Genetic Associations of the Severity of Psychopathological Symptoms in Patients with Schizophrenia with and without Depressive Symptoms

Background: depressive symptoms often accompany schizophrenia, changing the severity and perception of its main clinical manifestations. The severity of psychopathological symptoms affects the course and development of the disease. Genetic studies have revealed a partial overlap of genetic risk between schizophrenia and depressive disorders. Objective: to find out whether the genetic associations of the severity of positive and negative symptoms of schizophrenia differ in patients with and without depressive symptoms. Patients and Methods: a comparative cross-sectional study of patients with schizophrenia was conducted. The study participants belonged to one of three ethnic groups: Russians, Bashkirs, and Tatars. The study included 390 patients, of whom 124 (31.8%) had signs of depressive disorder. The assessment of depressive symptoms was carried out using the CDSS scale. The PANSS scale was used to assess the severity of psychopathological symptoms. The following polymorphisms were selected to determine the genetic associations: MTNR1A rs34532313, MTNR1B rs10830963, CLOCK rs 1801260, HTR2A rs6313, PER2 rs934945, eNOS rs1549758, eNOS rs1799983. The data was analyzed using nonparametric statistical methods: the Mann–Whitney test, the Student's t-test, and the Pearson χ² test. Results: in patients with depressive symptoms, the carriage of the minor allele of polymorphism MTNR1A rs34532313 was associated with a lower severity of symptoms P4, N7; polymorphism HTR2A rs6313 — with a lower severity of P4; polymorphism PER2 rs934945 — with a lower severity of P7 of PANSS. In the group of patients without significant depressive manifestations, an association was found between the carriage of the minor MTNR1A allele rs34532313 and a greater severity of the P6 symptom. Conclusions: depressive symptoms in patients with schizophrenia can modify associations between polymorphic gene variants and the severity of individual psychopathological symptoms.

1. Pelizza L, Leuci E, Quattrone E, Paulillo G, Azzali S, Pupo S, Pellegrini P. Depressed mood in first episode schizophrenia: findings from a 1-year follow-up in an Italian real-world care setting. Psychiatry. 2023;86(2):164–166. doi: 10.1080/00332747.2022.2120308

2. Mavrogiorgou P, Haller K, Juckel G. Death anxiety and attitude to death in patients with schizophrenia and depression. Psychiatry Res. 2020;290:113148. doi: 10.1016/j.psychres.2020.113148

3. Cosgrave J, Wulff K, Gehrman P. Sleep, circadian rhythms, and schizophrenia: where we are and where we need to go. Curr Opin Psychiatry. 2018;31(3):176– 182. doi: 10.1097/YCO.0000000000000419

4. Gashkarimov VR, Sultanova RI, Islamova ED, Gasenko KA, Efremov IS, Gizatullin TR, Asadullin AR. The structure of insomnia and its relation to the severity of psychopathological symptoms in people with schizophrenia (pilot study). Mental Health. 2021;(7):36–42. (In Russ.). doi: 10.25557/2074-014X.2021.07.36-42

5. Gebreegziabhere Y, Habatmu K, Mihretu A, Cella M, Alem A. Cognitive impairment in people with schizophrenia: an umbrella review. Eur Arch Psychiatry Clin Neurosci. 2022;272(7):1139–1155. doi: 10.1007/s00406-022-01416-6

6. McCutcheon RA, Keefe RS, McGuire PK. Cognitive impairment in schizophrenia: aetiology, pathophysiology, and treatment. Mol Psychiatry. 2023;28(5):1902– 1918. doi: 10.1038/s41380-023-01949-9

7. Etchecopar-Etchart D, Korchia T, Loundou A, Llorca PM, Auquier P, Lançon C, Boyer L, Fond G. Comorbid major depressive disorder in schizophrenia: a systematic review and meta-analysis. Schizophr Bull. 2021;47(2):298–308. doi: 10.1093/schbul/sbaa153

8. Upthegrove R, Birchwood M, Ross K, Brunett K, Mc-Collum R, Jones L. The evolution of depression and suicidality in first episode psychosis. Acta Psychiatr Scand. 2010;122(3):211–218. doi: 10.1111/j.1600-0447.2009.01506.x

9. Andrianarisoa M, Boyer L, Godin O, Brunel L, Bulzacka E, Aouizerate B, Berna F, Capdevielle D, Dorey JM, Dubertret J, Dubreucq C, Faget C, Gabayet F, Llorca PM, Mallet J, Misdrahi D, Rey R, Richieri R, Passerieux C, Schandrin A, Zinetti-Bertschy A. Childhood trauma, depression and negative symptoms are independently associated with impaired quality of life in schizophrenia. Results from the national FACE-SZ cohort. Schizophr Res. 2017;185:173–181. doi: 10.1016/j.schres.2016.12.021

10. Dutta R, Murray RM, Allardyce J, Jones PB, Boydell J. Early risk factors for suicide in an epidemiological first episode psychosis cohort. Schizophr Res. 2011;126(1– 3):11–19. doi: 10.1016/j.schres.2010.11.021

11. van Rooijen G, Isvoranu AM, Kruijt OH, van Borkulo CD, Meijer CJ, Wigman JT, Ruhé HG, Bartels-Velthuis AA. A state-independent network of depressive, negative and positive symptoms in male patients with schizophrenia spectrum disorders. Schizophr Res. 2018;193:232–239. doi: 10.1016/j.schres.2017.07.035

12. Sher L, Kahn RS. Suicide in schizophrenia: an educational overview. Medicina (Kaunas). 2019;55(7):361. doi: 10.3390/medicina55070361

13. Chapman CL, Mullin K, Ryan CJ, Kuffel A, Nielssen O, Large MM. Meta-analysis of the association between suicidal ideation and later suicide among patients with either a schizophrenia spectrum psychosis or a mood disorder. Acta Psychiatr Scand. 2015;131(3):162–173. doi: 10.1111/acps.12359

14. Krynicki CR, Upthegrove R, Deakin JFW, Barnes TR. The relationship between negative symptoms and depression in schizophrenia: a systematic review. Acta Psychiatr Scand. 2018;137(5):380–390. doi: 10.1111/acps.12873

15. Sultanova RI, Gashkarimov VR, Efremov IS, Asadullin AR. Association of depressive manifestations with the severity of psychopathological symptoms in people with schizophrenia. Mental Health. 2022;17(4):26–32. (In Russ.). doi: 10.25557/2074-014X.2022.04.26-32

16. Witkowski G, Januszko P, Skalski M, Mach A, Wawrzyniak ZM, Poleszak E, Ciszek B, Radziwoń-Zaleska M. Factors contributing to risk of persistence of positive and negative symptoms in schizophrenia during hospitalization. Int J Environ Res Public Health. 2023;20(5):4592. doi: 10.3390/ijerph20054592

17. Fenton WS, McGlashan TH, Victor BJ, Blyler CR. Symptoms, subtype, and suicidality in patients with schizophrenia spectrum disorders. Am J Psychiatry. 1997;154(2):199–204.

18. Bocharova AV, Marusin AV, Ivanova SA, Fedorenko OU, Semke AV, Stepanov VA. Genetic variants of the TCF4, LSM1 and CCDC60 genes are associated with schizophrenia. Medical genetics. 2020;19(4):17–19. (In Russ.). doi: 10.25557/2073-7998.2020.04.17-19

19. Boiko AS, Pozhidaev IV, Paderina OZ, Semke AV. Genes of dopamine receptors and transporter in patients with schizophrenia: associations with the clinical characteristics of the disorder. Bekhterev Review of Psychiatry and Medical Psychology 2019;(4–1):93–94. (In Russ.). doi: 10.31363/2313-7053-2019-4-1-93-94

20. Lezheiko TV, Andryushchenko AV, Korovaitseva GI, Kondratyev NV, Gabaeva MV, Krikova EV, Golimbet VE. A study on the association of genes for pro-inflammatory cytokines and depression. S.S. Korsakov Journal of Neurology and Psychiatry. 2018;118(3):89–93. (In Russ.). doi: 10.17116/jnevro20181183189-93

21. Rafikova EI, Shibalev DV, Ryskov AP, Vasilyev VA, Shadrina MI, Slominsky PA, Guekht AB. Influence of polymorphic gene variants of the dopaminergic system on the risk of disorders with depressive symptoms. Russian Journal of Genetics. 2021;57(8):941– 948. (In Russ.). doi: 10.31857/S0016675821070110

22. Frielingsdorf H, Bath KG, Soliman F, DiFede J, Casey BJ, Lee FS. Variant brain-derived neurotrophic factor Val66Met endophenotypes: implications for posttraumatic stress disorder. Ann N Y Acad Sci. 2010;1208(1):150–157. doi: 10.1111/j.1749-6632.2010.05722.x

23. Borkowska P, Kucia K, Rzezniczek S, Paul-Samojedny M, Kowalczyk M, Owczarek A, Suchanek R, Medrala T, Kowalski J. Interleukin-1beta promoter (−31T/C and −511C/T) polymorphisms in major recurrent depression. J Mol Neurosci. 2011;44(1):12–16. doi: 10.1007/s12031-011-9507-5

24. Gouin JP, Connors J, Kiecolt-Glaser JK, Malarkey WB, Atkinson C, Beversdorfl D, Quan N. Altered expression of circadian rhythm genes among individuals with a history of depression. J Affect Disord. 2010;126(1–2):161–166. doi: 10.1016/j.jad.2010.04.002

25. Shnayder NA, Novitsky MA, Neznanov NG, Limankin OV, Asadullin AR, Petrov AV, Dmitrenko DV, Narodova EA, Popenko NV, Nasyrova RF. Genetic predisposition to schizophrenia and depressive disorder comorbidity. Genes. 2022;13(3):457. doi: 10.3390/genes13030457

26. Song Y, Li L, Jiang Y, Peng B, Jiang H, Chao Z, Chang X. Multitrait genetic analysis identifies novel pleiotropic loci for depression and schizophrenia in East Asians. Schizophr Bull. 2024;50(2):sbae145. doi: 10.1093/schbul/sbae145

27. Keshri N, Nandeesha H, Rajappa M, Menon V. Neural cell adhesion molecule-1 gene polymorphism increases the risk of cognitive dysfunction in schizophrenia spectrum disorder. Indian J Clin Biochem. December 2024:1–7. doi: 10.1007/s12291-024-01290-0

28. Alfimova MV, Nikitina SG, Lezheiko TV, Simashkova NV, Golimbet VE. Impact on the risk and severity of childhood onset schizophrenia of schizophrenia risk genetic variants at the DRD2 and ZNF804A loci. Child Psychiatry Hum Dev. 2023;54(1):241–247. doi: 10.1007/s10578-021-01245-z

29. Xavier RM, Vorderstrasse A. Genetic basis of positive and negative symptom domains in schizophrenia. Biol Res Nurs. 2017;19(5):559–575. doi: 10.1177/1099800417715907

30. Germain A, Kupfer DJ. Circadian rhythm disturbances in depression. Hum Psychopharmacol. 2008;23(7):571–85. doi: 10.1002/hup.964

31. Saravani R, Esmaeilzaei E, Noorzehi N, Galavi HR. Melatonin receptor 1B gene polymorphisms, haplotypes and susceptibility to schizophrenia. Rev Rom Med Lab. 2017;25(2):125–33. doi: 10.1515/rrlm-2017-0009

32. McCarthy MJ, Welsh DK. Cellular circadian clocks in mood disorders. J Biol Rhythms. 2012;27(5):339–52. doi: 10.1177/0748730412456367

33. Kishi T, Kitajima T, Ikeda M, Yamanouchi Y, Kinoshita Y, Kawashima K, Okochi T, Okumura T, Tsunoka T, Inada T, Ozaki N, Iwata N. Association study of clock gene (CLOCK) and schizophrenia and mood disorders in the Japanese population. Eur Arch Psychiatry Clin Neurosci. 2009;259:293–7 doi: 10.1007/s00406-009-0869-4

34. Abdolmaleky HM, Yaqubi S, Papageorgis P, Lambert AW, Ozturk S, Sivaraman V, Thiagalingam S. Epigenetic dysregulation of HTR2A in the brain of patients with schizophrenia and bipolar disorder. Schizophr Res. 2011;129(2–3):183–90. doi: 10.1016/j.schres.2011.04.007

35. Maffioletti E, Valsecchi P, Minelli A, Magri C, Bonvicini C, Barlati S, Sacchetti E, Vita A, Gennarelli M. Association study between HTR2A rs6313 polymorphism and early response to risperidone and olanzapine in schizophrenia patients. Drug Dev Res. 2020;81(6):754–61. doi: 10.1002/ddr.21686

36. Oh SJ, Fan X. Current understanding on the role of nitric oxide and therapeutic potential of NO supplementation in schizophrenia. Schizophr Res. 2020;222:23–30. doi: 10.1016/j.schres.2020.05.050

37. Bruenig D, Morris CP, Mehta D, Harvey W, Lawford B, Young RM, Voisey J. Nitric oxide pathway genes (NOS1AP and NOS1) are involved in PTSD severity, depression, anxiety, stress and resilience. Gene. 2017;625:42–8. doi: 10.1016/j.gene.2017.04.048

38. Katusic ZS, d'Uscio LV, He T. Emerging roles of endothelial nitric oxide in preservation of cognitive health. Stroke. 2023;54(3):686–96. doi: 10.1161/strokeaha.122.041444

39. Addington D, Addington J, Schissel B. A depression rating scale for schizophrenics. Schizophr Res. 1990;3(4):247–251. doi: 10.1016/0920-9964(90)90005-R

40. Kay SR, Fiszbein A, Opler LA. The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261–276. doi: 10.1093/schbul/13.2.261

41. Kholghi G, Eskandari M, Saadlou MSSQ, Zarrindast MR, Vaseghi S. Night shift hormone: How does melatonin affect depression? Physiol Behav. 2022;252:113835. doi: 10.1016/j.physbeh.2022.113835

42. Paribello P, Manchia M, Bosia M, Pinna F, Carpiniello B, Comai S. Melatonin and aggressive behavior: A systematic review of the literature on preclinical and clinical evidence. J Pineal Res. 2022;72(4):e12794. doi: 10.1111/jpi.12794

43. Park C, Rosenblat JD, Brietzke E, Pan Z, Lee Y, Cao B, Zuckerman H, Kalantarova A, McIntyre RS. Stress, epigenetics and depression: a systematic review. Neurosci Biobehav Rev. 2019;102:139–52. doi: 10.1016/j.neubiorev.2019.04.010

44. Chen Q, Li D, Jin W, Shi Y, Li Z, Ma P, Sun J, Chen S, Li P, Lin P. Research progress on the correlation between epigenetics and schizophrenia. Front Neurosci. 2021;15:688727. doi: 10.3389/fnins.2021.688727

45. Bagot RC, Labonté B, Peña CJ, Nestler EJ. Epigenetic signaling in psychiatric disorders: stress and depression. Dialogues Clin Neurosci. 2014;16(3):281–95. doi: 10.31887/DCNS.2014.16.3/rbagot

46. Domschke K. Clinical and molecular genetics of psychotic depression. Schizophr Bull. 2013;39(4):766– 775. doi: 10.1093/schbul/sbt040

47. Fang X, Chen Y, Wang Y, Ren J, Zhang C. Depressive symptoms in schizophrenia patients: A possible relationship between SIRT1 and BDNF. Prog Neuropsychopharmacol Biol Psychiatry. 2019;95:109673. doi: 10.1016/j.pnpbp.2019.109673