Abstract
Genes involved in the hypothalamic-pituitary-adrenal axis may be a robust biomarker of psychiatric disorders. Genetic polymorphisms of the SKA2 gene are associated with several behavioral disorders. In this study, we embarked on a systematic search of all possible reports of genetic association with SKA2 and affective disorder, post-traumatic stress disorder, and suicide behavior; the functional consequences of nsSNPs were explored through computational tools with an in silico analysis. Eight eligible articles were included. Our study identified that SKA2 did not show association with risk of Major Depression Disorder. Epigenetic variation at SKA2 mediates vulnerability to Post-Traumatic Stress Disorder. Studies provide strong preliminary evidence that alterations at the SKA2 gene covary with types of suicide behavior, including suicidal ideation, attempts, and completions. Results from in silico analysis predicted that I22S, I22G, I78T, A15L, D18R, R25L, N42I, Y21S, K14I, K14L, and L60R were the most structurally and functionally significant nsSNPs in SKA2. Amino acid conservation analysis revealed that the amino acids were highly conserved and some dissimilarities of mutant type amino acids from wild-type amino acids such as charge, size, and hydrophobicity were observed. In the future, SKA2 gene have the potential to be evaluated as prognostic biomarkers for diagnosis and research.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
References
Berent D, Emilien G, Podgórski M, Kusideł E, Kulczycka-Wojdala D, Szymańska B,…. Pawłowska Z (2017) SSTR4, Childhood adversity, self-efficacy and suicide risk in alcoholics. Transl Neurosci 8:76–86. https://doi.org/10.1515/tnsci-2017-0013
Boks MP, Rutten BP, Geuze E, Houtepen LC, Vermetten E, Kaminsky Z, Vinkers CH (2016) SKA2 methylation is involved in cortisol stress reactivity and Predicts the Development of Post-Traumatic Stress Disorder (PTSD) after military deployment. Neuropsychopharmacology 41(5):1350–1356. https://doi.org/10.1038/npp.2015.286
Broom A, Jacobi Z, Trainor K, Meiering EM (2017) Computational tools help improve protein stability but with a solubility tradeoff. J Biol Chem 292(35):14349–14361. https://doi.org/10.1074/jbc.M117.784165
Chasman D, Adams RM (2001) Predicting the functional consequences of non-synonymous single nucleotide polymorphisms: structure-based assessment of amino acid variation. J Mol Biol 307(2):683–706. https://doi.org/10.1006/jmbi.2001.4510
Del Arco A, Mora F (2009) Neurotransmitters and prefrontal cortex-limbic system interactions: implications for plasticity and psychiatric disorders. J Neural Transm (Vienna) 116(8):941–952. https://doi.org/10.1007/s00702-009-0243-8
Deller MC, Kong L, Rupp B (2016) Protein stability: a crystallographer’s perspective. Acta Crystallogr F Struct Biol Commun 72(Pt 2):72–95. https://doi.org/10.1107/s2053230x15024619
Di Iorio CR, Carey CE, Michalski LJ, Corral-Frias NS, Conley ED, Hariri AR, Bogdan R (2017) Hypothalamic-pituitary-adrenal axis genetic variation and early stress moderates amygdala function. Psychoneuroendocrinology 80:170–178. https://doi.org/10.1016/j.psyneuen.2017.03.016
González-Castro TB, Juárez-Rojop IE, Tovilla-Zárate CA, Ovando-Ricárdez JA, Hernández-Díaz Y, López-Narváez ML, … Rodríguez-Pérez C (2023). Gene-environment interaction between HPA-axis genes and trauma exposure in the suicide behavior: A systematic review. J Psychiatr Res 164:162–170.https://doi.org/10.1016/j.jpsychires.2023.06.011
Guintivano J, Brown T, Newcomer A, Jones M, Cox O, Maher BS, … Kaminsky ZA (2014) Identification and replication of a combined epigenetic and genetic biomarker predicting suicide and suicidal behaviors. Am J Psychiatry 171(12):1287–1296. https://doi.org/10.1176/appi.ajp.2014.14010008
Hernández-Díaz Y, Genis-Mendoza AD, González-Castro TB, Tovilla-Zárate CA, Juárez-Rojop IE, López-Narváez ML, Nicolini H (2021) Association and genetic expression between genes involved in HPA axis and suicide behavior: A systematic review. Genes (Basel) 12(10). https://doi.org/10.3390/genes12101608
Juruena MF, Eror F, Cleare AJ, Young AH (2020) The role of early life stress in HPA axis and anxiety. Adv Exp Med Biol 1191:141–153. https://doi.org/10.1007/978-981-32-9705-0_9
Kaminsky Z, Wilcox HC, Eaton WW, Van Eck K, Kilaru V, Jovanovic T, … Smith AK (2015) Epigenetic and genetic variation at SKA2 predict suicidal behavior and post-traumatic stress disorder. Transl Psychiatry 5(8):e627. https://doi.org/10.1038/tp.2015.105
Lira SS, Ahammad I (2021) A comprehensive in silico investigation into the nsSNPs of Drd2 gene predicts significant functional consequences in dopamine signaling and pharmacotherapy. Sci Rep 11(1):23212. https://doi.org/10.1038/s41598-021-02715-z
Mora C, Zonca V, Riva MA, Cattaneo A (2018) Blood biomarkers and treatment response in major depression. Expert Rev Mol Diagn 18(6):513–529. https://doi.org/10.1080/14737159.2018.1470927
Murphy F, Nasa A, Cullinane D, Raajakesary K, Gazzaz A, Sooknarine V, … Roddy DW (2022) Childhood trauma, the HPA axis and psychiatric illnesses: a targeted literature synthesis. Front Psychiatry 13:748372. https://doi.org/10.3389/fpsyt.2022.748372
Nakajima M, Hattori E, Yamada K, Iwayama Y, Toyota T, Iwata Y, … Yoshikawa T (2007) Association and synergistic interaction between promoter variants of the DRD4 gene in Japanese schizophrenics. J Hum Genet 52(1):86–91. https://doi.org/10.1007/s10038-006-0084-3
Navapour L, Mogharrab N (2021) In silico screening and analysis of nonsynonymous SNPs in human CYP1A2 to assess possible associations with pathogenicity and cancer susceptibility. Sci Rep 11(1):4977. https://doi.org/10.1038/s41598-021-83696-x
Ng QX, Yong BZJ, Ho CYX, Lim DY, Yeo WS (2018) Early life sexual abuse is associated with increased suicide attempts: An update meta-analysis. J Psychiatr Res 99:129–141. https://doi.org/10.1016/j.jpsychires.2018.02.001
Nobile B, Ramoz N, Jaussent I, Dubois J, Guillaume S, Gorwood P, Courtet P (2020) Polymorphisms of stress pathway genes and emergence of suicidal ideation at antidepressant treatment onset. Transl Psychiatry 10(1):320. https://doi.org/10.1038/s41398-020-01003-0
O’Connell KS, Frei O, Bahrami S, Smeland OB, Bettella F, Cheng W, … Andreassen OA (2021) Characterizing the genetic overlap between psychiatric disorders and sleep-related phenotypes. Biol Psychiatry 90(9):621–631.https://doi.org/10.1016/j.biopsych.2021.07.007
Pandey GN, Rizavi HS, Zhang H, Bhaumik R, Ren X (2016) The expression of the suicide-associated gene SKA2 is decreased in the prefrontal cortex of suicide victims but not of nonsuicidal patients. Int J Neuropsychopharmacol 19(8). https://doi.org/10.1093/ijnp/pyw015
Pettersson E, Lichtenstein P, Larsson H, Song J, Agrawal A, Børglum AD, … Polderman TJC (2019) Genetic influences on eight psychiatric disorders based on family data of 4 408 646 full and half-siblings, and genetic data of 333 748 cases and controls. Psychol Med 49(7):1166–1173. https://doi.org/10.1017/s0033291718002039
Rice L, Waters CE, Eccles J, Garside H, Sommer P, Kay P, … Ray DW (2008) Identification and functional analysis of SKA2 interaction with the glucocorticoid receptor. J Endocrinol 198(3):499–509.https://doi.org/10.1677/joe-08-0019
Sabbagh JJ, Cordova RA, Zheng D, Criado-Marrero M, Lemus A, Li P, … Blair LJ (2018) Targeting the FKBP51/GR/Hsp90 complex to identify functionally relevant treatments for depression and PTSD. ACS Chem Biol 13(8):2288–2299.https://doi.org/10.1021/acschembio.8b00454
Sadeh N, Wolf EJ, Logue MW, Hayes JP, Stone A, Griffin LM, … Miller MW (2016) Epigenetic Variation at SKA2 predicts suicide phenotypes and internalizing psychopathology. Depress Anxiety 33(4):308–315.https://doi.org/10.1002/da.22480
Stoyanov DS (2021) Molecular pathway phenotypes and endophenotypes in psychiatry: Part I. Curr Top Med Chem 21(11):937. https://doi.org/10.2174/156802662111210719101559
Valderrama J, Macrynikola N, Miranda R (2022) Early life trauma, suicide ideation, and suicide attempts: The role of rumination and impulsivity. Arch Suicide Res 26(2):731–747. https://doi.org/10.1080/13811118.2020.1828208
Valenzuela-García LI, Ayala-García VM, Ramos-Rosales DF, Jacquez-Flores RE, Urtiz-Estrada N, Hernández EMM, Barraza-Salas M (2023) The rs7208505 polymorphism and differential expression of the SKA2 gene in the prefrontal cortex of suicide victims from the Mexican Population. Arch Suicide Res 1–12. https://doi.org/10.1080/13811118.2023.2209155
van Bodegom M, Homberg JR, Henckens M (2017) Modulation of the hypothalamic-pituitary-adrenal axis by early life stress exposure. Front Cell Neurosci 11:87. https://doi.org/10.3389/fncel.2017.00087
Witham S, Takano K, Schwartz C, Alexov E (2011) A missense mutation in CLIC2 associated with intellectual disability is predicted by in silico modeling to affect protein stability and dynamics. Proteins 79(8):2444–2454. https://doi.org/10.1002/prot.23065
Xie M, Bu Y (2019) SKA2/FAM33A: A novel gene implicated in cell cycle, tumorigenesis, and psychiatric disorders. Genes Dis 6(1):25–30. https://doi.org/10.1016/j.gendis.2018.11.001
Yin H, Galfalvy H, Pantazatos SP, Huang YY, Rosoklija GB, Dwork AJ, … Mann JJ (2016) Glucocorticoid receptor-related genes: genotype and brain gene expression relationships to suicide and major depressive disorder. Depress Anxiety 33(6):531–540. https://doi.org/10.1002/da.22499
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Author information
Authors and Affiliations
Contributions
All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Thelma Beatriz González-Castro, Itzel Rodríguez-Fuentes and Yazmín Hernández-Díaz. The first draft of the manuscript was written by Yazmin Hernández-Díaz and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Ethics approval
Not applicable.
Consent to participate
Not applicable.
Consent to publish
Not applicable.
Conflicting interests
The authors declare that there is no conflict of interest.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
González-Castro, T.B., Rodríguez-Fuentes, I., Tovilla-Zárate, C.A. et al. The role of SKA2 on affective disorder, post-traumatic stress disorder and suicide behavior: systematic review and in silico analysis. Metab Brain Dis (2024). https://doi.org/10.1007/s11011-024-01346-3
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s11011-024-01346-3