Genetic Variations Associated with Brain Disorders: Focus on Synaptic Plasticity and Apoptosis Regulatory Genes in Schizophrenia, Posttraumatic Stress Disorder and Ischemic Stroke

Anna Boyajyan; Ani Stepanyan; Diana Avetyan; Hovsep Ghazaryan; Sofi Atshemyan; Roksana Zakharyan; Kristina Pirumyan; Gohar Tsakanova

doi:doi:10.11648/j.ijgg.20140202.12

Genetic Variations Associated with Brain Disorders: Focus on Synaptic Plasticity and Apoptosis Regulatory Genes in Schizophrenia, Posttraumatic Stress Disorder and Ischemic Stroke

Anna Boyajyan, Ani Stepanyan, Diana Avetyan, Hovsep Ghazaryan, Sofi Atshemyan, Roksana Zakharyan, Kristina Pirumyan, Gohar Tsakanova

Published in International Journal of Genetics and Genomics (Volume 2, Issue 2)

Received: 20 April 2014 Accepted: 20 May 2014 Published: 30 May 2014

Views: Downloads:

Download PDF

Share This Article

Twitter
Linked In
Facebook

Abstract

Epidemiologic, clinical and experimental data indicates that a majority of brain disorders including schizophrenia (SCZ), posttraumatic stress disorder (PTSD), and ischemic stroke (IS) are multifactorial disorders with strong and complex genetic component. Identification of all genetic variations associated with these disorders may sufficiently contribute to understanding of their basic pathomechanisms and encourage development of new innovative approaches to their early diagnosis and treatment. The aim of this review article is to provide overview of our recent studies on evaluation of potential association of SCZ, PTSD and IS with functional single nucleotide polymorphisms (SNPs) of synaptic plasticity and apoptosis regulatory genes in Armenian population. Here, our attention was focused on genes encoding netrin G1 (NTNG1), brain-derived neurotrophic factor (BDNF), complexin-2 (CPLX2), nerve growth factor (NGF) and its receptor (NGFR), annexin family proteins - annexin A5 and annexin A11 (ANXAV, ANXA11), and B-cell lymphoma 2 (Bcl-2) family proteins - Bcl-2 proper and Bcl-2-associated X protein (BCL2, BAX). Genomic DNA samples of diseased and healthy individuals were genotyped for a number of SNPs of the mentioned genes using polymerase chain reaction with sequence-specific primers (PCR-SSP). The significance of differences in genotype and allele frequencies and minor allele carriage between patients and healthy control subjects was determined using Pearson’s Chi-square test. P-values less than 0.05 were considered statistically significant. Significant associations were found between: (1) SCZ and BDNF rs6265, CPLX2 rs1366116, rs3892909, NGF rs6330, rs4839435, NGFR rs734194, rs11466155, rs2072446, ANXAV rs11575945, BAX rs1057369 SNPs; (2) PTSD and CPLX2 rs1366116, BCL2 rs956572 SNPs; (3) IS and NTNG1 rs628117, CPLX2 rs1366116, ANXAV rs11575945 SNPs. The obtained results indicated the involvement of genetically determined alterations in synaptic plasticity and apoptosis in pathomechanisms of SCZ, PTSD and IS. The minor T allele of the CPLX2 gene rs1366116 polymorphism represents risk factor for all studied diseased conditions indicating important functional significance of this genetic variation in maintenance of synaptic plasticity. Another important conclusion of these studies is that minor alleles of some polymorphic variants of genes, encoding synaptic plasticity and apoptosis regulatory proteins, may play a protective role relative to SCZ decreasing the risk for development of this disorder. In summary, our studies emphasize the important contribution of changes in synaptic plasticity and apoptosis regulation to pathomechanisms of SCZ, PTSD, and IS as well as significant input of genetic factors to these changes.

Published in	International Journal of Genetics and Genomics (Volume 2, Issue 2)
DOI	10.11648/j.ijgg.20140202.12
Page(s)	19-29
Creative Commons	This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.
Copyright	Copyright © The Author(s), 2024. Published by Science Publishing Group

Keywords

Schizophrenia, Posttraumatic Stress Disorder, Ischemic Stroke, Synaptic Plasticity, Apoptosis, Regulatory Genes, Single Nucleotide Polymorphisms, Genotyping, Association

References

[1]	Tsuang MT, Bar JL, Stone WS, Faraone SV. Gene-environment interactions in mental disorders. World Psychiatry 2004;3(2):73-83.
[2]	Dauncey MJ. Genomic and epigenomic insights into nutrition and brain disorders. Nu-trients 2013;5(3):887-914.
[3]	McCarroll SA, Hyman SE. Progress in the genetics of polygenic brain disorders: significant new challenges for neurobiology. Neuron 2013;80(3):578 -87.
[4]	Gejman PV, Sanders AR, Kendler KS. Genetics of schizophrenia: new findings and challenges. Annu Rev Genomics Hum Genet 2011;12:121-44.
[5]	Segman RH, Shalev AY. Genetics of Posttraumatic Stress Disorder. CNS Spectr 2003;8(9):693-98.
[6]	Hassan А, Markus HS. Genetics and ischaemic stroke. Brain 2000;123(9):1784-812.
[7]	Barbato A. Schizophrenia and Public Health. World Health Organization, Geneva, 1998.
[8]	Zohar J, Fostick L. Comparison of mortality rates between Israeli veterans with and without post traumatic stress disorder. Eur Neuropsychopharmacol 2014;24:117-24.
[9]	Di Carlo А. Human and economic burden of stroke. Age Ageing 2009;38(1):4-5.
[10]	Broughton BRS, Reutens DC, Sobey CG. Apoptotic me-chanisms after cerebral ischemia. Stroke 2009; 40:e331-9.
[11]	Font MA, Arboix A, Krupinsi J. Angiogenesis, neurogenesis and neuroplasticity in ischemic stroke. Curr Cardiol Rev 2010;6(3):238-44
[12]	Sumiyoshi T (ed.) Schizophrenia Research: Recent Advances, Nova Science Publishers Inc., USA, 2012.
[13]	Chavushyan АS. Annexin-А5 as a marker of apoptotic hyperfunction in schizophrenia. Biol J Armenia 2012;64(4): 91-3.
[14]	Boyajyan A, Mkrtchyan G, Hovhannisyan L, Avetyan D. Chapter 5. Alterations in the immune response, apoptosis and synaptic plasticity in posttraumatic stress disorder: molecular indicators and relation to clinical symptoms. In: Durbano F (ed.) New Insights Into Anxiety Disorders, InTech, Croatia, 2013, pp.105-33.
[15]	Mkrtchyan GM, Boyajyan AS, Avetyan DG, Sukiasyan SG. The involvement of anomalous apoptosis in disturbance of synaptic plasticity in posttraumatic stress disorder. Zh Nevrol Psikhiatr Im S S Korsakova; 2013;113(1):26-9.
[16]	Ghazaryan H. Annexin 11 expression pattern in schizophrenia. Electronic J Natural Sciences (NAS RA) 2013;2(21): 74-6.
[17]	Hakobjanyan A, Boyajyan A, Hovsepyan L, Petrek M. Changes of ANXA11 expression level and apoptosis during aging and brain ischemic stroke. Biol J Armenia 2013;65(suppl.1):66-7.
[18]	Mkrtchyan GM, Boyadzhyan AS, Avetyan DG, Sukiasyan SG. Involvement of anomalous apoptosis in impairments to synaptic plasticity in post-traumatic stress disorder. Neurosci Behav Physiol 2014;44(4):442-6.
[19]	Boyajyan A, Tsakanova G, Sim R. Collectins, C3 complement protein, annexin V and C-reactive protein in acute ischemic stroke: interrelation and implication to upregulated apoptosis and inflammation. Inflamm Cell Signal 2014;1(2): 44-50.
[20]	Zakharyan R, Boyajyan A, Arakelyan A, Gevorgyan A, Mrazek F, Petrek M. Functional variants of the genes involved in neurodevelopment and susceptibility to schizophrenia in an Armenian population. Human Immunol 2011;72 (9):746-8.
[21]	Zakharyan R, Boyajyan A, Arakelyan A, Mrazek F, Petrek M. The BDNF genetic variant as a risk factor for schizophrenia in Armenian population. Tissue Antigens 2011;77:493.
[22]	Boyajyan A., Zakharyan R., Khoyetsyan A. Chapter 11. Molecular and genetic indicators of aberrant immunity and apoptosis in schizophrenia. In: Sumiyoshi T (ed.) Schizophrenia Research: Recent Advances, Nova Science Publishers Inc., USA, 2012, pp.183-240.
[23]	Stepanyan A, Zakharyan R, Boyajyan A. The netrin G1 gene rs628117 polymorphism is associated with ischemic stroke. Neuroscience Lett 2013;549:74-7.
[24]	Zakharyan RV, Boyajyan AS. Neurotrophin family gene as potential target for schizoph-renia. Electronic J Natural Sciences (NAS RA) 2013;2(21):82-6.
[25]	Boyajyan AS, Chavushyan AS, Zakha-ryan RV, Mkrtchyan GM. Markers of apoptotic dysfunctions in schizophrenia. Mol Biol (Moscow) 2013;47(4):587-91.
[26]	Boyajyan A, Avetyan D, Mkrtchyan G, Sukiasyan S, Zakharyan R, Atshemyan S, Gevorgyan A, Melkumova M, Torosyan S. Population genomics study of molecular pathomechanisms responsible for apoptotic and synaptic plasticity dysfunction in posttraumatic stress disorder and schizophrenia. Armenian J Mental Health 2013;4(Suppl. 1): 66-7.
[27]	Zakharyan R, Atshemyan S, Gevorgyan A, Boyajyan A. Synaptic plasticity regulating genes in schizophrenia. Biol J Armenia 2013;65(Suppl. 1):150-2.
[28]	Zakharyan R, Gevorgyan A, Atshemyan S, Torosyan S, Boyajyan A. Genetic risk factors for schizophrenia among synaptogenesis regulating proteins. Armenian J Mental Health 2013;4 (Suppl. 1):91-2.
[29]	Zakharyan R, Atshemyan S, Boyajyan A. The role of neuroprotein in schizophrenia pathogenesis. J Neurolog Sci 2013;333(Suppl. 1):e335-6.
[30]	Boyajyan A, Chavushyan A, Zakharyan R, Mkrtchyan G, Atshemyan S. Implication of genetic polymorphisms and changes in expression levels of proteins regulating neuronal plasticity and apoptosis in schizophrenia disorder. Eur Psychiatry 2013;28(Suppl. 1):43.
[31]	Avetyan DA. Changes in apoptotic rate and synaptic plasticity in patients with posttraumatic stress disorder. Electronic J Natural Sciences (NAS RA) 2013;2(21):70-3.
[32]	Pirumyan K, Boyajyan A. Study of association between schizophrenia and functional polymorphisms of genes encoding Bcl-2 family proteins. International Journal of Biological Sciences and Applications, 2014;1(1):28-34.
[33]	Zakharyan R, Atshemyan S, Gevorgyan A, Boyajyan A. Nerve growth factor and its receptor in schizophrenia. BBA Clinical, 2014 (in press).
[34]	Sambrook J, Russell DW. Molecular Cloning: A Laboratory Manual (3rd edition). Cold Spring Harbor Laboratory Press, USA, 2001.
[35]	Bunce M, O’Neil CM, Barnado MC, Krausa P, Browning MJ, Morris PJ, Welsh KI. Phototyping: comprehensive DNA typing for HLA-A, B, C, DRB3, DRB4, DRB5 & DQB1 by PCR with 144 primer mixes utilizing sequence-specific primers (PCR-SSP). Tissue Antigens 1995;46:355-67.
[36]	Cunha C, Brambilla R, Thomas KL. A simple role for BDNF in learning and memory? Front J Mol Neurosci 2010;3:1.
[37]	Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, Zaitsev E, Gold B, Goldman D, Dean M, Lu B, Weinberger DR. The BDNF Val66Met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 2003;112(2): 257-69.
[38]	Pezawas L, Verchinski BA, Mattay VS, Callicott JH, Kolachana BS, Straub RE, Egan MF, Meyer-Lindenberg A, Weinberger DR. The brain-derived neurotrophic factor val66met polymorphism and variation in human cortical morphology. J Neurosci 2004;24(45):10099-102.
[39]	Buckley PF, Pillai A, Howell KR. Brain-derived neurotrophic factor: findings in schizophrenia. Curr Opin Psychiatry 2011; 24(2):122-7.
[40]	Numata S, Ueno S, Iga J, Yamauchi K, Yamauchi K, Hongwei S, Ohta K, Kinouchi S, Shibuya-Tayoshi S, Tayoshi S, Aono M, Kameoka N, Sumitani S, Tomotake M, Kaneda Y, Taniguchi T, Ishimoto Y, Ohmori T. Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism in schizophrenia is associated with age at onset and symptoms. Neurosci Lett 2006;401(1-2):1-5.
[41]	Spalletta G, Morris DW, Angelucci F, Rubino IA, Spoletini I, Bria P,Martinotti G, Siracusano A, Bonaviri G, Bernardini S, Caltagirone C, Bossù P, Donohoe G, Gill M, Corvin AP. BDNF Val66Met polymorphism is associated with aggressive behavior in schizophrenia. Eur Psychiatry 2010; 25(6):311-3.
[42]	Gratacòs M, González JR, Mercader JM, de Cid R, Urretavizcaya M, Estivill X. Brain-derived neurotrophic factor Val66Met and psychiatric disorders: meta-analysis of case-control studies confirm association to substance-related disorders, eating disorders, and schizophrenia. Biol Psychiatry 2007;61(7):911-22.
[43]	Kanazawa T, Glatt SJ, Kia-Keating B, Yoneda H, Tsuang MT. Meta-analysis reveals no association of the Val66Met polymorphism of brain-derived neurotrophic factor with either schizophrenia or bipolar disorder. Psychiatr Genet 2007;17(3):165-70.
[44]	Moore SW, Tessier-Lavigne M, Kennedy TE. Netrins and their receptors. Adv Exp Med Biol 2007;621:17-31.
[45]	Aoki-Suzuki M, Yamada K, Meerabux J, Iwayama-Shigeno Y, Ohba H, Iwamoto K, Takao H, Toyota T, Suto Y, Nakatani N, Dean B, Nishimura S, Seki K, Kato T, Itohara S, Nishikawa T, Yoshikawa T. A family-based association study and gene expression analyses of netrin-G1 and -G2 genes in schizophrenia. Biol Psychiatry 2005;57(4):382-93.
[46]	Borg I, Freude K, Kübart S, Hoffmann K, Menzel C, Laccone F, Firth H, Ferguson-Smith MA, Tommerup N, Ropers HH, Sargan D, Kalscheuer VM. Disruption of Netrin G1 by a balanced chromosome translocation in a girl with Rett syndrome. Eur J Hum Genet 2005;13(8):921-7.
[47]	Eastwood SL, Harrison PJ. Decreased mRNA expression of netrin-G1 andnetrin-G2 in the temporal lobe in schizophrenia and bipolar disorder. Neuropsychopharmacology 2008;33(4): 933-45.
[48]	Ohtsuki T, Horiuchi Y, Koga M, Ishiguro H, Inada T, Iwata N, Ozaki N, Ujike H, Watanabe Y, Someya T, Arinami T. Association of polymorphisms in the haplotype block spanning the alternatively spliced exons of the NTNG1 gene at 1p13.3 with schizophrenia in Japanese populations. Neurosci Lett 2008;435(3):194-7.
[49]	Pan Y, Liu G, Fang M, Shen L, Wang L, Han Y, Shen D, Wang X. Abnormal expression of netrin-G2 in temporal lobe epilepsy neurons in humans and a rat model. Exp Neurol 2010; 224:340-6.
[50]	Wang K, Zhang H, Bloss CS, Duvvuri V, Kaye W, Schork NJ, Berrettini W, Hakonarson H. A genome-wide association study on common SNPs and rare CNVs in anorexia nervosa. Mol Psychiatry 2011;16(9):949-59.
[51]	Zhu Y, Yang H, Bi Y, Zhang Y, Zhen C, Xie S, Qin H, He J, Liu L, Liu Y. Positive association between NTNG1 and schizophrenia in Chinese Han population. J Genet 2011;90(3): 499-502.
[52]	Harrison PJ, Eastwood SL. Preferential involvement of excitatory neurons in medial temporal lobe in schizophrenia. Lancet 1998;352(9141):1669-73.
[53]	Brose N. Altered complexin expression in psychiatric and neurological disorders: cause or consequence? Mol Cells 2008;25(1):7-19.
[54]	Glynn D, Gibson HE, Harte MK, Reim K, Jones S, Reynolds GP, Morton AJ. Clorgyline-mediated reversal of neurological deficits in a Complexin 2 knockout mouse. Hum Mol Genet 2010;19(17): 3402-12.
[55]	Eastwood SL, Harrison PJ. Hippocampal synaptic pathology in schizophrenia, bipolar disorder and major depression: a study of complexin mRNAs. Mol Psychiatry 2000;5:425-32.
[56]	Begemann M, Grube S, Papiol S, Malzahn D, Krampe H, Ribbe K, Friedrichs H, Radyushkin KA, El-Kordi A, Benseler F, Hannke K, Sperling S, Schwerdtfeger D, Thanhäuser I, Gerchen MF, Ghorbani M, Gutwinski S, Hilmes C, Leppert R, Ronnenberg A, Sowislo J, Stawicki S, Stödtke M, Szuszies C, Reim K, Riggert J, Eckstein F, Falkai P, Bickeböller H, Nave KA, Brose N, Ehrenreich H. Modification of cognitive performance in schizophrenia by complexin 2 gene polymorphisms. Arch Gen Psychiatry 2010;67(9):879-88.
[57]	McAllister AK, Katz LC, Lo DC. Neurotrophins and synaptic plasticity. Annu Rev Neurosci 1999;22:295-318.
[58]	Buckley PF, Mahadik S, Pillai A, Terry JrA. Neurotrophins and schizophrenia. Schizophr Res 2007;94:1-11.
[59]	Stanisz AM, Stanisz JA. Nerve growth factor and neuroimmune interactions in inflammatory diseases. Ann N Y Acad Sci 2000;917:268-72.
[60]	Jockers-Scherubl MC, Zubraegel D, Baer T, Linden M, Danker-Hopfe H, Schulte-Herbruggen O, Neu P, Hellweg R. Nerve growth factor serum concentrations rise after successful cognitive-behavioural therapy of generalized anxiety disorder. Prog Neuropsychopharmacol Biol Psychiatry 2007;31(1):200-4.
[61]	Xiong P, Zeng Y, Zhu Z, Tan D, Xu F, Lu J, Wan J, Ma M. Reduced NGF serum levels and abnormal P300 event-related potential in first episode schizophrenia. Schizophr Res 2010;119(1-3):34-9.
[62]	Xiong P, Zeng Y, J Wan J, Xiaohan DH, Tan D, Lu J, Xu F, Li HY, Zhu Z, Ma M. The role of NGF and IL-2 serum level in assisting the diagnosis in first episode schizophrenia. Psychiatry Res 2011;189(1):72-6.
[63]	Jockers-Scherubl MC, Matthies U, Danker-Hopfe H, Lang UE, Mahlberg R, Hellweg R. Chronic cannabis abuse raises nerve growth factor serum concentrations in drug-naive schizophrenic patients. J Psychopharmacol 2003;17(4):439- 45.
[64]	Syed Z, Dudbridge F, Kent L. An investigation of the neurotrophic factor genes GDNF, NGF, and NT3 in susceptibility to ADHD. Am J Med Genet B 2007;144B(3): 375-8.
[65]	Di Maria E, Giorgio E, Uliana V, Bonvicini C, Faravelli F, Cammarata S, Novello MC, Galimberti D, Scarpini E, Zanetti O, Gennarelli M, Tabaton M. Possible influence of a non-synonymous polymorphism located in the NGF precursor on susceptibility to late-onset Alzheimer's disease and mild cognitive impairment. J Alzheimers Dis 2012;29(3): 699-705.
[66]	Park JK, Lee SM, Kang WS, Kim SK, Cho AR. NGF polymorphisms and haplotypes are associated with schizophrenia in Korean population. Mol Cell Toxicol 2011;7:375-80.
[67]	Cheng HC, Sun Y, Lai LC, Chen SY, Lee WC, Chen JH, Chen TF, Chen HH, Wen LL, Yip PK, Chu YM, Chen WJ, Chen YC. Genetic polymorphisms of nerve growth factor receptor (NGFR) and the risk of Alzheimer's disease. J Negat Results Biomed 2012;11:5
[68]	Gerke V, Moss SE. Annexins: from structure to function. Physiol Rev 2002;82(2):331-71
[69]	Boersma HH, Kietselaer BL, Stolk LM, Bennaghmouch A, Hofstra L, Narula J, Heidendal GA, Reutelingsperger CP. Past, present, and future of annexin A5: from protein discovery to clinical applications. J Nucl Med 2005;46(12):2035-50.
[70]	Munoz L, Frey B, Pausch F, Baum W, Mueller R, Brachvogel B, Poschl E, Rodel F, von der Mark K, Herrmann M, Gaipl U. The role of annexin A5 in the modulation of the immune response against dying and dead cells. Curr Med Chem 2007;14(3):271-7.
[71]	Gaipl US, Munoz LE, Rodel F, Pausch F, Frey B, Brachvogel B, von der Mark K, Poschl E. Modulation of the immune system by dying cells and the phosphatidylserine-ligand annexin A5. Autoimmunity 2007;40(4):254-9.
[72]	Martin M, Leffler J, Blom AM. Annexin A2 and A5 serve as new ligands for C1Q on apoptotic cells. J Biol Chem 2012; 287(40):33733-44.
[73]	Di Napoli M, Arakelyan A, Boyajyan A, Godoy A, Papa F. Chapter 2. The acute phase inflammatory response in stroke: systemic inflammation and neuroinflammation. In: Pitzer JA (ed.) Progress in Inflammation Research, Nova Science Publishers Inc., USA, 2005, pp.95-145.
[74]	Francesconi LP, Ceresér KM, Mascarenhas R, Stertz L, Gama CS, Belmonte-de-Abreu P. Increased annexin-V and decreased TNF-alpha serum levels in chronic-medicated patients with schizophrenia. Neurosci Lett 2011;502(3):143- 6.
[75]	González-Conejero R, Corral J, Roldán V, Martínez C, Marín F, Rivera J, Iniesta JA, Lozano ML, Marco P, Vicente V. A common polymorphism in the annexin V Kozak sequence (-1C>T) increases translation efficiency and plasma levels of annexin V, and decreases the risk of myocardial infarction in young patients. Blood 2002;100(6):2081-6.
[76]	Van Heerde WL, DeGroot PG, Reutelingsperger CPM. The complexity of the phospholipid binding protein Annexin V. Thromb Haemost 1995;73(2):172-9.
[77]	Liu CM, Fann CS, Chen CY, Liu YL, Oyang YJ, Yang WC, Chang CC, Wen CC, Chen WJ, Hwang TJ, Hsieh MH, Liu CC, Faraone SV, Tsuang MT, Hwu HG. ANXA7, PPP3CB, DNAJC9, and ZMYND17 genes at chromosome 10q22 associated with the subgroup of schizophrenia with deficits in attention and executive function. Biol Psychiatry 2011;70(1):51-8.
[78]	Roset R, Ortet L, Gil-Gomez G. Role of Bcl-2 family members on apoptosis: what we have learned from knock-out mice. Front Biosci 2007;12:4722-30.
[79]	Youle RJ, Strasser A.The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 2008;9(1):47-59.
[80]	Korsmeyer SJ, Shutter JR, Veis DJ, Merry DE, Oltvai ZN. Bcl2/Bax: a rheostat that regulates an anti-oxidant pathway and cell death. Semin Cancer Biol 1993;4(6):327-32.
[81]	Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J, Peng TI, Jones DP, Wang X. Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science 1997;275(5303):1129-32.
[82]	Chen G, Manji HK. The extracellular signal-regulated kinase pathway: An emerging promising target for mood stabilizers. Curr Opin Psychiatry 2006;19:313-23.
[83]	Chen DF, Schneider GE, Martinou JC, Tonegawa S. Bcl-2 promotes regeneration of severed axons in mammalian CNS. Nature 1997;385:435-9.
[84]	Jonas E. Bcl-xl regulates synaptic plasticity. Mol Interv 2006;6:208-22.
[85]	Oltwai ZN, Milliman CL, Korsemeyer SJ. Bcl2 heterodimers in vivo with a conserved homolog Bax, that accelerates programmed cell death. Cell 1993;74:609-19.
[86]	Surhone LM, Tennoe MT, Henssonow SF. Bcl-2-associated X Protein. Beau Bassin: Betascript Publishing, 2011.
[87]	Jarskog LF, Selinger ES, Lieberman JA, Gilmore JH. Cortical Bcl2 protein expression and apoptotic regulation in schizophrenia. Biol Psychiatry 2000;48:641-50.
[88]	Jarskog LF, Selinger ES, Lieberman JA, Gilmore JH. Apoptotic proteins in the temporal cortex in schizophrenia: high Bax/Bcl2 ratio without caspase-3 activation. Am J Psychiatry 2004;161:109-15.
[89]	Milani L, Gupta M, Andersen M, Dhar S, Fryknäs M, Isaksson A, Larsson R, Syvänen AC. Allelic imbalance in gene expression as a guide to cis-acting regulatory single nucleotide polymorphisms in cancer cells. Nucleic Acids Res 2007;35(5):34.
[90]	Kim DH, Xu W, Ma C, Liu X, Siminovitch K, Messner HA, Lipton JH. Genetic variants in the candidate genes of the apoptosis pathway and susceptibility to chronic myeloid leukemia. Blood 2009;113(11):2517-25.
[91]	Eun YG, Hong IK, Kim SK, Park HK, Kwon S, Chung DH, Kwon KH. Polymorphism (rs1801018, Thr7Thr) of BCL2 is associated with papillary thyroid cancer in Korean population. Clin Exp Otorhinolaryngol 2011;4(3):149-54.
[92]	Gu S, Wu Q, Zhao X, Wu W, Gao Z, Tan X, Qian J, Chen H, Xie Y, Jin L, Han B, Lu D. Association of CASP3 polymorphism with hematologic toxicity in patients with advanced non-small-cell lung carcinoma treated with platinum-based chemotherapy. Cancer Sci 2012;103(8):1451-9.
[93]	Hoh NZ, Wagner AK, Alexander SA, Clark RB, Beers SR, Okonkwo DO, Ren D, Conley YP. BCL2 genotypes: functional and neurobehavioral outcomes after severe traumatic brain injury. J Neurotrauma 2010;27(8):1413-27.
[94]	Manji HK. Bcl-2: A key regulator of affective resilience in the pathophysiology and treatment of severe mood disorders. Biol Psychiatry 2008;63(Suppl 1):243S.
[95]	Yuan P, Baum AE, Zhou R, Wang Y, Laje G, McMahon FJ. Bcl-2 polymorphisms associated with mood disorders and antidepressant-responsiveness regulate Bcl-2 gene expression and cellular resilience in human lymphoblastoid cell lines. Biol Psychiatry 2008;63(Suppl 1):63S.
[96]	Salvadore G, Nugent AC, Chen G, Akula N, Yuan P, Cannon DM, Zarate CA Jr, McMahon FJ, Manji HK, Drevets WC. Bcl-2 polymorphism influences gray matter volume in the ventral striatum in healthy humans. Biol Psychiatry 2009;66(8):804-7.
[97]	Liu ME, Huang CC, Hwang JP, Yang AC, Tu PC, Yeh HL, Hong CJ, Liou YJ, Chen JF, Lin CP, Tsai SJ. Effect of Bcl-2 rs956572 SNP on regional gray matter volumes and cognitive function in elderly males without dementia. Age (Dordr) 2013;35(2):343-52.
[98]	Soeiro-de-Souza MG, Salvadore G, Moreno RA, Otaduy MC, Chaim KT, Gattaz WF, Zarate CA Jr, Machado-Vieira R. Bcl-2 rs956572 polymorphism is associated with increased anterior cingulate cortical glutamate in euthymic bipolar I disorder. Neuropsychopharmacology 2013;38(3):468-75.
[99]	Uemura T, Green M, Corson TW, Perova T, Li PP, Warsh JJ. Bcl-2 SNP rs956572 associates with disrupted intracellular calcium homeostasis in bipolar I disorder. Bipolar Disord 2011;13(1):41-51

Cite This Article

Plain Text BibTeX RIS

APA Style

Anna Boyajyan, Ani Stepanyan, Diana Avetyan, Hovsep Ghazaryan, Sofi Atshemyan, et al. (2014). Genetic Variations Associated with Brain Disorders: Focus on Synaptic Plasticity and Apoptosis Regulatory Genes in Schizophrenia, Posttraumatic Stress Disorder and Ischemic Stroke. International Journal of Genetics and Genomics, 2(2), 19-29. https://doi.org/10.11648/j.ijgg.20140202.12

Copy | Download

ACS Style

Anna Boyajyan; Ani Stepanyan; Diana Avetyan; Hovsep Ghazaryan; Sofi Atshemyan, et al. Genetic Variations Associated with Brain Disorders: Focus on Synaptic Plasticity and Apoptosis Regulatory Genes in Schizophrenia, Posttraumatic Stress Disorder and Ischemic Stroke. Int. J. Genet. Genomics 2014, 2(2), 19-29. doi: 10.11648/j.ijgg.20140202.12

Copy | Download

AMA Style

Anna Boyajyan, Ani Stepanyan, Diana Avetyan, Hovsep Ghazaryan, Sofi Atshemyan, et al. Genetic Variations Associated with Brain Disorders: Focus on Synaptic Plasticity and Apoptosis Regulatory Genes in Schizophrenia, Posttraumatic Stress Disorder and Ischemic Stroke. Int J Genet Genomics. 2014;2(2):19-29. doi: 10.11648/j.ijgg.20140202.12

Copy | Download

@article{10.11648/j.ijgg.20140202.12,
  author = {Anna Boyajyan and Ani Stepanyan and Diana Avetyan and Hovsep Ghazaryan and Sofi Atshemyan and Roksana Zakharyan and Kristina Pirumyan and Gohar Tsakanova},
  title = {Genetic Variations Associated with Brain Disorders: Focus on Synaptic Plasticity and Apoptosis Regulatory Genes in Schizophrenia, Posttraumatic Stress Disorder and Ischemic Stroke},
  journal = {International Journal of Genetics and Genomics},
  volume = {2},
  number = {2},
  pages = {19-29},
  doi = {10.11648/j.ijgg.20140202.12},
  url = {https://doi.org/10.11648/j.ijgg.20140202.12},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.ijgg.20140202.12},
  abstract = {Epidemiologic, clinical and experimental data indicates that a majority of brain disorders including schizophrenia (SCZ), posttraumatic stress disorder (PTSD), and ischemic stroke (IS) are multifactorial disorders with strong and complex genetic component. Identification of all genetic variations associated with these disorders may sufficiently contribute to understanding of their basic pathomechanisms and encourage development of new innovative approaches to their early diagnosis and treatment. The aim of this review article is to provide overview of our recent studies on evaluation of potential association of SCZ, PTSD and IS with functional single nucleotide polymorphisms (SNPs) of synaptic plasticity and apoptosis regulatory genes in Armenian population. Here, our attention was focused on genes encoding netrin G1 (NTNG1), brain-derived neurotrophic factor (BDNF), complexin-2 (CPLX2), nerve growth factor (NGF) and its receptor (NGFR), annexin family proteins - annexin A5 and annexin A11 (ANXAV, ANXA11), and B-cell lymphoma 2 (Bcl-2) family proteins - Bcl-2 proper and Bcl-2-associated X protein (BCL2, BAX). Genomic DNA samples of diseased and healthy individuals were genotyped for a number of SNPs of the mentioned genes using polymerase chain reaction with sequence-specific primers (PCR-SSP). The significance of differences in genotype and allele frequencies and minor allele carriage between patients and healthy control subjects was determined using Pearson’s Chi-square test. P-values less than 0.05 were considered statistically significant. Significant associations were found between: (1) SCZ and BDNF rs6265, CPLX2 rs1366116, rs3892909, NGF rs6330, rs4839435, NGFR rs734194, rs11466155, rs2072446, ANXAV rs11575945, BAX rs1057369 SNPs; (2) PTSD and CPLX2 rs1366116, BCL2 rs956572 SNPs; (3) IS and NTNG1 rs628117, CPLX2 rs1366116, ANXAV rs11575945 SNPs. The obtained results indicated the involvement of genetically determined alterations in synaptic plasticity and apoptosis in pathomechanisms of SCZ, PTSD and IS. The minor T allele of the CPLX2 gene rs1366116 polymorphism represents risk factor for all studied diseased conditions indicating important functional significance of this genetic variation in maintenance of synaptic plasticity. Another important conclusion of these studies is that minor alleles of some polymorphic variants of genes, encoding synaptic plasticity and apoptosis regulatory proteins, may play a protective role relative to SCZ decreasing the risk for development of this disorder. In summary, our studies emphasize the important contribution of changes in synaptic plasticity and apoptosis regulation to pathomechanisms of SCZ, PTSD, and IS as well as significant input of genetic factors to these changes.},
 year = {2014}
}

Copy | Download

TY  - JOUR
T1  - Genetic Variations Associated with Brain Disorders: Focus on Synaptic Plasticity and Apoptosis Regulatory Genes in Schizophrenia, Posttraumatic Stress Disorder and Ischemic Stroke
AU  - Anna Boyajyan
AU  - Ani Stepanyan
AU  - Diana Avetyan
AU  - Hovsep Ghazaryan
AU  - Sofi Atshemyan
AU  - Roksana Zakharyan
AU  - Kristina Pirumyan
AU  - Gohar Tsakanova
Y1  - 2014/05/30
PY  - 2014
N1  - https://doi.org/10.11648/j.ijgg.20140202.12
DO  - 10.11648/j.ijgg.20140202.12
T2  - International Journal of Genetics and Genomics
JF  - International Journal of Genetics and Genomics
JO  - International Journal of Genetics and Genomics
SP  - 19
EP  - 29
PB  - Science Publishing Group
SN  - 2376-7359
UR  - https://doi.org/10.11648/j.ijgg.20140202.12
AB  - Epidemiologic, clinical and experimental data indicates that a majority of brain disorders including schizophrenia (SCZ), posttraumatic stress disorder (PTSD), and ischemic stroke (IS) are multifactorial disorders with strong and complex genetic component. Identification of all genetic variations associated with these disorders may sufficiently contribute to understanding of their basic pathomechanisms and encourage development of new innovative approaches to their early diagnosis and treatment. The aim of this review article is to provide overview of our recent studies on evaluation of potential association of SCZ, PTSD and IS with functional single nucleotide polymorphisms (SNPs) of synaptic plasticity and apoptosis regulatory genes in Armenian population. Here, our attention was focused on genes encoding netrin G1 (NTNG1), brain-derived neurotrophic factor (BDNF), complexin-2 (CPLX2), nerve growth factor (NGF) and its receptor (NGFR), annexin family proteins - annexin A5 and annexin A11 (ANXAV, ANXA11), and B-cell lymphoma 2 (Bcl-2) family proteins - Bcl-2 proper and Bcl-2-associated X protein (BCL2, BAX). Genomic DNA samples of diseased and healthy individuals were genotyped for a number of SNPs of the mentioned genes using polymerase chain reaction with sequence-specific primers (PCR-SSP). The significance of differences in genotype and allele frequencies and minor allele carriage between patients and healthy control subjects was determined using Pearson’s Chi-square test. P-values less than 0.05 were considered statistically significant. Significant associations were found between: (1) SCZ and BDNF rs6265, CPLX2 rs1366116, rs3892909, NGF rs6330, rs4839435, NGFR rs734194, rs11466155, rs2072446, ANXAV rs11575945, BAX rs1057369 SNPs; (2) PTSD and CPLX2 rs1366116, BCL2 rs956572 SNPs; (3) IS and NTNG1 rs628117, CPLX2 rs1366116, ANXAV rs11575945 SNPs. The obtained results indicated the involvement of genetically determined alterations in synaptic plasticity and apoptosis in pathomechanisms of SCZ, PTSD and IS. The minor T allele of the CPLX2 gene rs1366116 polymorphism represents risk factor for all studied diseased conditions indicating important functional significance of this genetic variation in maintenance of synaptic plasticity. Another important conclusion of these studies is that minor alleles of some polymorphic variants of genes, encoding synaptic plasticity and apoptosis regulatory proteins, may play a protective role relative to SCZ decreasing the risk for development of this disorder. In summary, our studies emphasize the important contribution of changes in synaptic plasticity and apoptosis regulation to pathomechanisms of SCZ, PTSD, and IS as well as significant input of genetic factors to these changes.
VL  - 2
IS  - 2
ER  -

Copy | Download

Author Information

Anna Boyajyan

Laboratory of Human Genomics and Immunomics, Department of Applied Molecular Biology, Institute of Molecular Biology NAS RA, Yerevan, Armenia
Ani Stepanyan

Laboratory of Human Genomics and Immunomics, Department of Applied Molecular Biology, Institute of Molecular Biology NAS RA, Yerevan, Armenia
Diana Avetyan

Laboratory of Human Genomics and Immunomics, Department of Applied Molecular Biology, Institute of Molecular Biology NAS RA, Yerevan, Armenia
Hovsep Ghazaryan

Laboratory of Human Genomics and Immunomics, Department of Applied Molecular Biology, Institute of Molecular Biology NAS RA, Yerevan, Armenia
Sofi Atshemyan

Laboratory of Human Genomics and Immunomics, Department of Applied Molecular Biology, Institute of Molecular Biology NAS RA, Yerevan, Armenia
Roksana Zakharyan

Laboratory of Human Genomics and Immunomics, Department of Applied Molecular Biology, Institute of Molecular Biology NAS RA, Yerevan, Armenia
Kristina Pirumyan

Laboratory of Human Genomics and Immunomics, Department of Applied Molecular Biology, Institute of Molecular Biology NAS RA, Yerevan, Armenia
Gohar Tsakanova

Laboratory of Human Genomics and Immunomics, Department of Applied Molecular Biology, Institute of Molecular Biology NAS RA, Yerevan, Armenia

Download PDF

Sections

Plain Text BibTeX RIS

APA Style

Anna Boyajyan, Ani Stepanyan, Diana Avetyan, Hovsep Ghazaryan, Sofi Atshemyan, et al. (2014). Genetic Variations Associated with Brain Disorders: Focus on Synaptic Plasticity and Apoptosis Regulatory Genes in Schizophrenia, Posttraumatic Stress Disorder and Ischemic Stroke. International Journal of Genetics and Genomics, 2(2), 19-29. https://doi.org/10.11648/j.ijgg.20140202.12

Copy | Download

ACS Style

Anna Boyajyan; Ani Stepanyan; Diana Avetyan; Hovsep Ghazaryan; Sofi Atshemyan, et al. Genetic Variations Associated with Brain Disorders: Focus on Synaptic Plasticity and Apoptosis Regulatory Genes in Schizophrenia, Posttraumatic Stress Disorder and Ischemic Stroke. Int. J. Genet. Genomics 2014, 2(2), 19-29. doi: 10.11648/j.ijgg.20140202.12

Copy | Download

AMA Style

Anna Boyajyan, Ani Stepanyan, Diana Avetyan, Hovsep Ghazaryan, Sofi Atshemyan, et al. Genetic Variations Associated with Brain Disorders: Focus on Synaptic Plasticity and Apoptosis Regulatory Genes in Schizophrenia, Posttraumatic Stress Disorder and Ischemic Stroke. Int J Genet Genomics. 2014;2(2):19-29. doi: 10.11648/j.ijgg.20140202.12

Copy | Download

@article{10.11648/j.ijgg.20140202.12,
  author = {Anna Boyajyan and Ani Stepanyan and Diana Avetyan and Hovsep Ghazaryan and Sofi Atshemyan and Roksana Zakharyan and Kristina Pirumyan and Gohar Tsakanova},
  title = {Genetic Variations Associated with Brain Disorders: Focus on Synaptic Plasticity and Apoptosis Regulatory Genes in Schizophrenia, Posttraumatic Stress Disorder and Ischemic Stroke},
  journal = {International Journal of Genetics and Genomics},
  volume = {2},
  number = {2},
  pages = {19-29},
  doi = {10.11648/j.ijgg.20140202.12},
  url = {https://doi.org/10.11648/j.ijgg.20140202.12},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.ijgg.20140202.12},
  abstract = {Epidemiologic, clinical and experimental data indicates that a majority of brain disorders including schizophrenia (SCZ), posttraumatic stress disorder (PTSD), and ischemic stroke (IS) are multifactorial disorders with strong and complex genetic component. Identification of all genetic variations associated with these disorders may sufficiently contribute to understanding of their basic pathomechanisms and encourage development of new innovative approaches to their early diagnosis and treatment. The aim of this review article is to provide overview of our recent studies on evaluation of potential association of SCZ, PTSD and IS with functional single nucleotide polymorphisms (SNPs) of synaptic plasticity and apoptosis regulatory genes in Armenian population. Here, our attention was focused on genes encoding netrin G1 (NTNG1), brain-derived neurotrophic factor (BDNF), complexin-2 (CPLX2), nerve growth factor (NGF) and its receptor (NGFR), annexin family proteins - annexin A5 and annexin A11 (ANXAV, ANXA11), and B-cell lymphoma 2 (Bcl-2) family proteins - Bcl-2 proper and Bcl-2-associated X protein (BCL2, BAX). Genomic DNA samples of diseased and healthy individuals were genotyped for a number of SNPs of the mentioned genes using polymerase chain reaction with sequence-specific primers (PCR-SSP). The significance of differences in genotype and allele frequencies and minor allele carriage between patients and healthy control subjects was determined using Pearson’s Chi-square test. P-values less than 0.05 were considered statistically significant. Significant associations were found between: (1) SCZ and BDNF rs6265, CPLX2 rs1366116, rs3892909, NGF rs6330, rs4839435, NGFR rs734194, rs11466155, rs2072446, ANXAV rs11575945, BAX rs1057369 SNPs; (2) PTSD and CPLX2 rs1366116, BCL2 rs956572 SNPs; (3) IS and NTNG1 rs628117, CPLX2 rs1366116, ANXAV rs11575945 SNPs. The obtained results indicated the involvement of genetically determined alterations in synaptic plasticity and apoptosis in pathomechanisms of SCZ, PTSD and IS. The minor T allele of the CPLX2 gene rs1366116 polymorphism represents risk factor for all studied diseased conditions indicating important functional significance of this genetic variation in maintenance of synaptic plasticity. Another important conclusion of these studies is that minor alleles of some polymorphic variants of genes, encoding synaptic plasticity and apoptosis regulatory proteins, may play a protective role relative to SCZ decreasing the risk for development of this disorder. In summary, our studies emphasize the important contribution of changes in synaptic plasticity and apoptosis regulation to pathomechanisms of SCZ, PTSD, and IS as well as significant input of genetic factors to these changes.},
 year = {2014}
}

Copy | Download

TY  - JOUR
T1  - Genetic Variations Associated with Brain Disorders: Focus on Synaptic Plasticity and Apoptosis Regulatory Genes in Schizophrenia, Posttraumatic Stress Disorder and Ischemic Stroke
AU  - Anna Boyajyan
AU  - Ani Stepanyan
AU  - Diana Avetyan
AU  - Hovsep Ghazaryan
AU  - Sofi Atshemyan
AU  - Roksana Zakharyan
AU  - Kristina Pirumyan
AU  - Gohar Tsakanova
Y1  - 2014/05/30
PY  - 2014
N1  - https://doi.org/10.11648/j.ijgg.20140202.12
DO  - 10.11648/j.ijgg.20140202.12
T2  - International Journal of Genetics and Genomics
JF  - International Journal of Genetics and Genomics
JO  - International Journal of Genetics and Genomics
SP  - 19
EP  - 29
PB  - Science Publishing Group
SN  - 2376-7359
UR  - https://doi.org/10.11648/j.ijgg.20140202.12
AB  - Epidemiologic, clinical and experimental data indicates that a majority of brain disorders including schizophrenia (SCZ), posttraumatic stress disorder (PTSD), and ischemic stroke (IS) are multifactorial disorders with strong and complex genetic component. Identification of all genetic variations associated with these disorders may sufficiently contribute to understanding of their basic pathomechanisms and encourage development of new innovative approaches to their early diagnosis and treatment. The aim of this review article is to provide overview of our recent studies on evaluation of potential association of SCZ, PTSD and IS with functional single nucleotide polymorphisms (SNPs) of synaptic plasticity and apoptosis regulatory genes in Armenian population. Here, our attention was focused on genes encoding netrin G1 (NTNG1), brain-derived neurotrophic factor (BDNF), complexin-2 (CPLX2), nerve growth factor (NGF) and its receptor (NGFR), annexin family proteins - annexin A5 and annexin A11 (ANXAV, ANXA11), and B-cell lymphoma 2 (Bcl-2) family proteins - Bcl-2 proper and Bcl-2-associated X protein (BCL2, BAX). Genomic DNA samples of diseased and healthy individuals were genotyped for a number of SNPs of the mentioned genes using polymerase chain reaction with sequence-specific primers (PCR-SSP). The significance of differences in genotype and allele frequencies and minor allele carriage between patients and healthy control subjects was determined using Pearson’s Chi-square test. P-values less than 0.05 were considered statistically significant. Significant associations were found between: (1) SCZ and BDNF rs6265, CPLX2 rs1366116, rs3892909, NGF rs6330, rs4839435, NGFR rs734194, rs11466155, rs2072446, ANXAV rs11575945, BAX rs1057369 SNPs; (2) PTSD and CPLX2 rs1366116, BCL2 rs956572 SNPs; (3) IS and NTNG1 rs628117, CPLX2 rs1366116, ANXAV rs11575945 SNPs. The obtained results indicated the involvement of genetically determined alterations in synaptic plasticity and apoptosis in pathomechanisms of SCZ, PTSD and IS. The minor T allele of the CPLX2 gene rs1366116 polymorphism represents risk factor for all studied diseased conditions indicating important functional significance of this genetic variation in maintenance of synaptic plasticity. Another important conclusion of these studies is that minor alleles of some polymorphic variants of genes, encoding synaptic plasticity and apoptosis regulatory proteins, may play a protective role relative to SCZ decreasing the risk for development of this disorder. In summary, our studies emphasize the important contribution of changes in synaptic plasticity and apoptosis regulation to pathomechanisms of SCZ, PTSD, and IS as well as significant input of genetic factors to these changes.
VL  - 2
IS  - 2
ER  -

Copy | Download