Genotype Variations of rs13381800 in TCF4 Gene and rs17039988 in NRXN1 Gene among a Sample of Iranian Patients with Schizophrenia
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Abstract
Objective: Schizophrenia is a complicated mental disorder that affects about 1% of the world's population. It is a complex disease and is approximately 80% inherited. One of the candidate genes in schizophrenia is transcription factor 4 (TCF4), which is positioned on chromosome 18 and is a transcription factor that plays a role in the transcription of Neurexin 1(NRXN1) gene, which is one of the candidate genes for developing schizophrenia. This case-control study aimed to investigate the correlation of TCF4 rs13381800 and NRXN1 rs17039988 polymorphisms with the risk of schizophrenia in a sample of Iranian patients with schizophrenia.
Method: A total of 200 individuals were included in this study: 100 patients with schizophrenia (65 males and 35 females), with the mean age of 40.80 ± 11.298 years, and 100 as a control group (63 males and 37 females), with the mean age 32.92 ± 7.391 years. Allele specific polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) were done, respectively, for genotyping of rs13381800 (T/C) and rs17039988 (A/C) polymorphisms.
Results: The results showed that the frequency of C / C genotype in rs13381800 in patients’ group was 9%, while it was 13% in the control group. Also, the frequency of C / C genotype in rs17039988 was 9% in patients and 7% in control groups. Statistical analysis of polymorphisms showed no correlation between patients and controls in rs13381800 (OR = 1.51; CI = 95%; P = 0.366) and rs17039988 (OR = 0.76; CI = 95%; P = 0.602).
Conclusion: No significant difference was found between rs13381800 and rs17039988 genotypes between patients and control groups in terms of gender, age and education in the patients group. Our study suggests that there was no correlation between desired polymorphisms with schizophrenia in the studied population.
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3. Dickson H, Laurens KR, Cullen AE, Hodgins S. Meta-analyses of cognitive and motor function in youth aged 16 years and younger who subsequently develop schizophrenia. Psychological Medicine. 2012;42(4):743-755.
4. Cardno AG, Owen MJ. Genetic relationships between schizophrenia, bipolar disorder, and schizoaffective disorder. Schizophr Bull. 2014;40(3):504-15.
5. St Pourcain B, Eaves LJ, Ring SM, Fisher SE, Medland S, Evans DM, et al. Developmental Changes Within the Genetic Architecture of Social Communication Behavior: A Multivariate Study of Genetic Variance in Unrelated Individuals. Biol Psychiatry. 2018;83(7):598-606.
6. Singha S, Kumara A, Agarwala S, Phadke SR, Jaiswal Y. Genetic insight of schizophrenia: past and future perspectives. Gene. 2014;535(2):97-100.
7. Harrison PJ. Recent genetic findings in schizophrenia and their therapeutic relevance. J Psychopharmacol. 2015;29(2):85-96.
8. Sullivan PF, Daly MJ, O'Donovan M. Genetic architectures of psychiatric disorders: the emerging picture and its implications. Nat Rev Genet. 2012;13(8):537-51.
9. Rodriguez-Murillo L, Gogos JA, Karayiorgou M. The Genetic Architecture of Schizophrenia: New Mutations and Emerging Paradigms. Annu Rev Med. 2012;63:63-80.
10. 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. Am J Med Genet B Neuropsychiatr Genet. 2013;162B(1):1-16.
11. Verzi MP, Hatzis P, Sulahian R, Philips J, Schuijers J, Shin H, et al. TCF4 and CDX2, major transcription factors for intestinal function, converge on the same cis regulatory regions. Proc Natl Acad Sci U S A. 2010 ;107(34):15157-62.
12. Panaccione I, Napoletano F, Forte AM, Kotzalidis GD, Del Casale A, Rapinesi C, et al. Neurodevelopment in Schizophrenia: The Role of the Wnt Pathways. Curr Neuropharmacol. 2013;11(5):535-58.
13. D’Rozario M, Zhang T, Waddell EA, Zhang Y, Sahin C, Sharoni M, Marenda DR. Type I bHLH proteins Daughterless and TCF4 restrict neurite branching and synapse formation by repressing Neurexin in postmitotic neurons Cell Rep. 2016;15(2):386-97.
14. Forrest M, Chapman RM, Doyle AM, Tinsley CL, Waite A, Blake DJ. Functional analysis of TCF4 missense mutations that cause Pitt-Hopkins syndrome. Hum Mutat. 2012;33(12):1676-86.
15. Ching MS, Shen Y, Tan WH, Jeste SS, Morrow EM, Chen X, et al. Deletions of NRXN1 (neurexin-1) predispose to a wide spectrum of developmental disorders. Am J Med Genet B Neuropsychiatr Genet. 2010;153B(4):937-47.
16. Tucker T, Zahir FR, Griffith M, Delaney A, Chai D, Tsang E, Friedman JM. Single exon-resolution targeted chromosomal microarray analysis of known and candidate intellectual disability genes. Eur J Hum Genet. 2014;22(6):792-800.
17. Südhof TC. Neuroligins and neurexins link synaptic function to cognitive disease. Nature. 2008;455(7215):903-11.
18. de Wit J, Sylwestrak E, O'Sullivan ML, Otto S, Tiglio K, Savas JN, et al. LRRTM2 Interacts with Neurexin1 and Regulates Excitatory Synapse Formation. Neuron. 2009;64(6):799-806.
19. Steinberg S, de Jong S; Irish Schizophrenia Genomics Consortium, Andreassen OA, Werge T, Børglum AD, e. Common variants at VRK2 and TCF4 conferring risk of schizophrenia. Hum Mol Genet. 2011;20(20):4076-81.
20. Wirgenes KV, Sonderby IE, Haukvik UK, Mattingsdal M, Tesli M, Athanasiu L, et al. TCF4 sequence variants and mRNA levels are associated with neurodevelopmental characteristics in psychotic disorders. Transl Psychiatry. 2012;2:e112.
21. Stefansson H, Ophoff RA, Steinberg S, Andreassen OA, Cichon S, Rujescu D, et al. Common variants conferring risk of schizophrenia. Nature. 2009;460(7256):744-7.
22. Li J, Chen Z, Wang F, Ouyang Y, Zhang N, Yang M, et al. Polymorphisms of the TCF4 Gene Are Associated With the Risk of Schizophrenia in the Han Chinese. Am J Med Genet B Neuropsychiatr Genet. 2016;171(8):1006-1012.
23. Liu L, Li J, Yan M, Li J, Chen J, Zhang Y, et al. TCF7L2 polymorphisms and the risk of schizophrenia in the Chinese Han population. Oncotarget. 2017;8(17):28614-28620..
24. Shah AK, Tioleco NM, Nolan K, Locker J, Groh K, Villa C, Lachman HM. Rare NRXN1 promoter variants in patients with schizophrenia. Neurosci Lett. 2010;475(2):80-4.
25. Yue W, Yang Y, Zhang Y, Lu T, Hu X, Wang L, et al. A case-control association study of NRXN1 polymorphisms with schizophrenia in Chinese Han population. Behav Brain Funct. 2011; 7: 7.
26. Lanning R, Lett TA, Tiwari AK, Brandl EJ, de Luca V, Voineskos AN, et al. Association study between the neurexin-1 gene and tardive dyskinesia. Hum Psychopharmacol. 2017;32(1): 10.1002/hup.2568.
27. Lennertz L, Rujescu D, Wagner M, Frommann I, Schulze-Rauschenbach S, Schuhmacher A, et al. Novel Schizophrenia Risk Gene TCF4 Influences Verbal Learning and Memory Functioning in Schizophrenia Patients. Neuropsychobiology. 2011;63(3):131-6.
28. Cousijn H, Eissing M, Fernández G, Fisher SE, Franke B, Zwiers M, et al. No effect of schizophrenia risk genes MIR137, TCF4, and ZNF804A on macroscopic brain structure. Schizophr Res. 2014;159(2-3):329-32.
29. Michalak-Wojnowska M, Gorczyca-Siudak D, Gorczyca T, Mosiewicz B, Kwaśniewska A, Filip A, et al. Association between rs7901695 and rs7903146 polymorphisms of the TCF7L2 gene and gestational diabetes in the population of Southern Poland. Ginekol Pol. 2016;87(11):745-50.
30. RaoBS, Tharigopala A, Rachapalli S, RajagopalR, Soumittra N. Association of polymorphisms in the intron of TCF4 gene to late-onset Fuchs endothelial corneal dystrophy: An Indian cohort study. Indian J Ophthalmol. 2017;65(10):931-5.
31. Lukacs K, Hosszufalusi N, Dinya E, Bakacs M, Madacsy L, Panczel P. The type 2 diabetes-associated variant in TCF7L2 is associated with latent autoimmune diabetes in adult Europeans and the gene effect is modified by obesity: a meta-analysis and an individual study. Diabetologia. 2012;55(3):689-93.
32. Torres K, Labrador L,Valderrama E, Chiurillo MA. TCF7L2 rs7903146 polymorphism is associated with gastric cancer: A case-control study in the Venezuelan population. World J Gastroenterol. 2016;22(28):6520-6.
33. Blake DJ, Forrest M, Chapman RM, Tinsley CL, O'Donovan MC, Owen MJ. TCF4, schizophrenia, and Pitt-Hopkins Syndrome. Schizophr Bull. 2010;36(3):443-7.
34. Nussbaum J, Xu Q, Payne TJ, Ma JZ, Huang W, Gelernter J, et al. Significant association of the neurexin-1 gene (NRXN1) with nicotine dependence in European- and African-American smokers. Hum Mol Genet. 2008;17(11):1569-77.
35. Li Y, Liu H, Dong Y. Significance of neurexin and neuroligin polymorphisms in regulating risk of Hirschsprung's disease. J Investig Med. 2018;66(5):1-8.
36. Neininger K, Marschall T, Helms V. SNP and indel frequencies at transcription start sites and at canonical and alternative translation initiation sites in the human genome. PLoS One. 2019;14(4):e0214816.
37. Altrock PM, Traulsen A, Reed FA. Stability Properties of Underdominance in Finite Subdivided Populations. PLoS Comput Biol. 2011;7(11):e1002260.
2. Li R, Ma X, Wang G, Yang J, Wang C. Why sex differences in schizophrenia?. J Transl Neurosci (Beijing). 2016;1(1):37-42.
3. Dickson H, Laurens KR, Cullen AE, Hodgins S. Meta-analyses of cognitive and motor function in youth aged 16 years and younger who subsequently develop schizophrenia. Psychological Medicine. 2012;42(4):743-755.
4. Cardno AG, Owen MJ. Genetic relationships between schizophrenia, bipolar disorder, and schizoaffective disorder. Schizophr Bull. 2014;40(3):504-15.
5. St Pourcain B, Eaves LJ, Ring SM, Fisher SE, Medland S, Evans DM, et al. Developmental Changes Within the Genetic Architecture of Social Communication Behavior: A Multivariate Study of Genetic Variance in Unrelated Individuals. Biol Psychiatry. 2018;83(7):598-606.
6. Singha S, Kumara A, Agarwala S, Phadke SR, Jaiswal Y. Genetic insight of schizophrenia: past and future perspectives. Gene. 2014;535(2):97-100.
7. Harrison PJ. Recent genetic findings in schizophrenia and their therapeutic relevance. J Psychopharmacol. 2015;29(2):85-96.
8. Sullivan PF, Daly MJ, O'Donovan M. Genetic architectures of psychiatric disorders: the emerging picture and its implications. Nat Rev Genet. 2012;13(8):537-51.
9. Rodriguez-Murillo L, Gogos JA, Karayiorgou M. The Genetic Architecture of Schizophrenia: New Mutations and Emerging Paradigms. Annu Rev Med. 2012;63:63-80.
10. 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. Am J Med Genet B Neuropsychiatr Genet. 2013;162B(1):1-16.
11. Verzi MP, Hatzis P, Sulahian R, Philips J, Schuijers J, Shin H, et al. TCF4 and CDX2, major transcription factors for intestinal function, converge on the same cis regulatory regions. Proc Natl Acad Sci U S A. 2010 ;107(34):15157-62.
12. Panaccione I, Napoletano F, Forte AM, Kotzalidis GD, Del Casale A, Rapinesi C, et al. Neurodevelopment in Schizophrenia: The Role of the Wnt Pathways. Curr Neuropharmacol. 2013;11(5):535-58.
13. D’Rozario M, Zhang T, Waddell EA, Zhang Y, Sahin C, Sharoni M, Marenda DR. Type I bHLH proteins Daughterless and TCF4 restrict neurite branching and synapse formation by repressing Neurexin in postmitotic neurons Cell Rep. 2016;15(2):386-97.
14. Forrest M, Chapman RM, Doyle AM, Tinsley CL, Waite A, Blake DJ. Functional analysis of TCF4 missense mutations that cause Pitt-Hopkins syndrome. Hum Mutat. 2012;33(12):1676-86.
15. Ching MS, Shen Y, Tan WH, Jeste SS, Morrow EM, Chen X, et al. Deletions of NRXN1 (neurexin-1) predispose to a wide spectrum of developmental disorders. Am J Med Genet B Neuropsychiatr Genet. 2010;153B(4):937-47.
16. Tucker T, Zahir FR, Griffith M, Delaney A, Chai D, Tsang E, Friedman JM. Single exon-resolution targeted chromosomal microarray analysis of known and candidate intellectual disability genes. Eur J Hum Genet. 2014;22(6):792-800.
17. Südhof TC. Neuroligins and neurexins link synaptic function to cognitive disease. Nature. 2008;455(7215):903-11.
18. de Wit J, Sylwestrak E, O'Sullivan ML, Otto S, Tiglio K, Savas JN, et al. LRRTM2 Interacts with Neurexin1 and Regulates Excitatory Synapse Formation. Neuron. 2009;64(6):799-806.
19. Steinberg S, de Jong S; Irish Schizophrenia Genomics Consortium, Andreassen OA, Werge T, Børglum AD, e. Common variants at VRK2 and TCF4 conferring risk of schizophrenia. Hum Mol Genet. 2011;20(20):4076-81.
20. Wirgenes KV, Sonderby IE, Haukvik UK, Mattingsdal M, Tesli M, Athanasiu L, et al. TCF4 sequence variants and mRNA levels are associated with neurodevelopmental characteristics in psychotic disorders. Transl Psychiatry. 2012;2:e112.
21. Stefansson H, Ophoff RA, Steinberg S, Andreassen OA, Cichon S, Rujescu D, et al. Common variants conferring risk of schizophrenia. Nature. 2009;460(7256):744-7.
22. Li J, Chen Z, Wang F, Ouyang Y, Zhang N, Yang M, et al. Polymorphisms of the TCF4 Gene Are Associated With the Risk of Schizophrenia in the Han Chinese. Am J Med Genet B Neuropsychiatr Genet. 2016;171(8):1006-1012.
23. Liu L, Li J, Yan M, Li J, Chen J, Zhang Y, et al. TCF7L2 polymorphisms and the risk of schizophrenia in the Chinese Han population. Oncotarget. 2017;8(17):28614-28620..
24. Shah AK, Tioleco NM, Nolan K, Locker J, Groh K, Villa C, Lachman HM. Rare NRXN1 promoter variants in patients with schizophrenia. Neurosci Lett. 2010;475(2):80-4.
25. Yue W, Yang Y, Zhang Y, Lu T, Hu X, Wang L, et al. A case-control association study of NRXN1 polymorphisms with schizophrenia in Chinese Han population. Behav Brain Funct. 2011; 7: 7.
26. Lanning R, Lett TA, Tiwari AK, Brandl EJ, de Luca V, Voineskos AN, et al. Association study between the neurexin-1 gene and tardive dyskinesia. Hum Psychopharmacol. 2017;32(1): 10.1002/hup.2568.
27. Lennertz L, Rujescu D, Wagner M, Frommann I, Schulze-Rauschenbach S, Schuhmacher A, et al. Novel Schizophrenia Risk Gene TCF4 Influences Verbal Learning and Memory Functioning in Schizophrenia Patients. Neuropsychobiology. 2011;63(3):131-6.
28. Cousijn H, Eissing M, Fernández G, Fisher SE, Franke B, Zwiers M, et al. No effect of schizophrenia risk genes MIR137, TCF4, and ZNF804A on macroscopic brain structure. Schizophr Res. 2014;159(2-3):329-32.
29. Michalak-Wojnowska M, Gorczyca-Siudak D, Gorczyca T, Mosiewicz B, Kwaśniewska A, Filip A, et al. Association between rs7901695 and rs7903146 polymorphisms of the TCF7L2 gene and gestational diabetes in the population of Southern Poland. Ginekol Pol. 2016;87(11):745-50.
30. RaoBS, Tharigopala A, Rachapalli S, RajagopalR, Soumittra N. Association of polymorphisms in the intron of TCF4 gene to late-onset Fuchs endothelial corneal dystrophy: An Indian cohort study. Indian J Ophthalmol. 2017;65(10):931-5.
31. Lukacs K, Hosszufalusi N, Dinya E, Bakacs M, Madacsy L, Panczel P. The type 2 diabetes-associated variant in TCF7L2 is associated with latent autoimmune diabetes in adult Europeans and the gene effect is modified by obesity: a meta-analysis and an individual study. Diabetologia. 2012;55(3):689-93.
32. Torres K, Labrador L,Valderrama E, Chiurillo MA. TCF7L2 rs7903146 polymorphism is associated with gastric cancer: A case-control study in the Venezuelan population. World J Gastroenterol. 2016;22(28):6520-6.
33. Blake DJ, Forrest M, Chapman RM, Tinsley CL, O'Donovan MC, Owen MJ. TCF4, schizophrenia, and Pitt-Hopkins Syndrome. Schizophr Bull. 2010;36(3):443-7.
34. Nussbaum J, Xu Q, Payne TJ, Ma JZ, Huang W, Gelernter J, et al. Significant association of the neurexin-1 gene (NRXN1) with nicotine dependence in European- and African-American smokers. Hum Mol Genet. 2008;17(11):1569-77.
35. Li Y, Liu H, Dong Y. Significance of neurexin and neuroligin polymorphisms in regulating risk of Hirschsprung's disease. J Investig Med. 2018;66(5):1-8.
36. Neininger K, Marschall T, Helms V. SNP and indel frequencies at transcription start sites and at canonical and alternative translation initiation sites in the human genome. PLoS One. 2019;14(4):e0214816.
37. Altrock PM, Traulsen A, Reed FA. Stability Properties of Underdominance in Finite Subdivided Populations. PLoS Comput Biol. 2011;7(11):e1002260.
| Files | ||
| Issue | Vol 14 No 4 (2019) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijps.v14i4.1976 | |
| Keywords | ||
| Neurexin 1 rs13381800 rs17039988 Schizophrenia Transcription Factor 4 | ||
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How to Cite
1.
Agahi M, Noormohammadi Z, Salahshourifar I, Mahdavi-Hezaveh N. Genotype Variations of rs13381800 in TCF4 Gene and rs17039988 in NRXN1 Gene among a Sample of Iranian Patients with Schizophrenia. Iran J Psychiatry. 2019;14(4):265-273.
