DNMT1 SNPs (rs2114724 and rs2228611) associated with positive symptoms in Chinese patients with schizophrenia
Tóm tắt
Schizophrenia is a serious mental disorder with complex clinical manifestations, while its pathophysiological mechanism is not fully understood. Accumulated evidence suggested the alteration in epigenetic pathway was associated with clinical features and brain dysfunctions in schizophrenia. DNA methyltransferases (DNMTs), a key enzyme for DNA methylation, are related to the development of schizophrenia, whereas the current research evidence is not sufficient. The aim of study was to explore the effects of gene polymorphisms of DNMTs on the susceptibility and symptoms of schizophrenia. The study was case–control study that designed and employed the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-5) as the diagnostic standard. 134 hospitalized patients with schizophrenia in the Third People's Hospital of Zhongshan City from January 2018 to April 2020 (Case group) as well as 64 healthy controls (Control group) from the same region were involved. Single nucleotide polymorphisms (SNPs) of DNMT1 genes (r s2114724 and rs 2228611) and DNMT3B genes (rs 2424932, rs 1569686, rs 6119954 and rs 2424908) were determined with massARRAY. Linkage disequilibrium analysis and haplotype analysis were performed, and genotype and allele frequencies were compared. The Hardy–Weinberg equilibrium was tested by the Chi-square test in SPSS software (version 20.0, SPSS Inc., USA). The severity of clinical symptoms was assessed by the Positive and Negative Syndrome Scale (PANSS). The correlation between DNMT1 genes (rs 2114724 and rs 2228611) and DNMT3B genes (rs2424932, rs1569686, rs6119954 and rs2424908) and clinical features was analyzed. There were no significant differences in genotype, allele frequency and haplotype of DNMT1 genes (rs 2114724 and rs 2228611) and DNMT3B genes (rs 2424932, rs 1569686, rs 6119954 and rs 2424908) between the case and healthy control group. There were significant differences in the PANSS total positive symptom scores, P3 (hallucinatory behavior), P6 (suspicious/persecution), G7 (motor retardation), and G15 (preoccupation) in patients with different DNMT1 gene rs 2114724 and rs 2228611 genotypes. The linkage disequilibrium analysis of gene polymorphic loci revealed that rs 2114724–rs 2228611 was complete linkage disequilibrium, and rs 1569686–rs 2424908, rs 2424932–rs 1569696 and rs 2424932–rs 2424908 were strongly linkage disequilibrium. The polymorphisms alteration in genetic pathway may be associated with development of specific clinical features in schizophrenia.
Tài liệu tham khảo
Stuchlik A, Sumiyoshi T. Cognitive deficits in schizophrenia and other neuropsychiatric disorders: convergence of preclinical and clinical evidence. Front Behav Neurosci. 2014;8:444.
James SL, Abate D, Abate KH, Abay SM, Abbafati C, Abbasi N, Abbastabar H, Abd-Allah F, Abdela J, Abdelalim A, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: A systematic analysis for the global burden of disease study 2017. Lancet. 2018;392:1789–858.
Birnbaum R, Weinberger DR. Genetic insights into the neurodevelopmental origins of schizophrenia. Nat Rev Neurosci. 2017;18:727–40.
Kim JS, Shin KS, Jung WH, Kim SN, Kwon JS, Chung CK. Power spectral aspects of the default mode network in schizophrenia: an MEG study. BMC Neurosci. 2014;15:104.
Moskowitz A, Heim G. Eugen Bleuler’s dementia praecox or the group of schizophrenias (1911): a centenary appreciation and reconsideration. Schizophr Bull. 2011;37:471–9.
Owen MJ, Sawa A, Mortensen PB. Schizophrenia. Lancet. 2016;388:86–97.
Howes OD, Murray RM. Schizophrenia: an integrated sociodevelopmental-cognitive model. Lancet. 2014;383:1677–87.
Hilker R, Helenius D, Fagerlund B, Skytthe A, Christensen K, Werge TM, Nordentoft M, Glenthøj B. Heritability of schizophrenia and schizophrenia spectrum based on the nationwide Danish twin register. Biol Psychiatry. 2018;83:492–8.
Mendizabal I, Berto S, Usui N, Toriumi K, Chatterjee P, Douglas C, Huh I, Jeong H, Layman T, Tamminga CA, et al. Cell type-specific epigenetic links to schizophrenia risk in the brain. Genome Biol. 2019;20:135.
Gusev A, Mancuso N, Won H, Kousi M, Finucane HK, Reshef Y, Song L, Safifi A, McCarroll S, Neale BM. Transcriptome wide association study of schizophrenia and chromatin activity yields mechanistic disease insights. Nat Genet. 2018;50:538–48.
Fromer M, Roussos P, Sieberts SK, Johnson JS, Kavanagh DH, Perumal TM, Ruderfer DM, Oh EC, Topol A, Shah HR. Gene expression elucidates functional impact of polygenic risk for schizophrenia. Nat Neurosci. 2016;19:1442–53.
Jaffe AE, Straub RE, Shin JH, Tao R, Gao Y, Collado-Torres L, Kam-Thong T, Xi HS, Quan J, Chen Q. Developmental and genetic regulation of the human cortex transcriptome illuminate schizophrenia pathogenesis. Nat Neurosci. 2018;21:1117–25.
Cardno AG, Gottesman II. Twin studies of schizophrenia: from bow-and-arrow concordances to star wars Mx and functional genomics. Am J Med Genet. 2000;97:12–7.
Reik W. Stability and flexibility of epigenetic gene regulation in mammalian development. Nature. 2007;447:425–32.
Zeng Y, Chen T. DNA methylation reprogramming during mammalian development. Genes. 2019;10:257.
Nishioka M, Bundo M, Kasai K, Iwamoto K. DNA methylation in schizophrenia: Progress and challenges of epigenetic studies. Genome Med. 2012;4:96.
Martinez-Jauand M, Sitges C, Rodriguez V, Picornell A, Ramon M, Buskila D, Montoya P. Pain sensitivity in fibromyalgia is associated with catechol-O-methyltransferase (COMT) gene. Eur J Pain. 2013;17:16–27.
Sozuguzel MD, Sazci A, Yildiz M. Female gender specific association of the Reelin (RELN) gene rs7341475 variant with schizophrenia. Mol Biol Rep. 2019;46:3411–6.
Janicijevic SM, Dejanovic SD, Borovcanin M. Interplay of brain-derived neurotrophic factor and cytokines in schizophrenia. Serb J Exp Clin Res. 2018;108:110–7.
Leonard S, Freedman R. Genetics of chromosome 15q13–q14 in schizophrenia. Biol Psychiatry. 2006;60:115–22.
Iwamoto K, Bundo M, Yamada K, Takao H, Iwayama-Shigeno Y, Yoshikawa T, Kato T. DNA methylation status of SOX10 correlates with its downregulation and oligodendrocyte dysfunction in schizophrenia. J Neurosci. 2005;25:5376–81.
Hu T-M, Chen S-J, Hsu S-H, Cheng M-C. Functional analyses and effect of DNA methylation on the EGR1 gene in patients with schizophrenia. Psychiatry Res. 2019;275:276–82.
Gowher H, Liebert K, Hermann A, Xu G, Jeltsch A. Mechanism of stimulation of catalytic activity of Dnmt3A and Dnmt3B DNA-(cytosine-C5)-methyltransferases by Dnmt3L. J Biol Chem. 2005;280(14):13341–8.
Symmank J, Bayer C, Schmidt C, et al. DNMT1 modulates interneuron morphology by regulating Pak6 expression through crosstalk with histone modifications. Epigenetics. 2018;13(5):536–56.
Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases DNMT3A and DNMT3B are essential for de novo methylation and mammalian development. Cell. 1999;99:247–57.
Bourc’his D, Bestor TH. Meiotic catastrophe and retrotransposon reactivation in male germ cells lacking DNMT3L. Nature. 2004;431:96–9.
Robertson KD. DNA methylation and human disease. Nat Rev Genet. 2005;6:597–610.
Ripke S, Neale BM, Corvin A, et al. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421–7.
Malhotra D, Sebat J. CNVs: harbingers of a rare variant revolution in psychiatric genetics. Cell. 2012;148(6):1223–41.
Saradalekshmi KR, Neetha NV, Sathyan S, Nair IV, Nair CM, Banerjee M. DNA methyl transferase (DNMT) gene polymorphisms could be a primary event in epigenetic susceptibility to schizophrenia. PLoS ONE. 2014;9(5):e98182–8.
Ping J, Zhang J, Wan J, Banerjee A, Huang C, Yu J, Jiang T, Du B. Correlation of four single nucleotide polymorphisms of the RELN gene with Schizophrenia. East Asian Arch Psychiatry. 2021;31(4):112–8. https://doi.org/10.12809/eaap2168.
Ping J, Zhang J, Wan J, Huang C, Luo J, Du B, Jiang T. A polymorphism in the BDNF gene (rs11030101) is associated with negative symptoms in Chinese Han patients with schizophrenia. Front Genet. 2022;16(13):849227.
Palha JA, Santos NC, Marques F, et al. Do genes and environment meet to regulate cerebrospinal fluid dynamics? Relevance for schizophrenia. Front Cell Neurosci. 2012;6(8):31.
Pogribny IP, Beland FA. DNA hypomethylation in the origin and pathogenesis of human diseases. Cell Mol Life Sci. 2009;66(14):2249–61.
Grayson DR, Guidotti A. The dynamics of DNA methylation in schizophrenia and related psychiatric disorders. Neuropsychopharmaeology. 2013;38(1):138–66.
Saradalekshmi KR, Neetha NV, Satyan S, et al. DNA methyltransferase (DNMT) gene polymorphisms could be a primary event in epigenetic susceptibility to schizophrenia. PLoS ONE. 2014;9(5):e98182.
Saxena S, Maroju PA, Choudhury S, Voina VC, Naik P, Gowdhaman K, Kkani P, Chennoju K, Ganesh Kumar S, Ramasubramanian C, Prasad Rao G, Jamma T, Narayan KP, Mohan KN. Functional analysis of DNMT1 SNPs (rs2228611 and rs2114724) associated with schizophrenia. Genet Res. 2021;31(2021):6698979. https://doi.org/10.1155/2021/6698979.
Zhai J, Miao Q, Gao Y, Chen M, Zhou YN, Wei XL, Li J. The relationship between DNA methyltransferase 1 gene polymorphism and cognitive function in the first episode, drug-naïve schizophrenia. Chin J Nerv Ment Dis. 2018;44:166–70.
Zhang C, Fang Y, Xie B, Cheng W, Du Y, Wang D, Yu S. DNA methyltransferase 3B gene increases risk of early onset schizophrenia. Neurosci Lett. 2009;462(3):308–11. https://doi.org/10.1016/j.neulet.2009.06.085.
Mill J, Tang T, Kaminsky Z, Khare T, Yazdanpanah S, Bouchard L, Jia P, Assadzadeh A, Flanagan J, Schumacher A, Wang SC, Petronis A. Epigenomic profiling reveals DNA methylation changes associated with major psychosis. Am J Hum Genet. 2008;82(3):696–711.
Wu X, Ye J, Wang Z, Zhao C. Epigenetic age acceleration was delayed in schizophrenia. Schizophr Bull. 2021;47(3):803–11.
Magwai T, Shangase KB, Oginga FO, Chiliza B, Mpofana T, Xulu KR. DNA methylation and schizophrenia: current literature and future perspective. Cells. 2021;10(11):2890. https://doi.org/10.3390/cells10112890.
Yoshino Y, Kawabe K, Mori T, Mori Y, Yamazaki K, Numata S, Nakata S, Yoshida T, Iga J, Ohmori T, Ueno S. Low methylation rates of dopamine receptor D2 gene promoter sites in Japanese schizophrenia subjects. World J Biol Psychiatry. 2016;17(6):449–56.
Huang HS, Akbarian S. GAD1 mRNA expression and DNA methylation in prefrontal cortex of subjects with schizophrenia. PLoS ONE. 2007;2(8):e809.
Kordi-Tamandani DM, Dahmardeh N, Torkamanzehi A. Evaluation of hypermethylation and expression pattern of GMR2, GMR5, GMR8, and GRIA3 in patients with schizophrenia. Gene. 2013;515(1):163–6.
Carrard A, Salzmann A, Malafosse A, Karege F. Increased DNA methylation status of the serotonin receptor 5HTR1A gene promoter in schizophrenia and bipolar disorder. J Affect Disord. 2011;132(3):450–3.