Ulyanovsk Medico-biological Journal

CLINICAL MEDICINE

Download article

DOI 10.34014/2227-1848-2022-3-6-22

RECONSTRUCTION OF SCHIZOPHRENIA GENE NETWORK IN SEARCH FOR TARGET GENES

A.Yu. Dokhoyan, M.V. Glushchenko, Yu.L. Orlov

Sechenov University, Moscow, Russia

 

Nowadays, schizophrenia is a poorly understood disease with a variety of symptoms attributed to other malconditions, and controversial diagnosis without well-defined treatment. Target therapy implies disease gene network reconstruction, gene clustering, identification of gene ontology categories and genes with the largest number of network contacts.

The aim of the study is to analyze schizophrenia-associated genes, determine their position in the gene network, establish their correlation, identify key genes related to the disease, and evaluate them as target genes for drug therapy.

Materials and Methods. The authors analyzed currently relevant data on schizophrenia using such online databases as OMIM, PANTHER, DAVID, GeneMANIA, STRING-DB, and GeneCards. They calculated categories of gene ontologies for 200 genes, such as biological processes, molecular functions and cellular compartments that reflect schizophrenia impact on the transmission of neuronal impulses. The authors also visualized and built gene networks containing the identified key objects and their interaction, identified the most relevant schizophrenia genes (COMT, DISC1, HTR2A, NRXN1) and a strongly connected cluster, including such genes as BDNF, SLC6A4, HTR2A, HTR2C, CHRM1, SRC, AKT, YWHAE, DISC1, DRD2, COMT, NDEL1, NOS1, CAMK28, etc.

Results. The biological interpretation of the results obtained is still a great challenge, since schizophrenia is a genetically complex disease with numerous causes and triggering events. Analysis of schizophrenia-associated genes, and identification of their position in the gene network (connectivity) makes it possible to find out their interaction, determine the key genes of the disease, and evaluate their prospects as target genes for drug therapy.

Key words: bioinformatics, schizophrenia, gene network reconstruction, gene ontologies

 

References

  1. Schizophrenia: Concise Medical Dictionary. Oxford University Press. 2010. Available at: https://www.oxfordreference.com/view/10.1093/acref/9780199557141.001.0001/acref-9780199557141-e-9060 (accessed: February 12, 2022). DOI: 10.1093/acref/9780199557141.001.0001.

  2. Institute of health Metrics and Evaluation (IHME). Global Health Data Exchange (GHDx). Available at: http://ghdx.healthdata.org/gbd-results-tool?params=gbd-api-2019-permalink/27a7644e8ad28e739382d31e77589dd7 (accessed: February 12, 022).

  3. Picchioni M.M., Murray R.M. Schizophrenia. BMJ. 2007; 335 (7610): 91–95. Available at: https://www. bmj.com/content/335/7610/91 (accessed: February 12, 2022). DOI: 10.1136/bmj.39227.616447.BE.

  4. Castle D., Wesseley S., Der G., Murray R.M. The incidence of operationally defined schizophrenia in Camberwell 1965–84. British Journal of Psychiatry: journal Royal College of Psychiatrists. 1991; 159: 790–794. Available at: https://www.cambridge.org/core/journals/the-british-journal-of-psychiatry/article/abs/incidence-of-operationally-defined-schizophrenia-in-camberwell-196584/6FD5AA8394856650 FE3004A71B49A564 (accessed: February 12, 2022). DOI: 10.1192/bjp.159.6.790.

  5. Gonthier M., Lyon M.A. Childhood‐onset schizophrenia: An overview. Psychology in the Schools. 2004; 41 (7): 803–811. Available at: https://onlinelibrary.wiley.com/doi/10.1002/pits.20013 (accessed: February 13, 2022). DOI: 10.1002/pits.20013.

  6. Mattai A.K., Hill J.L., Lenroot R.K. Treatment of early-onset schizophrenia. Curr Opin Psychiatry. 2010; 23 (4): 304–310. Available at: https://pubmed.ncbi.nlm.nih.gov/20502331 (accessed: February 13, 2022). DOI: 10.1097/YCO.0b013e32833b027e.

  7. Howard R., Rabins P.V., Seeman M.V., Jeste D.V. Late-onset schizophrenia and very-late-onset schizophrenia-like psychosis: an international consensus. The International Late-Onset Schizophrenia Group. Am. J. Psychiatry. 2000; 157 (2): 172–178. Available at: https://pubmed.ncbi.nlm.nih.gov/10671383 (accessed: February 13, 2022). DOI: 10.1176/appi.ajp.157.2.172.

  8. Owen M.J., Sawa A., Mortensen P.B. Schizophrenia. Lancet. 2016; 388 (10039): 86–97. Available at: https://pubmed.ncbi.nlm.nih.gov/26777917/ (accessed: February 14, 2022). DOI: 10.1016/S0140-6736(15)01121-6.

  9. Mullin A.P., Gokhale A., Moreno-De-Luca A., Sanyal S., Waddington J.L., Faundez V. Neurodevelopmental disorders: mechanisms and boundary definitions from genomes, interactomes and proteomes. Transl. Psychiatry. 2013; 3 (12): e329. Available at: https://www.nature.com/articles/tp2013108 (accessed: February 14, 2022). DOI: 10.1038/tp.2013.108.

  10. Davis J., Eyre H., Jacka F.N., Dodd S., Dean O., McEwen S., Debnath M., McGrath J., Maes M., Amminger P., McGorry P.D., Pantelis C., Berk M. A review of vulnerability and risks for schizophrenia: Beyond the two hit hypothesis. Neurosci Biobehav Rev. 2016; 65: 185–194. Available at: https://pubmed.ncbi.nlm.nih.gov/27073049 (accessed: February 14, 2022). DOI: 10.1016/j.neubiorev.2016.03.017.

  11. Van de Leemput J., Hess J.L., Glatt S.J., Tsuang M.T. Genetics of Schizophrenia: Historical Insights and Prevailing Evidence. Adv Genet. 2016; 96: 99–141. Available at: https://pubmed.ncbi.nlm.nih.gov/ 27968732 (accessed: February 16, 2022). DOI: 10.1016/bs.adgen.2016.08.001.

  12. Torrey E.F., Yolken R.H. Schizophrenia as a pseudogenetic disease: A call for more gene-environmental studies. Psychiatry Res. 2019; 278: 146–150. Available at: https://pubmed.ncbi.nlm.nih.gov/31200193 (accessed: February 16, 2022). DOI: 10.1016/j.psychres.2019.06.006.

  13. Combs D.R., Mueser K.T., Gutierrez M.M. Chapter 8: Schizophrenia: Etiological considerations. In: Hersen M., Beidel D.C. Adult psychopathology and diagnosis. 6th ed. John Wiley & Sons; 2011.

  14. Hassett A., Ames D., Chiu E. Psychosis in the Elderly. London: Taylor and Francis; 2005.

  15. Sullivan P.F., Kendler K.S., Neale M.C. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Archives of General Psychiatry. 2003; 60: 1187–1192. Available at: https://jamanet-\work.com/journals/jamapsychiatry/fullarticle/208134 (accessed: February 17, 2022). DOI: 10.1001/archpsyc.60.12.1187.

  16. Thibaut F. Schizophrenia: An example of complex genetic disease. World Journal of Biological Psychiatry. 2006; 7: 194–197. Available at: https://www.tandfonline.com/doi/full/10.1080/15622970600994313 (accessed: February 17, 2022). DOI:10.1080/15622970600994313.

  17. Cross-Disorder Group of the Psychiatric Genomics Consortium. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet. 2013; 381 (9875): 1371–1379. Available at: https://pubmed.ncbi.nlm.nih.gov/23453885 (accessed: February 17, 2022). DOI: 10.1016/S0140-6736(12)62129-1.

  18. Charlson F.J., Ferrari A.J., Santomauro D.F., Diminic S., Stockings E., Scott J.G., McGrath J.J., Whiteford H.A. Global Epidemiology and Burden of Schizophrenia: Findings From the Global Burden of Disease Study 2016. Schizophr Bull. 2018; 44 (6): 1195–1203. Available at: https://www.ncbi.nlm.nih.gov/ pmc/articles/PMC6192504 (accessed: March 10, 2022). DOI: 10.1093/schbul/sby058.

  19. Howes O.D., Kapur S. The dopamine hypothesis of schizophrenia: version III – the final common pathway. Schizophr Bull. 2009; 35 (3): 549–562. Available at: https://pubmed.ncbi.nlm.nih.gov/19325164 (accessed: March 10, 2022). DOI: 10.1093/schbul/sbp006.

  20. Mao Y., Ge X., Frank C.L., Madison J.M., Koehler A.N., Doud M.K., Tassa C., Berry E.M., Soda T., Singh K.K., Biechele T., Petryshen T.L., Moon R.T., Haggarty S.J., Tsai L.H. Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling. Cell. 2009; 136 (6): 1017–1031. Available at: https://pubmed.ncbi.nlm.nih.gov/19303846 (accessed: March 11, 2022). DOI: 10.1016/j.cell.2008.12.044.

  21. Meyer K.D., Morris J.A. Disc1 regulates granule cell migration in the developing hippocampus. Hum Mol Genet. 2009; 18 (17): 3286–3297. Available at: https://academic.oup.com/hmg/article/18/17/3286/2527378 (accessed: March 14, 2022). DOI:10.1093/hmg/ddp266.

Received 22 March 2022; accepted 25 June 2022.

 

Information about the authors

Dokhoyan Anastasiya Yur'evna, Student, Sechenov University. 119991, Russia, Moscow, Trubetskaya St., 8, bld. 2; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: https://orcid.org/0000-0001-6002-5339

Glushchenko Maksim Vital'evich, Student, Sechenov University. 119991, Russia, Moscow, Trubetskaya St., 8, bld. 2; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: https://orcid.org/0000-0003-1900-6149

Orlov Yuriy L'vovich, Doctor of Sciences (Biology), Professor, Russian Academy of Sciences, Sechenov University. 119991, Russia, Moscow, Trubetskaya St., 8, bld. 2; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: https://orcid.org/0000-0003-0587-1609

 

For citation

Dokhoyan A.Yu., Glushchenko M.V., Orlov Yu.L. Rekonstruktsiya gennoy seti shizofrenii dlya poiska genov-misheney [Reconstruction of schizophrenia gene network in search for target genes]. Ul'yanovskiy mediko-biologicheskiy zhurnal. 2022; 3: 6–22. DOI: 10.34014/2227-1848-2022-3-6-22 (in Russian).

 

 

Скачать статью

УДК 616.895.8; 577.218; 577.21; 611.811.013; 57.081.23

DOI 10.34014/2227-1848-2022-3-6-22

РЕКОНСТРУКЦИЯ ГЕННОЙ СЕТИ ШИЗОФРЕНИИ ДЛЯ ПОИСКА ГЕНОВ-МИШЕНЕЙ

А.Ю. Дохоян, М.В. Глущенко, Ю.Л. Орлов

ФГАОУ ВО Первый Московский государственный медицинский университет им. И.М. Сеченова (Сеченовский Университет), г. Москва, Россия

 

На данный момент шизофрения является плохо изученным заболеванием с многообразием симптомов, характерных для иных патологических состояний, и сложной диагностикой без однозначного лечения. Для поиска мишеней терапии необходима реконструкция генной сети заболевания, кластеризация генов в сети, выявление ключевых генов, обладающих наибольшим числом контактов в сети, нахождение категорий генных онтологий.

Цель исследования – анализ генов, связанных с шизофренией, определение их положения в генной сети, установление их взаимосвязи, распознавание ключевых при протекании болезни, оценка их перспективности в качестве генов-мишеней для лекарственных воздействий.

Материалы и методы. С помощью онлайн-инструментов биоинформатики OMIM, PANTHER и DAVID, GeneMANIA и STRING-DB, GeneCards был проанализирован актуальный на данный момент массив данных, связанных с шизофренией, рассчитаны категории генных онтологий для списка из 200 генов, такие как биологические процессы, молекулярные функции и клеточные компартменты, которые отражают влияние шизофрении на передачу нейронных импульсов, визуализированы и построены генные сети, содержащие выявленные ключевые объекты и их взаимосвязи, выделен сильно связанный кластер, включающий гены BDNF, SLC6A4, HTR2A, HTR2C, CHRM1, SRC, AKT, YWHAE, DISC1, DRD2, COMT, NDEL1, NOS1, CAMK28 и др., определены наиболее релевантные гены шизофрении: COMT, DISC1, HTR2A, NRXN1.

Результаты. Биологическая интерпретация полученных результатов все еще остается сложной задачей, так как шизофрения является генетически сложной болезнью с большой расходимостью причин и условий возникновения. Анализ генов, связанных с шизофренией, определение их положения в генной сети (связанности) позволяет выявить их взаимосвязь, установить, какие из них являются ключевыми при протекании болезни, оценить их перспективность в качестве генов-мишеней для лекарственных воздействий.

Ключевые слова: биоинформатика, шизофрения, реконструкция генных сетей, генные онтологии.

 

Литература

  1. Schizophrenia: Concise Medical Dictionary. Oxford University Press. 2010. URL: https://www.oxford-reference.com/view/10.1093/acref/9780199557141.001.0001/acref-9780199557141-e-9060 (дата обращения: 12.02.2022). DOI: 10.1093/acref/9780199557141.001.0001.

  2. Institute of health Metrics and Evaluation (IHME). Global Health Data Exchange (GHDx). URL: http://ghdx.healthdata.org/gbd-results-tool?params=gbd-api-2019-permalink/27a7644e8ad28e739382d31e77589dd7 (дата обращения: 12.02.2022).

  3. Picchioni M.M., Murray R.M. Schizophrenia. BMJ. 2007; 335 (7610): 91–95. URL: https://www.bmj.com/

    content/335/7610/91 (дата обращения: 12.02.2022). DOI: 10.1136/bmj.39227.616447.BE.

  4. Castle D., Wesseley S., Der G., Murray R.M. The incidence of operationally defined schizophrenia in Camberwell 1965–84. British Journal of Psychiatry: journal Royal College of Psychiatrists. 1991; 159: 790–794. URL: https://www.cambridge.org/core/journals/the-british-journal-of-psychiatry/article/abs/ incidence-of-operationally-defined-schizophrenia-in-camberwell-196584/6FD5AA8394856650FE3004A71B49A564 (дата обращения: 12.02.2022). DOI: 10.1192/bjp.159.6.790.

  5. Gonthier M., Lyon M.A. Childhood‐onset schizophrenia: An overview. Psychology in the Schools. 2004; 41 (7): 803–811. URL: https://onlinelibrary.wiley.com/doi/10.1002/pits.20013 (дата обращения: 13.02.2022). DOI: 10.1002/pits.20013.

  6. Mattai A.K., Hill J.L., Lenroot R.K. Treatment of early-onset schizophrenia. Curr Opin Psychiatry. 2010; 23 (4): 304–310. URL: https://pubmed.ncbi.nlm.nih.gov/20502331 (дата обращения: 13.02.2022). DOI: 10.1097/YCO.0b013e32833b027e.

  7. Howard R., Rabins P.V., Seeman M.V., Jeste D.V. Late-onset schizophrenia and very-late-onset schizophrenia-like psychosis: an international consensus. The International Late-Onset Schizophrenia Group. Am. J. Psychiatry. 2000; 157 (2): 172–178. URL: https://pubmed.ncbi.nlm.nih.gov/10671383 (дата обращения: 13.02.2022). DOI: 10.1176/appi.ajp.157.2.172.

  8. Owen M.J., Sawa A., Mortensen P.B. Schizophrenia. Lancet. 2016; 388 (10039): 86–97. URL: https://pubmed.ncbi.nlm.nih.gov/26777917/ (дата обращения: 14.02.2022). DOI: 10.1016/S0140-6736(15)01121-6.

  9. Mullin A.P., Gokhale A., Moreno-De-Luca A., Sanyal S., Waddington J.L., Faundez V. Neurodevelopmental disorders: mechanisms and boundary definitions from genomes, interactomes and proteomes. Transl. Psychiatry. 2013; 3 (12): e329. URL: https://www.nature.com/articles/tp2013108 (дата обращения: 14.02.2022). DOI: 10.1038/tp.2013.108.

  10. Davis J., Eyre H., Jacka F.N., Dodd S., Dean O., McEwen S., Debnath M., McGrath J., Maes M., Amminger P., McGorry P.D., Pantelis C., Berk M. A review of vulnerability and risks for schizophrenia: Beyond the two hit hypothesis. Neurosci Biobehav Rev. 2016; 65: 185–194. URL: https://pubmed.ncbi.nlm.nih.gov/27073049 (дата обращения: 14.02.2022). DOI: 10.1016/j.neubiorev.2016.03.017.

  11. Van de Leemput J., Hess J.L., Glatt S.J., Tsuang M.T. Genetics of Schizophrenia: Historical Insights and Prevailing Evidence. Adv Genet. 2016; 96: 99–141. URL: https://pubmed.ncbi.nlm.nih.gov/27968732 (дата обращения: 16.02.2022). DOI: 10.1016/bs.adgen.2016.08.001.

  12. Torrey E.F., Yolken R.H. Schizophrenia as a pseudogenetic disease: A call for more gene-environmental studies. Psychiatry Res. 2019; 278: 146–150. URL: https://pubmed.ncbi.nlm.nih.gov/31200193 (дата обращения: 16.02.2022). DOI: 10.1016/j.psychres.2019.06.006.

  13. Combs D.R., Mueser K.T., Gutierrez M.M. Chapter 8: Schizophrenia: Etiological considerations. In: Hersen M., Beidel D.C. Adult psychopathology and diagnosis. 6th ed. John Wiley & Sons; 2011.

  14. Hassett A., Ames D., Chiu E. Psychosis in the Elderly. London: Taylor and Francis; 2005.

  15. Sullivan P.F., Kendler K.S., Neale M.C. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Archives of General Psychiatry. 2003; 60: 1187–1192. URL: https://jamanetwork.com/journals/jamapsychiatry/fullarticle/208134 (дата обращения: 17.02.2022). DOI: 10.1001/archpsyc.60.12.1187.

  16. Thibaut F. Schizophrenia: An example of complex genetic disease. World Journal of Biological Psychiatry. 2006; 7: 194–197. URL: https://www.tandfonline.com/doi/full/10.1080/15622970600994313 (дата обращения: 17.02.2022). DOI:10.1080/15622970600994313.

  17. Cross-Disorder Group of the Psychiatric Genomics Consortium. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet. 2013; 381 (9875): 1371–1379. URL: https://pubmed.ncbi.nlm.nih.gov/23453885 (дата обращения: 17.02.2022). DOI: 10.1016/S0140-6736(12)62129-1.

  18. Charlson F.J., Ferrari A.J., Santomauro D.F., Diminic S., Stockings E., Scott J.G., McGrath J.J., Whiteford H.A. Global Epidemiology and Burden of Schizophrenia: Findings From the Global Burden of Disease Study 2016. Schizophr Bull. 2018; 44 (6): 1195–1203. URL: https://www.ncbi.nlm.nih.gov/ pmc/articles/PMC6192504 (дата обращения: 10.03.2022). DOI: 10.1093/schbul/sby058.

  19. Howes O.D., Kapur S. The dopamine hypothesis of schizophrenia: version III – the final common pathway. Schizophr Bull. 2009; 35 (3): 549–562. URL: https://pubmed.ncbi.nlm.nih.gov/19325164 (дата обращения: 10.03.2022). DOI: 10.1093/schbul/sbp006.

  20. Mao Y., Ge X., Frank C.L., Madison J.M., Koehler A.N., Doud M.K., Tassa C., Berry E.M., Soda T., Singh K.K., Biechele T., Petryshen T.L., Moon R.T., Haggarty S.J., Tsai L.H. Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling. Cell. 2009; 136 (6): 1017–1031. URL: https://pubmed.ncbi.nlm.nih.gov/19303846 (дата обращения: 11.03.2022). DOI: 10.1016/j.cell.2008.12.044.

  21. Meyer K.D., Morris J.A. Disc1 regulates granule cell migration in the developing hippocampus. Hum Mol Genet. 2009; 18 (17): 3286–3297. URL: https://academic.oup.com/hmg/article/18/17/3286/2527378 (дата обращения: 14.03.2022). DOI:10.1093/hmg/ddp266.

 

Поступила в редакцию 22.03.2022; принята 25.06.2022.

Авторский коллектив

Дохоян Анастасия Юрьевна – студентка, ФГАОУ ВО Первый Московский государственный медицинский университет им. И.М. Сеченова (Сеченовский Университет). 119991, Россия, г. Москва, ул. Трубецкая, 8, стр. 2; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: https://orcid.org/0000-0001-6002-5339

Глущенко Максим Витальевич – студент, ФГАОУ ВО Первый Московский государственный медицинский университет им. И.М. Сеченова (Сеченовский Университет). 119991, Россия, г. Москва, ул. Трубецкая, 8, стр. 2; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: https://orcid.org/0000-0003-1900-6149

Орлов Юрий Львович – доктор биологических наук, профессор РАН, ФГАОУ ВО Первый Московский государственный медицинский университет им. И.М. Сеченова (Сеченовский Университет). 119991, Россия, г. Москва, ул. Трубецкая, 8, стр. 2; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: https://orcid.org/0000-0003-0587-1609

 

Образец цитирования

Дохоян А.Ю., Глущенко М.В., Орлов Ю.Л. Реконструкция генной сети шизофрении для поиска генов-мишеней. Ульяновский медико-биологический журнал. 2022; 3: 6–22. DOI: 10.34014/2227-1848-2022-3-6-22.