Генетические основы предрасположенности к депрессивным расстройствам

Депрессия – это распространенное психическое расстройство, которое является одной из ведущих причин нетрудоспособности и смертности в мире. Несмотря на интенсивные исследования, проводимые в течение последних десятилетий, этиология депрессивных расстройств все еще остается не до конца изученной, однако генетические факторы, безусловно, играют важную роль в предрасположенности к депрессии. Настоящий обзор сфокусирован на результатах работ, основанных на генно-кандидатном подходе, полногеномных (Genome-Wide Association Studies, GWAS) и полноэкзомных (Whole Exome Sequencing, WES) исследованиях, продемонстрировавших связь полиморфных локусов генов с депрессивными расстройствами. Согласно первому подходу, формирование депрессивной симптоматики находится под влиянием генов серотонинергической (TPH1, TPH2, HTR1A, HTR2A, SLC6A4), дофаминергической (DRD4, SLC6A3) и норадренергической (SLC6A2) систем, а также генов ферментов их метаболизма (MAOA, COMT). Кроме того, имеются данные об участии генов гипоталамо-гипофизарной системы (OXTR, AVPR1A, AVPR1B) и рецепторов половых гормонов (ESR1, ESR2, AR), генов нейротрофического фактора мозга (BDNF) и фермента метилентетрагидрофолатредуктазы (MTHFR), нейронального апоптоза (CASP3, BCL-XL, BAX, NPY, APP, GRIN1) и воспалительной системы (TNF, CRP, IL6, IL1B, PSMB4, PSMD9, STAT3) в развитии депрессивных расстройств. Результаты второго подхода  (GWAS и WES) демонстрируют, что гены белков пикколо (PCLO) и сиртуина (SIRT1), фактора пролиферации стволовых клеток (GNL3), гликозилтрансферазы (GLT8D1), α-трипсинового ингибитора (ITIH3), мелатонинового рецептора (MTNR1A), костного морфогенного белка (BMP5), ломкой гистидиновой триады (FHIT) и киназного супрессора (KSR2), протокадгерина (PCDH9) и активатора транскрипции AUTS2, преимущественно участвующие в процессах нейрогенеза и клеточной адгезии, вовлечены в развитие депрессии. Таким образом, эти и другие литературные данные подтверждают, что формирование генетической предрасположенности к депрессивным расстройствам – сложный процесс, затрагивающий функционирование большого числа генов, в том числе тех, которые ранее не обсуждались в связи с депрессией, что требует обратить особое внимание на них в дальнейших исследованиях.

1. Amin N., Belonogova N.M., Jovanova O., Brouwerc R.W.W., van Rooij J.G.J., van den Hout M.C.G.N., Svishcheva G.R., Kraaij R., Zorkoltseva I.V., Kirichenko A.V., Hofman A., Uitterlinden A.G., van IJcken W.F.J., Tiemeier H., Axenovich T.I., van Duijn C.M. Nonsynonymous variation in NKPD1 increases depressive symptoms in european populations. Biol. Psychiatry. 2017a;81(8):702707. DOI 10.1016/j.biopsych.2016.08.008.

2. Amin N., Jovanova O., Adams H.H., Dehghan A., Kavousi M., Vernooij M.W., Peeters R.P., de Vrij F.M.S., van der Lee S.J., van Rooij J.G.J., van Leeuwen E.M., Chaker L., Demirkan A., Hofman A., Brouwer R.W.W., Kraaij R., van Dijk K.W., Hankemeier T., van Ijcken W.F.J., Uitterlinden A.G., Niessen W.J., Franco O.H., Kushner S.A., Ikram M.A., Tiemeier H., van Duijn C.M. Exome-sequencing in a large population-based study reveals a rare Asn396Ser variant in the LIPG gene associated with depressive symptoms. Mol. Psychiatry. 2017b;22(4):537-543. DOI 10.1038/mp.2016.101.

3. Amin N., de Vrij F.M.S., Baghdadi M., Brouwer R.W.W., van Rooij J.G.J., Jovanova O., Uitterlinden A.G., Hofman A., Janssen H.L.A., Darwish Murad S., Kraaij R., Stedehouder J., van den Hout M.C.G.N., Kros J.M., van IJcken W.F.J., Tiemeier H., Kushner S.A.C., van Duijn M. A rare missense variant in RCL1 segregates with depression in extended families. Mol. Psychiatry. 2018; 23(5):1120-1126. DOI 10.1038/mp.2017.49.

4. Bachis A., Cruz M.I., Nosheny R.L., Mocchetti I. Chronic unpredictable stress promotes neuronal apoptosis in the cerebral cortex. Neurosci. Lett. 2008;442(2):104-108. DOI 10.1016/j.neulet.2008.06.081.

5. Bîlc M.I., Vulturar R., Chiș A., Buciuman M., Nuţu D., Bunea I., Szentágotai-Tătar A., Miu A.C. Childhood trauma and emotion regulation: The moderator role of BDNF Val66Met. Neurosci. Lett. 2018;685:7-11. DOI 10.1016/j.neulet.2018.07.018.

6. Bleys D., Luyten P., Soenens B., Claes S. Gene-environment interactions between stress and 5-HTTLPR in depression: A meta-analytic update. J. Affect. Disord. 2018;226:339-345. DOI 10.1016/j.jad.2017.09.050.

7. CONVERGE consortium. Sparse whole-genome sequencing identifies two loci for major depressive disorder. Nature. 2015;523(7562): 588-591. DOI 10.1038/nature14659.

8. Culverhouse R.C., Saccone N.L., Horton A.C., Weinstein M., Whooley M., Nurnberger J.I.Jr. Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression. Mol. Psychiatry. 2018;23(1):133-142. DOI 10.1038/mp.2017.44.

9. Cusin C., Yang H., Yeung A., Fava M. Rating scales for depression. Eds. L. Baer, M.A. Blais. Handbook of Clinical Rating Scales and Assessment in Psychiatry and Mental Health. Totowa, N.J.: Humana Press, 2010;7-35.

10. Daches S., Vine V., Layendecker K.M., George C.J., Kovacs M. Family functioning as perceived by parents and young offspring at high and low risk for depression. J. Affect. Disord. 2018;226:355-360. DOI 10.1016/j.jad.2017.09.031.

11. Demirkan A., Lahti J., Direk N., Tiemeier H., van Duijn C.M., Räikkönen K. Somatic, positive and negative domains of the Center for Epidemiological Studies Depression (CES-D) scale: a metaanalysis of genome-wide association studies. Psychol. Med. 2016; 6(8):1613-1623. DOI 10.1017/S0033291715002081.

12. Direk N., Williams S., Smith J.A., Zhao W., Tiemeier H., Sullivan P.F. An analysis of two genome-wide association meta-analyses identifies a new locus for broad depression phenotype. Biol. Psychiatry. 2017;82(5):322-329. DOI 10.1016/j.biopsych.2016.11.013.

13. Dreval A.V. Age changes in the functioning of the reproductive system of men. RMJ: Endocrinologiya = Russian Medical Journal: Endocrinology. 2017;25(22):1661-1664. (in Russian)

14. Fitzgerald P.B., Laird A.R., Maller J., Daskalakis Z.J. A meta-analytic study of changes in brain activation in depression. Hum. Brain Mapp. 2008;29(6):683-695. DOI 10.1002/hbm.20426.

15. Gardiner S.L., van Belzen M.J., Boogaard M.W., van RoonMom W.M.C., Rozing M.P., van Hemert A.M., Smit J.H., Beekman A.T.F., van Grootheest G., Schoevers R.A., Oude Voshaar R.C., Comijs H.C., Penninx B.W.J.H., van der Mast R.C., Roos R.A.C., Aziz N.A. Large normal-range TBP and ATXN7 CAG repeat lengths are associated with increased lifetime risk of depression. Transl. Psychiatry. 2017;7(6):e1143. DOI 10.1038/tp.2017.116.

16. Gatt J.M., Burton K.L., Williams L.M., Schofield P.R. Specific and common genes implicated across major mental disorders: a review of meta-analysis studies. J. Psychiatr. Res. 2015;60:1-13. DOI 10.1016/j.jpsychires.2014.09.014.

17. Gerhard D.M., Duman R.S. Sex-specific molecular changes in depression. Biol. Psychiatry. 2018;84(1)2-4. DOI 10.1016/j.biopsych.2018.05.005.

18. Girgus J.S., Yang K. Gender and depression. Curr. Opin. Psychol. 2015; 4:53-60. DOI 10.1016/j.copsyc.2015.01.019.

19. Guo L., Costanzo-Garvey D.L., Smith D.R., Neilsen B.K., MacDonald R.G., Lewis R.E. Kinase Suppressor of Ras 2 (KSR2) expression in the brain regulates energy balance and glucose homeostasis. Mol. Metab. 2016;6(2):194-205. DOI 10.1016/j.molmet.2016.12.004.

20. Hajek T., Kozeny J., Kopecek M., Alda M., Höschl C. Reduced subgenual cingulate volumes in mood disorders: a meta-analysis. J. Psychiatry Neurosci. 2008;33:91-99.

21. Howard D.M., Adams M.J., Shirali M., … Breen G., Deary I.J., McIntosh A.M. Genome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways. Nat. Commun. 2018;9:1470. DOI 10.1038/s41467-018-03819-3.

22. ICD-10: International Statistical Classification of Diseases and Related Health Problems 10th Revision, version 2018. Available at: http://mkb-10.com/. (in Russian)

23. Jiang P., Dang R.-L., Li H.-D., Zhang L.H., Zhu W.Y., Xue Y., Tang M.M. The impacts of swimming exercise on hippocampal expression of neurotrophic factors in rats exposed to chronic unpredictable mild stress. Evid. Based Complement. Alternat. Med. 2014; 729827. DOI 10.1155/2014/729827.

24. Kazantseva A., Gaysina D., Kutlumbetova Y., Kanzafarova R., Malykh S., Lobaskova M., Khusnutdinova E. Brain derived neurotrophic factor gene (BDNF) and personality traits: the modifying effect of season of birth and sex. Prog. Neuropsychopharmacol. Biol. Psychiatry. 2015;56:58-65. DOI 10.1016/j.pnpbp.2014.08.001.

25. Kazantseva A.V., Kutlumbetova Y.Y., Malykh S.B., Lobaskova M.M., Khusnutdinova E.K. Arginine-vasopressin receptor gene (AVPR1A, AVPR1B) polymorphisms and their relation to personality traits. Russ. J. Genet. 2014;50(3):298-307. DOI 10.1134/S1022795414030041.

26. Kendler K.S., Gatz M., Gardner C.O., Pedersen N.L. A Swedish national twin study of lifetime major depression. Am. J. Psychiatry. 2006;163(1):109-114. DOI 10.1176/appi.ajp.163.1.109.

27. Keyes K., Agnew-Blais J., Roberts A.L., Hamilton A., de Vivo I., Ranu H., Koenen K. The role of allelic variation in estrogen receptor genes and major depression in the Nurses Health Study. Soc. Psychiatry Psychiatr. Epidemiol. 2015;50(12):1893-1904. DOI 10.1007/s00127-015-1087-1.

28. Kim M., Kim Y.-S., Kim D.-H., Yang T.W., Kwon O.Y. Major depressive disorder in epilepsy clinics: A meta-analysis. Epilepsy Behav. 2018;84:56-69. DOI 10.1016/j.yebeh.2018.04.015.

29. Kishi T., Yoshimura R., Fukuo Y., Okochi T., Matsunaga S., UmeneNakano W., Nakamura J., Serretti A., Correll C.U., Kane J.M., Iwata N. The serotonin 1A receptor gene confer susceptibility to mood disorders: results from an extended meta-analysis of patients with major depression and bipolar disorder. Eur. Arch. Psychiatry Clin. Neurosci. 2013;263(2):105-118. DOI 10.1007/s00406-0120337-4.

30. Koolschijn P.C., van Haren N.E., Lensvelt-Mulders G.J., Hulshoff Pol H.E., Kahn R.S. Brain volume abnormalities in major depressive disorder: a meta-analysis of magnetic resonance imaging studies. Hum. Brain Mapp. 2009;30(11):3719-3735. DOI 10.1002/hbm.20801.

31. Köhler C.A., Freitas T.H., Maes M., de Andrade N.Q., Liu C.S., Fernandes B.S., Stubbs B., Solmi M., Veronese N., Herrmann N., Raison C.L., Miller B.J., Lanctôt K.L., Carvalho A.F. Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies. Acta Psychiatr. Scand. 2017; 135(5):373-387. DOI 10.1111/acps.12698.

32. Kushner S.C., Herzhoff K., Vrshek-Schallhorn S., Tackett J.L. Depression in early adolescence: Contributions from relational aggression and variation in the oxytocin receptor gene. Aggress. Behav. 2018;44(1):60-68. DOI 10.1002/ab.21724.

33. Liu Y., Ho R.C., Mak A. Interleukin (IL)-6, tumour necrosis factor alpha (TNF-α) and soluble interleukin-2 receptors (sIL-2R) are elevated in patients with major depressive disorder: a meta-analysis and meta-regression. J. Affect. Disord. 2012;139(3):230-239. DOI 10.1016/j.jad.2011.08.003.

34. Liu Z., Huang L., Luo X.J., Wu L., Li M. MAOA Variants and genetic susceptibility to major psychiatric disorders. Mol. Neurobiol. 2016;53(7):4319-4327. DOI 10.1007/s12035-015-9374-0.

35. Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium. A mega-analysis of genome-wide association studies for major depressive disorder. Mol. Psychiatry. 2013;18(4):497511. DOI 10.1038/mp.2012.21.

36. Mbarek H., Milaneschi Y., Hottenga J.J., Ligthart L., de Geus E.J.C., Ehli E.A., Willemsen G., Davies G.E., Smit J.H., Boomsma D.I., Penninx B.W.J.H. Genome-wide significance for PCLO as a gene for major depressive disorder. Twin Res. Hum. Genet. 2017;20(4):267270. DOI 10.1017/thg.2017.30.

37. Miller A.H., Raison C.L. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat. Rev. Immunol. 2016;16(1):22-34. DOI 10.1038/nri.2015.5.

38. Mustafin R.N., Enikeeva R.F., Davydova Y.D., Khusnutdinova E.K. The role of epigenetic factors in the development of depressive disorders. Russ. J. Genet. 2018;54(12):1397-1409. DOI 10.1134/S1022795418120104.

39. Myung W., Kim J., Lim S.-W., Shim S., Won H.-H., Kim S., Kim S., Lee M.-S., Chang H.S., Kim J.-W., Carroll B.J., Kim D.K. A genome-wide association study of antidepressant response in Koreans. Transl. Psychiatry. 2015;5:e633. DOI 10.1038/tp.2015.127.

40. Naughton M., Dinan T.G., Scott L.V. Corticotropin-releasing hormone and the hypothalamic-pituitary-adrenal axis in psychiatric disease. Handb. Clin. Neurol. 2014;124:69-91. DOI 10.1016/B978-0-44459602-4.00005-8.

41. Neumann I.D., Landgraf R. Balance of brain oxytocin and vasopressin: implications for anxiety, depression, and social behaviors. Trends Neurosci. 2012;35(11):649-659. DOI 10.1016/j.tins.2012.08.004.

42. Okbay A., Baselmans B.M., de Neve J.E.,Benjamin D.J., Bartels M., Cesarini D. Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses. Nat. Genet. 2016;48(6):624-633. DOI 10.1038/ng.3552.

43. Popova N.K., Ilchibaeva T.V., Naumenko V.S. Neurotrophic factors (BDNF and GDNF) and the serotonergic system of the brain. Biochemistry (Moscow). 2017;82(3):308-317. DOI 10.1134/S0006297917030099.

44. Rai V. Association of C677T polymorphism (rs1801133) in MTHFR gene with depression. Cell. Mol. Biol. 2017;63(6):60-67. DOI 10.14715/cmb/2017.63.6.13.

45. Rui H., Qian H., Shi M., Zhang G., Wang L. Meta-analysis on the association between norepinephrine transporter gene rs2242446, rs5569 polymorphisms and risk of major depressive disorder. Arch. Med. Res. 2018;49(4):261-269. DOI 10.1016/j.arcmed.2018.08.010.

46. Sahu A., Gupta P., Chatterjee B. Depression is more than just sadness: a case of excessive anger and its management in depression. Indian J. Psychol. Med. 2014;36(1):77-79. DOI 10.4103/0253-7176.127259.

47. Sankar J.S., Hampson E. Testosterone levels and androgen receptor gene polymorphism predict specific symptoms of depression in young men. Gend. Med. 2012;9(4):232-243. DOI 10.1016/j.genm.2012.05.001.

48. Shadrina M., Bondarenko E.A., Slominsky P.A. Genetics factors in major depression disease. Front. Psychiatry. 2018;9:334. DOI 10.3389/fpsyt.2018.00334.

49. Smulevich A.B. Depression in Psychiatric and Medical Practices. Moscow: Medical Information Agency Publ., 2015. (in Russian)

50. Sullivan P.F., de Geus E.J., Willemsen G., James M.R., Smit J.H., Zandbelt T., Arolt V., Baune B.T., Blackwood D., Cichon S., Coventry W.L., Domschke K., Farmer A., Fava M., Gordon S.D., He Q., Heath A.C., Heutink P., Holsboer F., Hoogendijk W.J., Hottenga J.J., Hu Y., Kohli M., Lin D., Lucae S., MacIntyre D.J., Maier W., McGhee K.A., McGuffin P., Montgomery G.W., Muir W.J., Nolen W.A., Nöthen M.M., Perlis R.H., Pirlo K., Posthuma D., Rietschel M., Rizzu P., Schosser A., Smit A.B., Smoller J.W., Tzeng J.-Y., van Dyck R., Verhage M., Zitman F.G., Martin N.G., Wray N.R., Boomsma D.I., Penninx B.W. Genome-wide association for major depressive disorder: a possible role for the presynaptic protein piccolo. Mol. Psychiatry. 2009;14(4):359-375. DOI 10.1038/mp.2008.125.

51. Tammiste A., Jiang T., Fischer K., Mägi R., Krjutškov K., Pettai K., Esko T., Li Y., Tansey K.E., Carroll L.S., Uher R., McGuffin P., Võsa U., Tšernikova N., Saria A., Ng P.C., Eller T., Vasar V., Nutt D.J., Maron E., Wang J., Metspalu A. Whole-exome sequencing identifies a polymorphism in the BMP5 gene associated with SSRI treatment response in major depression. J. Psychopharmacol. 2013;27(10):915-920. DOI 10.1177/0269881113499829.

52. Taylor S. Association between COMT Val158Met and psychiatric disorders: A comprehensive meta-analysis. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 2018;177(2):199-210. DOI 10.1002/ajmg.b.32556.

53. Torres-Berrío A., Lopez J.P., Bagot R.C., Nouel D., Bo G.D., Cuesta S., Zhu L., Manitt C., Eng C., Cooper H.M., Storch K.-F., Turecki G., Nestler E.J., Flores C. DCC confers susceptibility to depression-like behaviors in humans and mice and is regulated by miR-218. Biol. Psychiatry. 2017;81(4):306-315. DOI 10.1016/j.biopsych.2016.08.017.

54. Wang M., Ma Y., Yuan W., Su K., Li M.D. Meta-analysis of the COMT Val158Met polymorphism in major depressive disorder: effect of ethnicity. J. Neuroimmune Pharmacol. 2016;11(3):434-445. DOI 10.1007/s11481-016-9651-3.

55. Wang S.S., Kamphuis W., Huitinga I., Zhou J.N., Swaab D.F. Gene expression analysis in the human hypothalamus in depression by laser microdissection and real-time PCR: the presence of multiple receptor imbalances. Mol. Psychiatry. 2008;13(8):786-799. DOI 10.1038/mp.2008.38.

56. Weisberg I., Tran P., Christensen B., Sibani S., Rozen R. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol. Genet. Metab. 1998;64(3):169-172. DOI 10.1006/mgme.1998.2714.

57. WHO: Depression and Other Common Mental Disorders. Global Health Estimates. 2017. available at: http://apps.who.int/iris/bitstream/handle/10665/254610/WHO-MSD-MER-2017.2-eng.pdf.

58. Wong M.L., Dong C., Maestre-Mesa J., Licinio J. Polymorphisms in inflammation-related genes are associated with susceptibility to major depression and antidepressant response. Mol. Psychiatry. 2008; 13(8):800-812. DOI 10.1038/mp.2008.59.

59. Xiao X., Zheng F., Chang H., Ma Y., Yao Y.G., Luo X.J., Li M. The gene encoding protocadherin 9 (PCDH9), a novel risk factor for major depressive disorder. Neuropsychopharmacology. 2018;43(5):11281137. DOI 10.1038/npp.2017.241.

60. Yankina M.A., Saik O.V., Ivanisenko V.A., Demenkov P.S., Khusnutdinova E.K. Evaluation of prioritization methods of extrinsic apoptotic signaling pathway genes for retrieval of the new candidates associated with major depressive disorder. Genetika = Genetics (Moscow). 2018;54(11):1338-1348. DOI 10.1134/S0016675818110176. (in Russian)

61. Youssef M.M., Underwood M.D., Huang Y.Y., Hsiung S., Liu Y., Simpson N.R., Bakalian M.J., Rosoklija G.B., Dwork A.J., Arango V., Mann J.J. Association of BDNF Val66Met polymorphism and brain BDNF levels with major depression and suicide. Int. J. Neuropsychopharmacol. 2018;21(6):528-538. DOI 10.1093/ijnp/pyy008.

62. Zhao X., Sun L., Sun Y.H., Ren C., Chen J., Wu Z.Q., Jiang Y.H., Lv X.L. Association of HTR2A T102C and A-1438G polymorphisms with susceptibility to major depressive disorder: a metaanalysis. Neurol. Sci. 2014;35(12):1857-1866. DOI 10.1007/s10072-014-1970-7.