Russian Journal of GeneticsRussian Journal of GeneticsГенетика0016-67583034-5103The Russian Academy of Sciences66706810.31857/S0016675823100053UEZTIUГЕНЕТИКА ЧЕЛОВЕКАGenome-Wide Association Study: Analysis of Association of Polymorphic Loci in 4p15.2 and 20q13.31 Regions with Paranoid SchizophreniaПолногеномное ассоциативное исследование: анализ ассоциации параноидной шизофрении с полиморфными локусами, локализованными в хромосомных областях 4p15.2 и 20q13.31GareevaA. E.ГарееваА. Э.annagareeva@yandex.ruInstitute of Biochemistry and Genetics, Ufa Federal Research Center of the Russian Academy of SciencesИнститут биохимии и генетики Уфимского федерального исследовательского центра Российской академии наукBashkir State Medical UniversityБашкирский государственный медицинский университет Минздрава России0110202359101179119026022025Copyright ©; 2023, А.Э. ГарееваCopyright ©; 2023, А.Э. Гареева2023А.Э. ГарееваА.Э. Гарееваhttps://transsyst.ru/0016-6758/article/view/667068

Over fifteen years, genome-wide association studies (GWAS) have identified several million polymorphic risk markers for schizophrenia, significantly advancing our understanding of the genetic architecture of schizophrenia. The aim of this study was to study genetic risk factors for the development of schizophrenia in a genome-wide association analysis in Russians, Tatars, and Bashkirs from the Republic of Bashkortostan. The studied sample consisted of 816 patients with paranoid schizophrenia and 989 healthy individuals. GWAS genotyping of DNA samples was carried out on the PsychChip, which included 610 000 single nucleotide polymorphic variants (SNPs). As a result of the study, for the first time, an association of SNPs rs73254185 (4p15.2) and rs587778384 of the GNAS gene (20q13.31) with the risk of paranoid schizophrenia in individuals of different ethnicity, Russians, Tatars and Bashkirs living in the Republic of Bashkortostan, was established, which probably may indicate involvement of PI4K2B and GNAS genes localized in these chromosomal regions in the pathogenesis of schizophrenia.

На протяжении пятнадцати лет полногеномные ассоциативные исследования (GWAS) позволили выявить несколько миллионов полиморфных маркеров риска развития шизофрении, значительно продвинув наше понимание генетической архитектуры шизофрении. Целью настоящего исследования явилось изучение генетических факторов риска развития шизофрении при проведении полногеномного анализ ассоциации у русских, татар и башкир из Республики Башкортостан. Исследованная выборка состояла из 816 больных параноидной шизофренией и 989 здоровых индивидов. Полногеномное генотипирование образцов ДНК было проведено на биочипе PsychChip, включавшим 610 000 однонуклеотидных полиморфных вариантов (ОНП). В результате проведенного исследования впервые установлена ассоциация ОНП rs73254185 (4p15.2) и rs587778384 гена GNAS (20q13.31) с риском развития параноидной шизофрении у индивидов различной этнической принадлежности, русских, татар и башкир, проживающих в Республике Башкортостан, что вероятно может свидетельствовать о вовлеченности, локализованных в данных хромосомных областях генов PI4K2B и GNAS в патогенез шизофрении.

geneticsschizophreniagenome-wide association analysisethnicityRepublic of BashkortostanPsychiatric genome consortium.генетикашизофренияполногеномный анализ ассоциацийэтническая принадлежностьРеспублика Башкортостанмеждународный консорциум по психиатрической генетике.Trubetskoy V., Pardiñas A.F., Qi T. et al. Mapping genomic loci implicates genes and synaptic biology in schizophrenia // Nature. 2022. V. 604. № 7906. P. 502–508. https://doi.org/10.1038/s41586-022-04434-5Singh T., Poterba T., Curtis D. et al. Rare coding variants in ten genes confer substantial risk for schizophrenia // Nature. 2022. V. 604. P. 509–516. https://doi.org/10.1038/s41586-022-04556-wPeriyasamy S., John S., Padmavati R. et al. Association of schizophrenia risk with disordered niacin metabolism in an Indian genome-wide association study // JAMA Psychiatry. 2019. V. 76. № 10. P. 1026–1034. https://doi.org/10.1001/jamapsychiatry.2019.1335Fiorica P.N., Wheeler H.E. Transcriptome association studies of neuropsychiatric traits in African Americans implicate PRMT7 in schizophrenia // Peer J. 2019. V. 26. № 7. https://doi.org/10.7717/peerj.7778Bigdeli T.B., Genovese G., Georgakopoulos P. et al. Contributions of common genetic variants to risk of schizophrenia among individuals of African and Latino ancestry // Mol. Psychiatry. 2020. V. 25. № 10. P. 2455–2467. https://doi.org/10.1038/s41380-019-0517-yIkeda M., Takahashi A., Kamatani Y. et al. Genome-wide association study detected novel susceptibility genes for schizophrenia and shared trans-populations/diseases genetic effect // Schizophr. Bull. 2019. V. 45. № 4. P. 824–834. https://doi.org/10.1093/schbul/sby140Lam M., Chen C.Y., Li Z. et al. Comparative genetic architectures of schizophrenia in East Asian and European populations // Nat. Genet. 2019. V. 51. № 12. P. 1670–1678. https://doi.org/10.1038/s41588-019-0512-xPurcell S., Neale B., Todd-Brown K. et al. PLINK: A toolset for whole-genome association and population-based linkage analysis // Am. J. Hum. Genet. 2007. V. 81. № 3. P. 559–575. https://doi.org/10.1086/519795Benjamini Y., Drai D., Elmer G., Kafkafi N., Golani I. Controlling the false discovery rate in behavior genetics research // Behav. Brain Res. 2001. V. 125. № 1–2. P. 279–284. https://doi.org/10.1016/s0166-4328(01)00297-2Price A.L., Patterson N.J., Plenge R.M. et al. Principal components analysis corrects for stratification in genome–wide association studies // Nat. Genet. 2006. V. 38. № 8. P. 904–909. https://doi.org/10.1038/ng1847Kunii Y., Matsumoto J., Izumi R. et al. Evidence for altered phosphoinositide signaling-associated molecules in the postmortem prefrontal cortex of patients with schizophrenia // Int. J. Mol. Sci. 2021. V. 22. № 15. https://doi.org/10.3390/ijms22158280Yates A.D., Achuthan P., Akanni W. et al. Ensembl 2020 // Nucl. Ac. Res. 2020. V. 48. № D1. P. D682–D688. https://doi.org/10.1093/nar/gkz966Minogue S. The many roles of type ii phosphatidylinositol 4-kinases in membrane trafficking: New tricks for old dogs // Bioessays. 2018. V. 40. № 2. P. 10. https://doi.org/10.1002/bies.201700145Baba T., Alvarez-Prats A., Kim Y.J. et al. Myelination of peripheral nerves is controlled by PI4KB through regulation of Schwann cell Golgi function // Proc. Natl Acad. Sci. USA. 2020. V. 117. № 45. P. 28102–28113. https://doi.org/10.1073/pnas.2007432117Alvarez-Prats A., Bjelobaba I., Aldworth Z. et al. Schwanncell – specific deletion of phosphatidylinositol 4-kinase alpha causes aberrant myelination // Cell Rep. 2018. V. 23. № 10. P. 2881–2890. https://doi.org/10.1016/j.celrep.2018.05.019Dafsari H.S., Pemberton J.G., Ferrer E.A. et al. PI4K2A deficiency causes innate error in intracellular trafficking with developmental and epileptic-dyskinetic encephalopathy // Ann. Clin. Transl. Neurol. 2022. V.9. № 9. P. 1345–1358. https://doi.org/10.1002/acn3.51634Asherson P., Mant R., Williams N. et al. A study of chromosome 4p markers and dopamine D5 receptor gene in schizophrenia and bipolar disorder // Mol. Psychiatry. 1998. V. 3. № 4. P. 310–320. https://doi.org/10.1038/sj.mp.4000399Detera-Wadleigh S.D., Badner J.A., Berrettini W.H. et al. A high-density genome scan detects evidence for a bipolar-disorder susceptibility locus on 13q32 and other potential loci on 1q32 and 18p11.2 // Proc. Natl Acad. Sci. USA. 1999. V. 96. № 10. P. 5604–5609. https://doi.org/10.1073/pnas.96.10.5604Christoforou A., Le Hellard S., Thomson P.A. et al. Association analysis of the chromosome 4p15-p16 candidate region for bipolar disorder and schizophrenia // Mol. Psychiatry. 2007. V. 12. № 11. P. 1011–1025. https://doi.org/10.1038/sj.mp.4002003Le Hellard S., Theisen F.M., Haberhausen M. et al. Association between the insulin-induced gene 2 (INSIG2) and weight gain in a German sample of antipsychotic-treated schizophrenic patients: perturbation of SREBP–controlled lipogenesis in drug-related metabolic adverse effects? // Mol. Psychiatry. 2009. V. 14. № 3. P. 308–317. https://doi.org/10.1038/sj.mp.4002133McClay J.L., Adkins D.E., Aberg K. et al. Genome-wide pharmacogenomic study of neurocognition as an indicator of antipsychotic treatment response in schizophrenia // Neuropsychopharmacology. 2011. V. 36. № 3. P. 616–626. https://doi.org/10.1038/npp.2010.193Blackwood D.H., He L., Morris S.W. et al. A locus for bipolar affective disorder on chromosome 4p // Nat. Genet. 1996. V. 12. № 4. P. 427–430. https://doi.org/10.1038/ng0496-427Chen F.P., Wu L., Shen Y. et al. // Acta Acad. Med. Sinicae. 2014. V. 36. № 5. P. 466–469. https://doi.org/10.3881/j.issn.1000-503X.2014.05.002Sherva R., Wang Q., Kranzler H. et al. Genome-wide association study of cannabis dependence severity, novel risk variants, and shared genetic risks // JAMA Psychiatry. 2016. V. 73. № 5. P. 472–480. https://doi.org/10.1001/jamapsychiatry.2016.0036Houlihan L.M., Christoforou A., Arbuckle M.I. et al. A case-control association study and family-based expression analysis of the bipolar disorder candidate gene PI4K2B // J. Psychiatr. Res. 2009. V. 43. № 16. P. 1272–1277. https://doi.org/10.1016/j.jpsychires.2009.05.004Flax J.F., Hare A., Azaro M.A. et al. Combined linkage and linkage disequilibrium analysis of a motor speech phenotype within families ascertained for autism risk loci // J. Neurodev. Disord. 2010. V. 2. № 4. P. 210–223. https://doi.org/10.1007/s11689-010-9063-2Maldžienė Ž., Preikšaitienė E., Ignotienė S. et al. A de novo pericentric inversion in chromosome 4 associated with disruption of PITX2 and a microdeletion in 4p15.2 in a patient with axenfeld-rieger syndrome and developmental delay // Cytogenet. Genome Res. 2017. V. 151. № 1. P. 5–9. https://doi.org/10.1159/000456695Liang L., Xie Y., Shen Y. et al. A rare de novo interstitial duplication at 4p15.2 in a boy with severe congenital heart defects, limb anomalies, hypogonadism, and global developmental delay // Cytogenet. Genome Res. 2016. V. 150. № 2. P. 112–117. https://doi.org/10.1159/000454698Turan S., Bastepe M. GNAS spectrum of disorders // Curr. Osteoporos Rep. 2015. V. 13. № 3. P. 146–158. https://doi.org/10.1007/s11914-015-0268-xPuzhko S., Goodyer C.G., Kerachian M.A. et al. Parathyroid hormone signaling via Gαs is selectively inhibited by an NH(2)-terminally truncated Gαs: Implications for pseudohypoparathyroidism // J. Bone Miner.Res. 2011. V. 26. № 10. P. 2473–2485. https://doi.org/10.1002/jbmr.461Jarskog L.F., Gilmore J.H., Selinger E.S., Lieberman J.A. Cortical bcl-2 protein expression and apoptotic regulation in schizophrenia // Biol. Psychiatry. 2000. V. 48. № 7. P. 641–650. https://doi.org/10.1016/s0006-3223(00)00988-4Jarskog L.F., Glantz L.A., Gilmore J.H., Lieberman J.A. Apoptotic mechanisms in the pathophysiology of schizophrenia // Prog. Neuropsychopharmacol. Biol. Psychiatry. 2005. V. 29. № 5. P. 846–858. https://doi.org/10.1016/j.pnpbp.2005.03.010Minoretti P., Politi P., Coen E. et al. The T393C polymorphism of the GNAS1 gene is associated with deficit schizophrenia in an Italian population sample // Neurosci. Lett. 2006. V. 397. № 1–2. P. 159–163. https://doi.org/10.1016/j.neulet.2005.12.028Song X., Li X., Gao J. et al. APOA-I: A possible novel biomarker for metabolic side effects in first episode schizophrenia // PLoS One. 2014. V. 9. № 4. https://doi.org/10.1371/journal.pone.0093902Zheng J., Thylin M.R., Ghorpade A. et al. Intracellular CXCR4 signaling, neuronal apoptosis and neuropathogenic mechanisms of HIV-1-associated dementia // J. Neuroimmunol. 1999. V. 98. № 2. P. 185–200. https://doi.org/10.1016/s0165-5728(99)00049-1Jin L.Q., Wang H.Y., Friedman E. Stimulated D1 dopamine receptors couple to multiple G alpha proteins in different brain regions // J. Neurochem. 2001. V. 78. № 5. P. 981–990. https://doi.org/10.1046/j.1471-4159.2001.00470.xGould T.J., Bizily S.P., Tokarczyk J. et al. Sensorimotor gating deficits in transgenic mice expressing a constitutively active form of Gs alpha // Neuropsychopharmacology. 2004. V. 29. № 3. P. 494–501.https://doi.org/10.1038/sj.npp.1300309Avissar S., Schreiber G. The involvement of G proteins and regulators of receptor G protein coupling in the pathophysiology, diagnosis and treatment of mood disorders // Clin. Chim. Acta. 2006. V. 366. № 1. P. 37–47. https://doi.org/10.1016/j.cca.2005.11.003Strawn J.R., Ekhator N.N., D’Souza B.B., Geracioti T.D., Jr. Pituitary-thyroid state correlates with central dopaminergic and serotonergic activity in healthy humans // Neuropsychobiology. 2004. V. 49. № 2. P. 84–87. https://doi.org/10.1159/000076415Hattori E., Liu C., Zhu H., Gershon E.S. Genetic tests of biologic systems in affective disorders // Mol. Psychiatry. Genetic tests of biologic systems in affective disorders // Mol. Psychiatry. 2005. V. 10. № 8. P. 719–740. https://doi.org/10.1038/sj.mp.4001695Plagge A., Gordon E., Dean W. et al. The imprinted signaling protein XLαs is required for postnatal adaptation to feeding // Nat. Genet. 2004. V. 36. № 8. P. 818–826. https://doi.org/10.1038/ng1397Grimaldi B., Bonnin A., Fillion M.P. et al. 5-Hydroxytryptamine-moduline: A novel endogenous peptide involved in the control of anxiety // Neuroscience. 1999. V. 93. № 4. P. 1223–1225. https://doi.org/10.1016/s0306-4522(99)00322-xGomot M., Bernard F.A., Davis M.H. et al. Change detection in children with autism: An auditory event-related fMRI study // Neuroimage. 2006. V. 29. № 2. P. 475–484. https://doi.org/10.1016/j.neuroimage.2005.07.027Bittel D.C., Kibiryeva N., Butler M.G. Whole genome microarray analysis of gene expression in subjects with fragile X syndrome // Genet. Med. 2007. V. 9. № 7. P. 464–472. https://doi.org/10.1097/gim.0b013e3180ca9a9aBastepe M., Jüppner H. GNAS locus and pseudohypoparathyroidism // Horm. Res. 2005. V. 63. № 2. P. 65–74. https://doi.org/10.1159/000083895Germain-Lee E.L., Schwindinger W., Crane J.L. et al. A mouse model of Albright hereditary osteodystrophy generated by targeted disruption of exon 1 of the Gnas gene // Endocrinology. 2005. V. 146. № 11. P. 4697–4709. https://doi.org/10.1210/en.2005-0681Heinrich T.W., Grahm G. Hypothyroidism presenting as psychosis: Myxedema madness revisited // Prim. Care Companion J. Clin. Psychiatry. 2003. V. 5. № 6. P. 260–266. https://doi.org/10.4088/pcc.v05n0603Crespi B. Genomic imprinting in the development and evolution of psychotic spectrum conditions // Biol. Rev. Camb. Philos. Soc. 2008. V. 83. № 4. P. 441–493. https://doi.org/10.1111/j.1469-185X.2008.00050.xWang L., Chang S., Wang Z. et al. Altered GNAS imprinting due to folic acid deficiency contributes to poor embryo development and may lead to neural tube defects // Oncotarget. 2017. V. 8. № 67. P. 10797–110810. https://doi.org/10.18632/oncotarget.22731Liu P., Liang J., Jiang F. et al. Gnas promoter hypermethylation in the basolateral amygdala regulates reconsolidation of morphine reward memory in rats // Genes (Basel). 2022. V. 13. № 3. https://doi.org/10.3390/genes13030553Oh J.H., Jo S., Park K.W. et al. Whole-genome sequencing reveals an association between small genomic deletions and an increased risk of developing Parkinson’s disease // Exp. Mol. Med. 2023. V. 55. № 3. P. 555–564. https://doi.org/10.1038/s12276-023-00952-yFrey U.H., Alakus H., Wohlschlaeger J. et al. GNAS1 T393C polymorphism and survival in patients with sporadic colorectal cancer // Clin. Cancer Res. 2005. V. 11. № 14. P. 5071–5077.https://doi.org/10.1158/1078-0432.CCR-05-0472Athanasiu L., Mattingsdal M., Kähler A.K. et al. Gene variants associated with schizophrenia in a Norwegian genome-wide study are replicated in a large European cohort // J. Psychiatr. Res. 2010. V. 44. № 12. P. 748–753. https://doi.org/10.1016/j.jpsychires.2010.02.002Fanous A.H., Zhou B., Aggen S.H. et al. Genome-wide association study of clinical dimensions of schizophrenia: Polygenic effect on disorganized symptoms // Am. J. Psychiatry. 2012. V. 169. № 12. P. 1309–1317. https://doi.org/10.1176/appi.ajp.2012.12020218Zlojutro M., Manz N., Rangaswamy M. et al. Genome-wide association study of theta band event-related oscillations identifies serotonin receptor gene HTR7 influencing risk of alcohol dependence // Am. J. Med. Genet. B. Neuropsychiatr. Genet. 2011. V. 156. № 1. P. 44–58. https://doi.org/10.1002/ajmg.b.31136Carmel M., Michaelovsky E., Weinberger R. et al. Differential methylation of imprinting genes and MHC locus in 22q11.2 deletion syndrome-related schizophrenia spectrum disorders // World J. Biol. Psychiatry. 2021. P. 22. № 1. P. 46–57. https://doi.org/10.1080/15622975.2020.1747113Park N., Juo S.H., Cheng R. et al. Linkage analysis of psychosis in bipolar pedigrees suggests novel putative loci for bipolar disorder and shared susceptibility with schizophrenia // Mol. Psychiatry. 2004. V. 9. № 12. P. 1091–1099. https://doi.org/10.1038/sj.mp.4001541McQueen M.B., Devlin B., Faraone S.V. et al. Combined analysis from eleven linkage studies of bipolar disorder provides strong evidence of susceptibility loci on chromosomes 6q and 8q // Am. J. Hum. Genet. 2005. V. 77. № 4. P. 582–595. https://doi.org/10.1086/491603