Association Studies of Common Variants of TCF4 Gene Conferring Risk of Schizophrenia in Pakistani Patients: Association Studies of Common Variants of TCF4 Gene

Faiza  Ijaz; Nabila  Ghaffar; Ayesha  Mazhar; Muhammad Khalil  Ahmad Khan; Muhammad Akram  Tariq

doi:10.54393/pjhs.v4i07.911

Authors

Faiza Ijaz Department of Biosciences, COMSATS Institute of Information Technology (CIIT), Sahiwal, Pakistan
Nabila Ghaffar Department of Biosciences, COMSATS Institute of Information Technology (CIIT), Sahiwal, Pakistan
Ayesha Mazhar Department of Biotechnology, University of Okara, Renala Khurd, Pakistan
Muhammad Khalil Ahmad Khan Department of Zoology University of Okara, Renala Khurd, Pakistan
Muhammad Akram Tariq Higher Education Department (HED), Punjab, Pakistan

DOI:

https://doi.org/10.54393/pjhs.v4i07.911

Keywords:

Schizophrenia, Association, Risk, Variants, Genetic, TCF4

Abstract

Schizophrenia is a psychiatric disorder and it is strongly inherited disease with a heritability of 80% or more. Rare genetic mutations are more frequent in schizophrenia patients. These genetic variations interfere with brain development and include hundreds of distinct genes. Transcription factor 4 (TCF4) has been emphasized as major players for disruption of brain development as well as function and consequently, the onset of schizophrenia. The dysregulation of TCF4 gene expression in brain affects the process of pre pulse inhibition (PPI) and consequently profound reduction in sensor motor gating that may results in to the onset of schizophrenia. Objective: To find out the genetic association of common variants of TCF4 gene conferring risk of schizophrenia. Methods: It was a case control study in which statistically significant number of blood samples of confirmed diagnosed schizophrenic patients as well as age matched healthy control subjects were analyzed to screen out selected Single Nucleotide Polymorphisms (rs9960767, rs4309482, rs12966547, and rs2958182) of TCF4 gene for their association with schizophrenia. Results: Out of these four SNPs rs9960767 and rs4309482 were significantly associated with schizophrenia. p-values for SNPs rs12966547 and rs2958182 were greater than 0.05 in both healthy controls and in patients. Conclusions: The results of this study offer compelling evidence for the link between particular TCF4 gene polymorphisms and schizophrenia. Two SNPs, rs9960767 and rs4309482, were found to have a strong correlation with schizophrenia in the research population, according to the analysis.

References

Correll CU and Schooler NR. Negative symptoms in schizophrenia: a review and clinical guide for recognition, assessment, and treatment. Neuropsychiatric Disease and Treatment. 2020 Feb; 16: 519-34. doi: 10.2147/NDT.S225643. DOI: https://doi.org/10.2147/NDT.S225643

Stilo SA and Murray RM. The epidemology of schizophrenia: replacing dogma with knowledge. Dialogues in Clinical Neuroscience. 2022 Apr; 12(3): 305-315. doi: 10.31887/DCNS.2010.12.3/sstilo. DOI: https://doi.org/10.31887/DCNS.2010.12.3/sstilo

Broyd SJ, Demanuele C, Debener S, Helps SK, James CJ, Sonuga-Barke EJ. Default-mode brain dysfunction in mental disorders: a systematic review. Neuroscience & Biobehavioral Reviews. 2009 Mar; 33(3): 279-96. doi: 10.1016/j.neubiorev.2008.09.002. DOI: https://doi.org/10.1016/j.neubiorev.2008.09.002

Navarrete K, Pedroso I, De Jong S, Stefansson H, Steinberg S, Stefansson K, et al. TCF4 (e2‐2; ITF2): A schizophrenia‐associated gene with pleiotropic effects on human disease. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. 2013 Jan; 162(1): 1-6. doi: 10.1002/ajmg.b.32109. DOI: https://doi.org/10.1002/ajmg.b.32109

Fu H, Cai J, Clevers H, Fast E, Gray S, Greenberg R, et al. A genome-wide screen for spatially restricted expression patterns identifies transcription factors that regulate glial development. Journal of Neuroscience. 2009 Sep; 29(36): 11399-408. doi: 10.1523/JNEUROSCI.0160-09.2009. DOI: https://doi.org/10.1523/JNEUROSCI.0160-09.2009

The Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium. Genome-wide association study identifies five new schizophrenia loci. Nature Genetics. 2011 Sep; 43(10): 969-976. doi: 10.1038/ng.940.

Brzózka MM, Radyushkin K, Wichert SP, Ehrenreich H, Rossner MJ. Cognitive and sensorimotor gating impairments in transgenic mice overexpressing the schizophrenia susceptibility gene Tcf4 in the brain. Biological Psychiatry. 2010 Jul; 68(1): 33-40. doi: 10.1016/j.biopsych.2010.03.015. DOI: https://doi.org/10.1016/j.biopsych.2010.03.015

Albanna A, Choudhry Z, Harvey PO, Fathalli F, Cassidy C, Sengupta SM, et al. TCF4 gene polymorphism and cognitive performance in patients with first episode psychosis. Schizophrenia Research. 2014 Jan; 152(1): 124-9. doi: 10.1038/ng.3725. DOI: https://doi.org/10.1016/j.schres.2013.10.038

Marshall CR, Howrigan DP, Merico D, Thiruvahindrapuram B, Wu W, Greer DS, et al. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nature Genetics. 2017 Jan; 49(1): 27-35. doi: 10.1016/j.schres.2013.10.038. DOI: https://doi.org/10.1038/ng1017-1558d

Zhu X, Gu H, Liu Z, Xu Z, Chen X, Sun X, et al. Associations between TCF4 gene polymorphism and cognitive functions in schizophrenia patients and healthy controls. Neuropsychopharmacology. 2013 Mar; 38(4): 683-9. doi: 10.1038/npp.2012.234. DOI: https://doi.org/10.1038/npp.2012.234

Quednow BB, Ettinger U, Mössner R, Rujescu D, Giegling I, Collier DA, et al. The schizophrenia risk allele C of the TCF4 rs9960767 polymorphism disrupts sensorimotor gating in schizophrenia spectrum and healthy volunteers. Journal of Neuroscience. 2011 May; 31(18): 6684-91. doi: 10.1523/JNEUROSCI.0526-11.2011. DOI: https://doi.org/10.1523/JNEUROSCI.0526-11.2011

Maniatis T. Molecular cloning. A laboratory manual. Cold Spring Harbor; 1982.

Hirotsu N, Murakami N, Kashiwagi T, Ujiie K, Ishimaru K. Protocol: a simple gel-free method for SNP genotyping using allele-specific primers in rice and other plant species. Plant Methods. 2010 Dec; 6(1): 1-10. doi: 10.1186/1746-4811-6-12. DOI: https://doi.org/10.1186/1746-4811-6-12

Stefansson H, Ophoff RA, Steinberg S, Andreassen OA, Cichon S, Rujescu D, et al. Common variants conferring risk of schizophrenia. Nature. 2009 Aug; 460(7256): 744-7.

Li T, Li Z, Chen P, Zhao Q, Wang T, Huang K, et al. Common variants in major histocompatibility complex region and TCF4 gene are significantly associated with schizophrenia in Han Chinese. Biological psychiatry. 2010 Oct; 68(7): 671-3. doi: 10.1016/j.biopsych.2010.06.014. DOI: https://doi.org/10.1016/j.biopsych.2010.06.014

Steinberg S, de Jong S, Andreassen OA, Werge T, Børglum AD, Mors O, et al. Common variants at VRK2 and TCF4 conferring risk of schizophrenia. Human Molecular Genetics. 2011 Oct; 20(20): 4076-81. doi: 10.1093/hmg/ddr325. DOI: https://doi.org/10.1093/hmg/ddr325

Ripke S, Sanders AR, Kendler KS, Levinson DF, Sklar P, Holmans P, et al. Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium Genome-wide association study identifies five new schizophrenia loci. Nature Genetics. 2011 Sep; 43: 969-76. doi: 10.1038/ng.940. DOI: https://doi.org/10.1038/ng.940

McInnis MG, Swift-Scanlanl T, Mahoney AT, Vincent J, Verheyen G, Lan TH, et al. Allelic distribution of CTG18. 1 in Caucasian populations: association studies in bipolar disorder, schizophrenia, and ataxia. Molecular Psychiatry. 2000 Jul; 5(4): 439-42. doi: 10.1038/sj.mp.4000747. DOI: https://doi.org/10.1038/sj.mp.4000747

Wirgenes KV, Sønderby IE, Haukvik UK, Mattingsdal M, Tesli M, Athanasiu L, Sundet K, Røssberg JI, Dale AM, Brown AA, Agartz I. TCF4 sequence variants and mRNA levels are associated with neurodevelopmental characteristics in psychotic disorders. Translational Psychiatry. 2012 May; 2(5): e112. doi: 10.1038/tp.2012.39. DOI: https://doi.org/10.1038/tp.2012.39

Shenton ME, Dickey CC, Frumin M, McCarley RW. A review of MRI findings in schizophrenia. Schizophrenia Research. 2001 Apr; 49(1-2): 1-52. doi: 10.1016/S0920-9964(01)00163-3. DOI: https://doi.org/10.1016/S0920-9964(01)00163-3