Association of СОМТ, DRD2/ANKK1, MTHFR, MIR 137, DNMT3B polymorphisms with the clinical features of schizophrenia patients in acute stage and remission

Updated view of genetic features of schizophrenia based on rare SNPs/CNVs with a huge influence on a disease and common SNPs with a small effect of each allele is presented. Altogether these genetic factors are acting to create neuropathophysiological disturbances observed in schizophrenia. Association of five polymorphisms MIR137 rs1625579, DRD2/ANKK1 rs1800497, MTHFR rs1801133, DNMT3B rs2424913, СОМТ rs4680 with the risk of schizophrenia in the Belarusian population, the level of symptoms of schizophrenia patients assessed by PANSS in the acute stage and remission, cognitive impairments, and treatment trajectory of schizophrenia patients during antipsychotic treatment were analyzed. The A/A-genotype of СОМТ rs4680 (р = 0.008) and the С/С-genotype of MTHFR rs1801133 (р = 0.02) are associated with the risk of schizophrenia among Belarusians. The T-allele of MTHFR rs1801133 is a risk factor of positive symptoms (р = 0.02). Combining the C/C-genotype (DNMT3B rs2424913) and the G-allele (COMT rs4680) is associated with a significant difference in negative symptoms level between men and women. The polymorphism of СОМТ rs4680 (р < 0.05) and the combination of СОМТ rs4680 + DRD2/ANKK1 rs1800497 (р = 0.005) as well as MTHFR rs1801133 + DNMT3B rs2424913 (р = 0.006) are related to the cognitive parameters measured by the WCST and Stroop test respectively. Schizophrenia patients who are the G-allele carriers of MIR137 rs1625579 demonstrated a more favorable negative symptom trajectory in comparison to Т/Тhomozygotes (F = 2.2, p = 0.03). The trajectory of negative symptoms (F = 2.2, p = 0.03) and general psychopathological symptoms (F = 4.3, p = 0.0001) is different between men and women under antipsychotic treatment. These differences are associated with a minor amount of alleles of MIR137 rs1625579, DRD2/ANKK1 rs1800497, MTHFR rs1801133 polymorphic sites.

schizophrenia, MIR137, DNMT3B, MTHFR, COMT, DRD2/ANKK1, PANSS, acute stage, remission, cognitive functioning, maintaining antipsychotic treatment

1. Diagnosis and treatment of schizophrenia: clinical guidelines. Available at: https://rokpb.ru/doc/Klin_rek/Shizofr.pdf (accessed 12 January 2021) (in Russian).

2. Osmanova D. Z., Tiguntsev V. V., Mikhalitskaia E. V., Pozhidaev I. V., Vyalova N. M., Stegniy V. N. The role of dopamine receptor genes in clinical polymorphism of schizophrenia, response to pharmacotherapy and antipsyhotic-induced side effects. Nauchnoe obozrenie. Biologicheskie nauki = Scientific Review. Biological science, 2018, no. 5, pp. 22–27 (in Russian).

3. Davis K. L., Kahn R. S., Ko G., Davidson M. Dopamine in schizophrenia: a review and reconceptualization. American Journal of Psychiatry, 1991, vol. 148, no. 11, pp. 1474–1486. https://doi.org/10.1176/ajp.148.11.1474

4. Nkam I., Ramoz N., Breton F., Mallet J., Gorwood P., Dubertret C. Impact of DRD2/ANKK1 and COMT Polymorphisms on Attentionand Cognitive Functions in Schizophrenia. PLoSONE, 2017, vol. 12, no. 1, pp. 147–170. https://doi.org/10.1371/journal.pone.0170147

5. Huang E., Clement C. Z., Lisoway A., Maciukiewicz M., Felsky D., Tiwari K. A., Bishop R. J., Ikeda M., Molero P., Ortuno F., Porcelli S., Samochowiec J., Mierzejewski P., Gao S., Crespo-Facorro B., Pelayo-Terán M. J., Kaur H., Kukreti R., Meltzer Y. H., Lieberman A. J., Potkin G. S., Müller J. D., Kennedy L. J. Catechol-O-Methyltransferase Val158Met Polymorphism and Clinical Response to Antipsychotic Treatment in Schizophrenia and Schizo-Affective Disorder Patients: a Meta-Analysis. International Journal of Neuropsychopharmacology, 2016, vol. 19, no. 5, pyv132. https://doi.org/10.1093/ijnp/pyv132

6. Harrison P. J., Tunbridge E. M. Catechol-O-methyltransferase (COMT): a gene contributing to sex differences in brain function, and to sexual dimorphism in the predisposition to psychiatric disorders. Neuropsychopharmacology, 2008, vol. 33, no. 13, pp. 3037–3045. https://doi.org/10.1038/sj.npp.1301543

7. Molero P., Ortuño F., Zalacain M., Patiño-García A. Clinical involvement of catechol-O-methyltransferase polymorphisms in schizophrenia spectrum disorders: influence on the severity of psychotic symptoms and on the response to neuroleptic treatment. Pharmacogenomics Journal, 2007, vol. 7, no. 6, pp. 418–426. https://doi.org/10.1038/sj.tpj.6500441

8. González-Castro T. B., Hernández-Díaz Y., Juárez-Rojop I. E., López-Narváez M. L., Tovilla-Zárate C. A., Fresan A. The Role of a Catechol-O-Methyltransferase (COMT) Val158Met Genetic Polymorphism in Schizophrenia: A Systematic Review and Updated Meta-analysis on 32,816 Subjects. Neuromolecular Medicine, 2016, vol. 18, no. 2, pp. 216–231. https://doi.org/10.1007/s12017-016-8392-z

9. Coppede F., Zitarosa M.-T., Migheli F., Gerfo A. L., Bagnoli S., Dardano A., Nacmias B., Mancuso M., Monzani F., Siciliano G., Sorbi S., Migliore L. DNMT3B promoter polymorphisms and risk of late onset Alzheimer’s disease. Current Alzheimer Research, 2012, vol. 9, no. 5, pp. 550–554. https://doi.org/10.2174/156720512800618062

10. Yadav U., Kumar P., Gupta S., Rai V. Role of MTHFR C677T gene polymorphism in the susceptibility of schizophrenia: an updated meta-analysis. Asian Journal of Psychiatry, 2016, vol. 20, pp. 41–51. https://doi.org/10.1016/j.ajp.2016.02.002

11. Biological insights from 108 schizophrenia-associated genetic loci. Nature, 2014, vol. 511, no. 7510, pp. 421–427. https://doi.org/10.1038/nature13595

12. Guan F., Zhang B., Yan T., Li L., Liu F., Li T., Feng Z., Zhang B., Liu X., Li S. MIR137 gene and target gene CACNA1C of miR-137 contribute to schizophrenia susceptibility in Han Chinese. Schizophrenia Research, 2014, vol. 152, no. 1, pp. 97–104. https://doi.org/10.1016/j.schres.2013.11.004

13. Warburton A., Breen G., Bubb V. J., Quinn J. P. A GWAS SNP for Schizophrenia is Linked to the Internal MIR137 Promoter and Supports Differential Allele-Specific Expression. Schizophrenia Bulletin, 2016, vol. 42, no. 4, pp. 1003–1008. https://doi.org/10.1093/schbul/sbv144

14. Liu B., Zhang X., Hou B., Li J., Qiu C., Qin W., Yu C., Jiang T. The impact of MIR137 on dorsolateral prefrontal-hippocampal functional connectivity in healthy subjects. Neuropsychopharmacology, 2014, vol. 39, no. 9, pp. 2153–2160. https://doi.org/10.1038/npp.2014.63