Abstract
In this study, we investigate the epigenetic mechanisms associated with current suicidal ideation. Gene expression changes have been found in post-mortem brain of suicide victims. However, it is not clear how in-vivo gene expression change confers risk for suicide. DNA methylation is a form of epigenetic modification that regulates gene expression. Our primary aim is to investigate genome-wide methylation in conferring risk for current suicidal ideation (SI) in schizophrenia. The presence of current SI and genome-wide methylation patterns were assessed in 107 patients with schizophrenia. DNA methylation has been measured in white blood cells as a possible peripheral biomarker of SI. SI was the primary outcome variable in a model including methylation status of white blood cells using the Illumina 450 array. We have tested the association with genome-wide methylation levels in 19 subjects with current SI and 88 subjects without current SI and we found that higher methylation level in the CpG cg06121808 located in the gene SLC20A1 on chromosome 2 was associated with current SI (p = 0.000003; beta difference = 0.06). Furthermore, the distal promoter analysis showed that the gene SMPD2 was hypermethylated in suicide ideators (p = 0.0001; beta difference = 0.02). Thus, molecular biomarkers could advance our understanding of the molecular mechanisms of stress-related SI. Furthermore, the methylation sites that we have identified should be replicated in other suicide related phenotypes to generate robust biomarkers with high translational value for proof of concept interventions aiming at reducing SI.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Alexander N, Wankerl M, Hennig J, Miller R, Zankert S, Steudte-Schmiedgen S, Stalder T, Kirschbaum C (2014) DNA methylation profiles within the serotonin transporter gene moderate the association of 5-HTTLPR and cortisol stress reactivity. Transl Psychiatry 4:e443. https://doi.org/10.1038/tp.2014.88
Bani-Fatemi A, Howe AS, Matmari M, Koga A, Zai C, Strauss J, De Luca V (2016) Interaction between methylation and CpG sing-nucleotide polymorphisms in the HTR2A gene: association analysis with suicide attempt in schizophrenia. Neuropsychobiology 73(1):10–15. https://doi.org/10.1159/000441191
Bani-Fatemi A, Jeremiah R, Wang KZ, Silveira J, Zai C, Kolla NJ, Graff A, Gerretsen P, Strauss J, De Luca V (2018) Epigenome-wide association study of suicide attempt in schizophrenia. J Psychiatr Res 104:192–197. https://doi.org/10.1016/j.jpsychires.2018.07.011
Bornheimer LA, Jaccard J (2017) Symptoms of depression, positive symptoms of psychosis, and suicidal ideation among adults diagnosed with schizophrenia within the clinical antipsychotic trials of intervention effectiveness. Arch Suicide Res 21(4):633–645. https://doi.org/10.1080/13811118.2016.1224990
Brown GW, Harris T (1982) Disease, distress and depression. A comment. J Affect Disord 4(1):1–8. https://doi.org/10.1016/0165-0327(82)90012-X
Chaix R, Fagny M, Cosin-Tomás M, Alvarez-Lopez M, Lemee L, Regnault B, Davidson RJ, Lutz A, Kaliman P (2020) Differential DNA methylation in experienced meditators after an intensive day of mindfulness-based practice: Implications for immune-related pathway. Brain Behav Immun 84:36–44. https://doi.org/10.1016/j.bbi.2019.11.003
De Luca V, Viggiano E, Dhoot R, Kennedy JL, Wong AH (2009) Methylation and QTDT analysis of the 5-HT2A receptor 102C allele: analysis of suicidality in major psychosis. J Psychiatr Res 43(5):532–537. https://doi.org/10.1016/j.jpsychires.2008.07.007
Dedeurwaerder S, Defrance M, Calonne E, Denis H, Sotiriou C, Fuks F (2011) Evaluation of the Infinium Methylation 450K technology. Epigenomics 3(6):771–784
Gardea-Resendez M, Kucuker MU, Blacker CJ, Ho AM-C, Croarkin PE, Frye MA, Veldic M (2020) Dissecting the epigenetic changes induced by non-antipsychotic mood stabilizers on schizophrenia and affective disorders: a systematic review. Front Pharmacol 11:467. https://doi.org/10.3389/fphar.2020.00467
Guintivano J, Brown T, Newcomer A, Jones M, Cox O, Maher BS, Eaton WW, Payne JL, Wilcox HC, 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
Heilä H, Heikkinen ME, Isometsä ET, Henriksson MM, Marttunen MJ, Lönnqvist JK (1999) Life events and completed suicide in schizophrenia: a comparison of suicide victims with and without schizophrenia. Schizophr Bull 25(3):519–531. https://doi.org/10.1093/oxfordjournals.schbul.a033398
Kaminsky Z, Wilcox HC, Eaton WW, Van Eck K, Kilaru V, Jovanovic T, Klengel T, Bradley B, Binder EB, Ressler KJ, Smith AK (2015) Epigenetic and genetic variation at SKA2 predict suicidal behavior and post-traumatic stress disorder. Transl Psychiatry 5:e627. https://doi.org/10.1038/tp.2015.105
Kendler KS (2010) Genetic and environmental pathways to suicidal behavior: reflections of a genetic epidemiologist. Eur Psychiatry 25(5):300–303. https://doi.org/10.1016/j.eurpsy.2010.01.005
Kouter K, Zupanc T, Videtič PA (2019) Genome-wide DNA methylation in suicide victims revealing impact on gene expression. J Affect Disord 253:419–425. https://doi.org/10.1016/j.jad.2019.04.077
Lahiri DK, Nurnberger JI (1991) A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies. Nucleic Acids Res 19(19):5444
Le-Niculescu H, Levey DF, Ayalew M, Palmer L, Gavrin LM, Jain N, Winiger E, Bhosrekar S, Shankar G, Radel M, Bellanger E, Duckworth H, Olesek K, Vergo J, Schweitzer R, Yard M, Ballew A, Shekhar A, Sandusky GE, Schork NJ, Kurian SM, Salomon DR, Niculescu AB (2013) Discovery and validation of blood biomarkers for suicidality. Mol Psychiatry 18(12):1249–1264. https://doi.org/10.1038/mp.2013.95
Lim U, Song MA (2012) Dietary and lifestyle factors of DNA methylation. Methods Mol Biol 863:359–376. https://doi.org/10.1007/978-1-61779-612-8_23
Mann JJ, Currier D, Stanley B, Oquendo MA, Amsel LV, Ellis SP (2006) Can biological tests assist prediction of suicide in mood disorders? Int J Neuropsychopharmacol 9(4):465–474. https://doi.org/10.1017/S1461145705005687
McGowan PO, Sasaki A, D’Alessio AC, Dymov S, Labonte B, Szyf M, Turecki G, Meaney MJ (2009) Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci 12(3):342–348. https://doi.org/10.1038/nn.2270
Oquendo MA, Galfalvy H, Russo S, Ellis SP, Grunebaum MF, Burke A, Mann JJ (2004) Prospective study of clinical predictors of suicidal acts after a major depressive episode in patients with major depressive disorder or bipolar disorder. Am J Psychiatry 161(8):1433–1441. https://doi.org/10.1176/appi.ajp.161.8.1433
Overall JE, Gorham DR (1962) The brief psychiatric rating scale. Psychol Rep 10(3):799–812. https://doi.org/10.2466/pr0.1962.10.3.799
Perlis RH, Huang J, Purcell S, Fava M, Rush AJ, Sullivan PF, Hamilton SP, McMahon FJ, Schulze TG, Potash JB, Zandi PP, Willour VL, Penninx BW, Boomsma DI, Vogelzangs N, Middeldorp CM, Rietschel M, Nöthen M, Cichon S, Gurling H, Bass N, McQuillin A, Hamshere M, Wellcome Trust Case Control Consortium Bipolar Disorder Group, Craddock N, Sklar P, Smoller JW (2010) Genome-wide association study of suicide attempts in mood disorder patients. Am J Psychiatry 167(12):1499–1507. https://doi.org/10.1176/appi.ajp.2010.10040541
Pidsley R, Zotenko E, Peters TJ, Lawrence MG, Risbridger GP, Molloy P, Van Djik S, Muhlhausler B, Stirzaker C, Clark SJ (2016) Critical evaluation of the Illumina MethylationEPIC BeadChip microarray for whole-genome DNA methylation profiling. Genome Biol 17(1):208
Posner K, Brent D, Lucas C, Gould M, Stanley B, Brown G, Fisher P, Zelazny J, Burke A, Oquendo M, Mann JJ (2008) Columbia-suicide severity rating scale (C-SSRS). Columbia University Medical Center, New York
Romens SE, McDonald J, Svaren J, Pollak SD (2015) Associations between early life stress and gene methylation in children. Child Dev 86(1):303–309. https://doi.org/10.1111/cdev.12270
Ryan J, Saffery R (2014) Crucial timing in schizophrenia: role of DNA methylation in early neurodevelopment. Genome Biol 15(10):495. https://doi.org/10.1186/s13059-014-0495-y
Schosser A, Butler AW, Ising M, Perroud N, Uher R, Ng MY, Cohen-Woods S, Craddock N, Owen MJ, Korszun A, Jones L, Jones I, Gill M, Rice JP, Maier W, Mors O, Rietschel M, Lucae S, Binder EB, Preisig M, Perry J, Tozzi F, Muglia P, Aitchison KJ, Breen G, Craig IW, Farmer AE, Müller-Myhsok B, McGuffin P, Lewis CM (2011) Genomewide association scan of suicidal thoughts and behaviour in major depression. PLoS ONE 6(7):e20690. https://doi.org/10.1371/journal.pone.0020690
Spitzer RL, Williams JB, Gibbon M, First MB (1992) The structured clinical interview for DSM-III-R (SCID). I: history, rationale, and description. Arch Gen Psychiatry 49(8):624–629. https://doi.org/10.1001/archpsyc.1992.01820080032005
Turecki G (2014) The molecular bases of the suicidal brain. Nat Rev Neurosci 15(12):802–816. https://doi.org/10.1038/nrn3839
Tyrka AR, Price LH, Marsit C, Walters OC, Carpenter LL (2012) Childhood adversity and epigenetic modulation of the leukocyte glucocorticoid receptor: preliminary findings in healthy adults. PLoS ONE 7(1):e30148. https://doi.org/10.1371/journal.pone.0030148
Wang D, Yan L, Hu Q, Sucheston LE, Higgins MJ, Ambrosone CB, Johnson CS, Smiraglia DJ, Liu S (2012) IMA: an R package for high-throughput analysis of Illumina's 450K Infinium methylation data. Bioinformatics 28(5):729–730. https://doi.org/10.1093/bioinformatics/bts013
Willour VL, Seifuddin F, Mahon PB, Jancic D, Pirooznia M, Steele J, Schweizer B, Goes FS, Mondimore FM, Mackinnon DF, Consortium BGS, Perlis RH, Lee PH, Huang J, Kelsoe JR, Shilling PD, Rietschel M, Nöthen M, Cichon S, Gurling H, Purcell S, Smoller JW, Craddock N, DePaulo JR, Schulze TG, McMahon FJ, Zandi PP, Potash JB (2012) A genome-wide association study of attempted suicide. Mol Psychiatry 17(4):433–444. https://doi.org/10.1038/mp.2011.4
Funding
This work was supported by a Miner’s Lamp Grant from the Department of Psychiatry at the University of Toronto, a pilot Grant from the American Foundation for Suicide Prevention (AFSP), and a Canadian Institutes of Health Research (CIHR) operating grant.
Author information
Authors and Affiliations
Corresponding author
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Bani-Fatemi, A., Adanty, C., Dai, N. et al. Genome-wide methylation association with current suicidal ideation in schizophrenia. J Neural Transm 127, 1315–1322 (2020). https://doi.org/10.1007/s00702-020-02225-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00702-020-02225-8