SNPStats.
- Xia, W., Liu, Y., & Jiao, J. (2015). GRM7 regulates embryonic neurogenesis via CREB and YAP. Stem Cell Reports, 4, 795–810.
- Yang, Y., & Pan, C. (2013). Role of metabotropic glutamate receptor 7 in autism spectrum disorders: A pilot study, Life Sciences, 92, 149–153.