Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Associations of altered leukocyte DDR1 promoter methylation and childhood trauma with bipolar disorder and suicidal behavior in euthymic patients

Molecular Psychiatry (2024)Cite this article

Subjects

Abstract

Altered DNA methylation (DNAm) patterns of discoidin domain receptor 1 (DDR1) have been found in the blood and brain of patients with schizophrenia (SCZ) and the brain of patients with bipolar disorder (BD). Childhood trauma (CT) is associated with changes in DNAm that in turn are related to suicidal behavior (SB) in patients with several psychiatric disorders. Here, using MassARRAY® technology, we studied 128 patients diagnosed with BD in remission and 141 healthy controls (HCs) to compare leukocyte DDR1 promoter DNAm patterns between patients and HCs and between patients with and without SB. Additionally, we investigated whether CT was associated with DDR1 DNAm and mediated SB. We found hypermethylation at DDR1 cg19215110 and cg23953820 sites and hypomethylation at cg14279856 and cg03270204 sites in patients with BD compared to HCs. Logistic regression models showed that hypermethylation of DDR1 cg23953820 but not cg19215110 and CT were risk factors for BD, while cg14279856 and cg03270204 hypomethylation were protective factors. In patients, CT was a risk factor for SB, but DDR1 DNAm, although associated with CT, did not mediate the association of CT with SB. This is the first study demonstrating altered leukocyte DDR1 promoter DNAm in euthymic patients with BD. We conclude that altered DDR1 DNAm may be related to immune and inflammatory mechanisms and could be a potential blood biomarker for the diagnosis and stratification of psychiatric patients.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Differential DDR1 DNAm between patients with BD and HCs.

Similar content being viewed by others

Data availability

The dataset supporting the conclusions of this article is available from the corresponding author upon reasonable request. All packages used in the data analysis were identified to ensure full reproducibility.

References

  1. Vilella E, Gas C, Garcia-Ruiz B, Rivera FJ. Expression of DDR1 in the CNS and in myelinating oligodendrocytes. Biochim Biophys acta Mol cell Res. 2019;1866:118483. https://doi.org/10.1016/j.bbamcr.2019.04.010.

    Article  PubMed  Google Scholar 

  2. Corty MM, Hulegaard AL, Hill JQ, Sheehan AE, Aicher SA, Freeman MR. Discoidin domain receptor regulates ensheathment, survival and caliber of peripheral axons. Development. 2022;149:dev200636. https://doi.org/10.1242/dev.200636.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Muntané G, Chillida M, Aranda S, Navarro A, Vilella E. Coexpression of the discoidin domain receptor 1 gene with oligodendrocyte-related and schizophrenia risk genes in the developing and adult human brain. Brain Behav. 2021;11:1–10. https://doi.org/10.1002/brb3.2309.

    Article  Google Scholar 

  4. Roig B, Abasolo N, Moyano S, Martorell L, Vilella E. Increased expression of the spliced DDR1c isoform in brain tissues from schizophrenia patients. J Psychiatr Res. 2012;46:825–7.

    Article  PubMed  Google Scholar 

  5. Franco-Pons N, Tomas J, Roig B, Auladell C, Martorell L, Vilella E. Discoidin domain receptor 1, a tyrosine kinase receptor, is upregulated in an experimental model of remyelination and during oligodendrocyte differentiation in vitro. J Mol Neurosci. 2009;38:2–11. https://doi.org/10.1007/s12031-008-9151-x.

    Article  CAS  PubMed  Google Scholar 

  6. Franco-Pons N, Virgos C, Vogel WF, Urena JM, Soriano E, del Rio JA. et al. Expression of discoidin domain receptor 1 during mouse brain development follows the progress of myelination. Neuroscience. 2006;140:463–75. https://doi.org/10.1016/j.neuroscience.2006.02.033.

    Article  CAS  PubMed  Google Scholar 

  7. Garcia-Ruiz B, De Moura MC, Muntané G, Martorell L, Bosch E, Esteller M. et al. DDR1 methylation is associated with bipolar disorder and the isoform expression and methylation of myelin genes. Epigenomics. 2021;13:845–58. https://doi.org/10.2217/epi-2021-0006.

    Article  CAS  PubMed  Google Scholar 

  8. Garcia-Ruiz B, Moreno L, Muntané G, Sánchez-Gistau V, Gutiérrez-Zotes A, Martorell L. et al. Leukocyte and brain DDR1 hypermethylation is altered in psychosis and is correlated with stress and inflammatory markers. Epigenomics. 2020;12:251–65. https://doi.org/10.2217/epi-2019-0191.

    Article  CAS  PubMed  Google Scholar 

  9. Canales-Rodríguez EJ, Pomarol-Clotet E, Radua J, Sarró S, Alonso-Lana S, Del Mar Bonnín C. et al. Structural abnormalities in bipolar euthymia: A multicontrast molecular diffusion imaging study. Biol Psychiatry. 2014;76:239–48. https://doi.org/10.1016/j.biopsych.2013.09.027.

    Article  PubMed  Google Scholar 

  10. Favre P, Pauling M, Stout J, Hozer F, Sarrazin S, Abé C. et al. Widespread white matter microstructural abnormalities in bipolar disorder: evidence from mega- and meta-analyses across 3033 individuals. Neuropsychopharmacology. 2019;44:2285–93. https://doi.org/10.1038/s41386-019-0485-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Poletti S, Bollettini I, Lorenzi C, Vitali A, Brioschi S, Serretti A. et al. White Matter Microstructure in Bipolar Disorder Is Influenced by the Interaction between a Glutamate Transporter EAAT1 Gene Variant and Early Stress. Mol Neurobiol. 2019;56:702–10. https://doi.org/10.1007/s12035-018-1117-6.

    Article  CAS  PubMed  Google Scholar 

  12. Tkachev D, Mimmack ML, Ryan MM, Wayland M, Freeman T, Jones PB. et al. Oligodendrocyte dysfunction in schizophrenia and bipolar disorder. Lancet. 2003;362:798–805. https://doi.org/10.1016/S0140-6736(03)14289-4.

    Article  CAS  PubMed  Google Scholar 

  13. Gordovez FJA, McMahon FJ. The genetics of bipolar disorder. Mol Psychiatry. 2020;25:544–59. https://doi.org/10.1038/s41380-019-0634-7.

    Article  PubMed  Google Scholar 

  14. Mullins N, Forstner AJ, O’Connell KS, Coombes B, Coleman JRI, Qiao Z. et al. Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology. Nat Genet. 2021;53:817–29. https://doi.org/10.1038/s41588-021-00857-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hara T, Owada Y, Takata A. Genetics of bipolar disorder: insights into its complex architecture and biology from common and rare variants. J Hum Genet. 2023;68:183–91. https://doi.org/10.1038/s10038-022-01046-9.

    Article  PubMed  Google Scholar 

  16. Arsenault-Lapierre G, Kim C, Turecki G. Psychiatric diagnoses in 3275 suicides: A meta-analysis. BMC Psychiatry. 2004;4:1–11. https://doi.org/10.1186/1471-244X-4-37.

    Article  Google Scholar 

  17. Miller JN, Black DW. Bipolar Disorder and Suicide: a Review. Curr Psychiatry Rep. 2020;22:6. https://doi.org/10.1007/s11920-020-1130-0.

    Article  PubMed  Google Scholar 

  18. Plans L, Barrot C, Nieto E, Rios J, Schulze TG, Papiol S, et al. Association between completed suicide and bipolar disorder: A systematic review of the literature. J Affect Disord. 2019;242:111–22. https://doi.org/10.1016/j.jad.2018.08.054.

    Article  CAS  PubMed  Google Scholar 

  19. Palmier-Claus JE, Berry K, Bucci S, Mansell W, Varese F. Relationship between childhood adversity and bipolar affective disorder: systematic review and meta-analysis. Br J Psychiatry. 2016;209:454–9. https://doi.org/10.1192/bjp.bp.115.179655.

    Article  CAS  PubMed  Google Scholar 

  20. Kessler RC, McLaughlin KA, Green JG, Gruber MJ, Sampson NA, Zaslavsky AM, et al. Childhood adversities and adult psychopathology in the WHO world mental health surveys. Br J Psychiatry. 2010;197:378–85. https://doi.org/10.1192/BJP.BP.110.080499.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Sahle BW, Reavley NJ, Li W, Morgan AJ, Yap MBH, Reupert A, et al. The association between adverse childhood experiences and common mental disorders and suicidality: an umbrella review of systematic reviews and meta-analyses. Eur Child Adolesc Psychiatry. 2022;31:1489–99. https://doi.org/10.1007/s00787-021-01745-2.

    Article  PubMed  Google Scholar 

  22. Parade SH, Huffhines L, Daniels TE, Stroud LR, Nugent NR, Tyrka AR. A systematic review of childhood maltreatment and DNA methylation: candidate gene and epigenome-wide approaches. Transl Psychiatry. 2021;11:134. https://doi.org/10.1038/s41398-021-01207-y.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Løkhammer S, Stavrum A, Polushina T, Aas M, Ottesen A, Andreassen O, et al. An epigenetic association analysis of childhood trauma in psychosis reveals possible overlap with methylation changes associated with PTSD. Transl Psychiatry. 2022;12:177. https://doi.org/10.1038/s41398-022-01936-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Fachim HA, Corsi-Zuelli F, Loureiro CM, Iamjan Sarun, Shuhama R, Joca S, et al. Early-life stress effects on BDNF DNA methylation in first-episode psychosis and in rats reared in isolation. Prog Neuro-Psychopharmacol Biol Psychiatry. 2021;108:110188. https://doi.org/10.1016/j.pnpbp.2020.110188.

    Article  CAS  Google Scholar 

  25. Dunn EC, Soare TW, Zhu Y, Simpkin AJ, Suderman MJ, Klengel T, et al. Sensitive Periods for the Effect of Childhood Adversity on DNA Methylation: Results From a Prospective, Longitudinal Study. Biol Psychiatry. 2019;85:838–49. https://doi.org/10.1016/j.biopsych.2018.12.023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lutz PE, Mechawar N, Turecki G. Neuropathology of suicide: Recent findings and future directions. Mol Psychiatry. 2017;22:1395–412. https://doi.org/10.1038/mp.2017.141.

    Article  PubMed  Google Scholar 

  27. Turecki G, Meaney M. Effects of the social environment and stress on glucocorticoid receptor gene methylation: a systematic review. Biol Psychiatry. 2016;79:87–96. https://doi.org/10.1016/j.biopsych.2014.11.022.

    Article  CAS  PubMed  Google Scholar 

  28. McLaughlin KA, Sheridan MA, Nelson CA. Neglect as a Violation of Species-Expectant Experience: Neurodevelopmental Consequences. Biol Psychiatry. 2017;82:462–71. https://doi.org/10.1016/j.biopsych.2017.02.1096.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Montalvo-Ortiz JL. A New Perspective on the Mechanisms of Neglect. Biol Psychiatry. 2017;82:e49–50. https://doi.org/10.1016/j.biopsych.2017.07.013.

    Article  PubMed  Google Scholar 

  30. Salagre E, Arango C, Artigas F, Ayuso-Mateos JL, Bernardo M, Castro-Fornieles J, et al. CIBERSAM: Ten years of collaborative translational research in mental disorders. Rev Psiquiatr Salud Ment. 2019;12:1–8. https://doi.org/10.1016/j.rpsm.2018.10.001.

    Article  Google Scholar 

  31. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56–62. https://doi.org/10.1136/JNNP.23.1.56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry. 1978;133:429–35. https://doi.org/10.1192/bjp.133.5.429.

    Article  CAS  PubMed  Google Scholar 

  33. Wechsler D. WAIS-III administration and scoring manual. San Anotnio, TX: The Psychological Corporation; 1997.

    Google Scholar 

  34. Leucht S, Samara M, Heres S, Patel MX, Woods SW, Davis JM. Dose equivalents for second-generation antipsychotics: The minimum effective dose method. Schizophr Bull. 2014;40:314–26. https://doi.org/10.1093/schbul/sbu001.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Rothe PH, Heres S, Leucht S. Dose equivalents for second generation long-acting injectable antipsychotics: The minimum effective dose method. Schizophr Res. 2018;193:23–8. https://doi.org/10.1016/j.schres.2017.07.033.

    Article  PubMed  Google Scholar 

  36. Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011;168:1266–77. https://doi.org/10.1176/appi.ajp.2011.10111704.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Bernstein DP, Fink L. Childhood Trauma Questionnaire: A retrospective self-report manual. San Anotnio, TX: The Psychological Corporation; 1998.

    Google Scholar 

  38. Ehrich M, Nelson MR, Stanssens P, Zabeau M, Liloglou T, Xinarianos G, et al. Quantitative high-throughput analysis of DNA methylation patterns by base-specific cleavage and mass spectrometry. Proc Natl Acad Sci USA. 2005;102:15785–90. https://doi.org/10.1073/pnas.0507816102.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  39. Roig B, Virgos C, Franco N, Martorell L, Valero J, Costas J, et al. The discoidin domain receptor 1 as a novel susceptibility gene for schizophrenia. Mol Psychiatry. 2007;12:833–41. https://doi.org/10.1038/sj.mp.4001995.

    Article  CAS  PubMed  Google Scholar 

  40. Gas C, Canales-Rodriguez EJ, Radua J, Abasolo N, Cortes MJ, Salvado E, et al. Discoidin domain receptor 1 gene variants are associated with decreased white matter fractional anisotropy and decreased processing speed in schizophrenia. J Psychiatr Res. 2019;110:74–82. https://doi.org/10.1016/j.jpsychires.2018.12.021.

    Article  PubMed  Google Scholar 

  41. Roig B, Moyano S, Martorell L, Costas J, Vilella E. The discoidin domain receptor 1 gene has a functional A2RE sequence. J Neurochem. 2012;120:408–18.

    Article  CAS  PubMed  Google Scholar 

  42. UCSC Genome Browser. http://genome.ucsc.edu.

  43. Encyclopedia of DNA elements (ENCODE) project. https://www.encodeproject.org.

  44. Lesurf R, Cotto KC, Wang G, Griffith M, Kasaian K, Jones SJM, et al. ORegAnno 3.0: A community-driven resource for curated regulatory annotation. Nucleic Acids Res. 2016;44:D126–32. https://doi.org/10.1093/nar/gkv1203.

    Article  CAS  PubMed  Google Scholar 

  45. R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing; 2021. https://www.r-project.org/.

  46. Wheeler RE, Torchiano M. lmPerm: Permutation tests for linear models. 2016. https://cran.r-project.org/package=lmPerm.

  47. Fox J, Weisberg S. An {R} Companion to Applied Regression, Third Edition. Thousand Oaks, CA; 2019. https://socialsciences.mcmaster.ca/jfox/Books/Companion/.

  48. Lele SR, Keim JL, Solymos P. ResourceSelection: Resource Selection (Probability) Functions for Use-Availability Data. 2019. https://cran.r-project.org/package=ResourceSelection.

  49. Yu Q, Li B. mma: Multiple Mediation Analysis. 2021. https://cran.r-project.org/web/packages/mma/index.html.

  50. Wickham H. Elegant Graphics for Data Analysis. New York: Springer-Verlag; 2016. https://ggplot2.tidyverse.org.

    Google Scholar 

  51. Benjamini Y, Hochberg Y. Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing. J R Stat Soc Ser B. 1995;57:289–300. https://doi.org/10.1111/j.2517-6161.1995.tb02031.x.

    Article  MathSciNet  Google Scholar 

  52. Igarashi H, Medina KL, Yokota T, Rossi MID, Sakaguchi N, Comp PC, et al. Early lymphoid progenitors in mouse and man are highly sensitive to glucocorticoids. Int Immunol. 2005;17:501–11. https://doi.org/10.1093/intimm/dxh230.

    Article  CAS  PubMed  Google Scholar 

  53. Chrousos GP. Stress, chronic inflammation, and emotional and physical well-being: Concurrent effects and chronic sequelae. J Allergy Clin Immunol. 2000;106:S275–91. https://doi.org/10.1067/mai.2000.110163.

    Article  CAS  PubMed  Google Scholar 

  54. Lu X, Chu CS, Fang T, Rayon-Estrada V, Fang F, Patke A, et al. MTA2/NuRD Regulates B Cell Development and Cooperates with OCA-B in Controlling the Pre-B to Immature B Cell Transition. Cell Rep. 2019;28:472–485.e5. https://doi.org/10.1016/j.celrep.2019.06.029.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Rybakowski JK. Lithium. Eur Neuropsychopharmacol. 2022;57:86–7. https://doi.org/10.1016/j.euroneuro.2022.01.111.

    Article  CAS  PubMed  Google Scholar 

  56. Fountoulakis KN, Tohen M, Zarate CA. Lithium treatment of Bipolar disorder in adults: A systematic review of randomized trials and meta-analyses. Eur Neuropsychopharmacol. 2022;54:100–15. https://doi.org/10.1016/j.euroneuro.2021.10.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Pisanu C, Meloni A, Severino G, Squassina A. Genetic and Epigenetic Markers of Lithium Response. Int J Mol Sci. 2022;23:1–23. https://doi.org/10.3390/ijms23031555.

    Article  CAS  Google Scholar 

  58. Marie-Claire C, Lejeune FX, Mundwiller E, Ulveling D, Moszer I, Bellivier F, et al. A DNA methylation signature discriminates between excellent and non-response to lithium in patients with bipolar disorder type 1. Sci Rep. 2020;10:1–9. https://doi.org/10.1038/s41598-020-69073-0.

    Article  CAS  Google Scholar 

  59. Viana J, Hannon E, Dempster E, Pidsley R, Macdonald R, Knox O, et al. Schizophrenia-associated methylomic variation: molecular signatures of disease and polygenic risk burden across multiple brain regions. Hum Mol Genet. 2017;26:210–25. https://doi.org/10.1093/hmg/ddw373.

    Article  CAS  PubMed  Google Scholar 

  60. Turecki G, Brent DA, Gunnell D, O’Connor RC, Oquendo MA, Pirkis J, et al. Suicide and suicide risk. Nat Rev Dis Prim. 2019;5:74. https://doi.org/10.1038/s41572-019-0121-0.

    Article  PubMed  Google Scholar 

  61. Clive ML, Boks MP, Vinkers CH, Osborne LM, Payne JL, Ressler KJ, et al. Discovery and replication of a peripheral tissue DNA methylation biosignature to augment a suicide prediction model. Clin Epigenet. 2016;8:1–14. https://doi.org/10.1186/s13148-016-0279-1.

    Article  CAS  Google Scholar 

  62. Rice L, Waters CE, Eccles J, Garside H, Sommer P, Kay P, et al. Identification and functional analysis of SKA2 interaction with the glucocorticoid receptor. J Endocrinol. 2008;198:499–509. https://doi.org/10.1677/JOE-08-0019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Guintivano J, Brown T, Newcomer A, Jones M, Cox O, Maher BS, et al. Identification and Replication of a Combined Epigenetic and Genetic Biomarker Predicting Suicide and Suicidal Behaviors. Am J Psychiatry. 2014;171:1287–96. https://doi.org/10.1176/appi.ajp.2014.14010008.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Kaminsky Z, Wilcox HC, Eaton WW, Van Eck K, Kilaru V, Jovanovic T, et al. Epigenetic and genetic variation at SKA2 predict suicidal behavior and post-traumatic stress disorder. Transl Psychiatry. 2015;5:627. https://doi.org/10.1038/tp.2015.105.

    Article  CAS  Google Scholar 

  65. Sadeh N, Wolf EJ, Logue MW, Hayes JP, Stone A, Griffin LM, et al. Epigenetic variation at SKA2 predicts suicide phenotypes and internalizing psychopathology. Depress Anxiety. 2016;33:308–15. https://doi.org/10.1002/da.22480.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Moyon S, Huynh JL, Dutta D, Zhang F, Ma D, Yoo S, et al. Functional Characterization of DNA Methylation in the Oligodendrocyte Lineage. Cell Rep. 2016;15:748–60. https://doi.org/10.1016/j.celrep.2016.03.060.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Duarte D, Belzeaux R, Etain B, Greenway KT, Rancourt E, Correa H, et al. Childhood-maltreatment subtypes in bipolar patients with suicidal behavior: systematic review and meta-analysis. Braz J Psychiatry. 2020;42:558–67. https://doi.org/10.1590/1516-4446-2019-0592.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Segura AG, Mitjans M, Jiménez E, Fatjó-Vilas M, Ruiz V, Saiz PA, et al. Association of childhood trauma and genetic variability of CRH-BP and FKBP5 genes with suicidal behavior in bipolar patients. J Affect Disord. 2019;255:15–22. https://doi.org/10.1016/j.jad.2019.05.014.

    Article  CAS  PubMed  Google Scholar 

  69. Montoro I, Moreno L, Mulet P, Miró C, Leunda A, Llaurador-Coll M, et al. Maximal Sensitivity to Child Maltreatment at the Ages of 6 and 11 Years is Associated with the Risk of Bipolar Disorder. J Interpers Violence. 2023;38:3030–54. https://doi.org/10.1177/08862605221106128.

    Article  PubMed  Google Scholar 

  70. Schönfelder A, Hallensleben N, Spangenberg L, Forkmann T, Rath D, Glaesmer H. The role of childhood abuse for suicidality in the context of the interpersonal theory of suicide: An investigation in German psychiatric inpatients with depression. J Affect Disord. 2019;245:788–97. https://doi.org/10.1016/j.jad.2018.11.063.

    Article  PubMed  Google Scholar 

  71. Turecki G. The molecular bases of the suicidal brain. Nat Rev Neurosci. 2014;15:802–16. https://doi.org/10.1038/nrn3839.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Brewin CR, Andrews B, Gotlib IH. Psychopathology and early experience: a reappraisal of retrospective reports. Psychol Bull. 1993;113:82–98. https://doi.org/10.1037/0033-2909.113.1.82.

    Article  CAS  PubMed  Google Scholar 

  73. Hogg B, Valiente-Gómez A, Redolar-Ripoll D, Gardoki-Souto I, Fontana-McNally M, Lupo W, et al. High incidence of PTSD diagnosis and trauma-related symptoms in a trauma exposed bipolar I and II sample. Front psychiatry. 2022;13:931374 https://doi.org/10.3389/fpsyt.2022.931374.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Jones GH, Vecera CM, Pinjari OF, Machado-Vieira R. Inflammatory signaling mechanisms in bipolar disorder. J Biomed Sci. 2021;28:1–22. https://doi.org/10.1186/s12929-021-00742-6.

    Article  Google Scholar 

  75. Rowland T, Perry BI, Upthegrove R, Barnes N, Chatterjee J, Gallacher D, et al. Neurotrophins, cytokines, oxidative stress mediators and mood state in bipolar disorder: Systematic review and meta-analyses. Br J Psychiatry. 2018;213:514–25. https://doi.org/10.1192/bjp.2018.144.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are extremely grateful to all the subjects who participated in this study. We also thank the IISPV Biobank staff for their excellent work in the preparation and processing of the biological samples used in this study and for their technical support. This study was supported by grants from the Brain and Behavior Research Foundation (2017 NARSAD Independent grant, #25811 to El. V.), Instituto de Salud Carlos III (Research Project PI15/00852 and PI18/00945 to El. V., PI15/00283 to Ed. V.), Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) (Intramural project grant to E Vieta) and Agència de Gestió d’Ajuts Universitaris i de Recerca (2017SGR00444 to El. V., 2017SGR01365 to Ed. V., 2017SGR01271 to E. P-C.). Selena Aranda was the recipient of a predoctoral fellowship granted by the Instituto de Salud Carlos III (PFIS FI19/00268), and Mar Fatjó-Vilas was the recipient of a Miguel Servet contract (CP20/00072; Instituto de Salud Carlos III; cofunded by the European Regional Development Fund (ERDF)/European Social Fund “Investing in your future”).

Author information

Authors and Affiliations

  1. Hospital Universitari Institut Pere Mata, Reus, Spain

    Beatriz Garcia-Ruiz, Selena Aranda, Alfonso Gutiérrez-Zotes, Cristina Sáez, Elisa Losantos & Elisabet Vilella

  2. Institut d’Investigació Sanitària Pere Virgili (IISPV)-CERCA, Tarragona, Spain

    Beatriz Garcia-Ruiz, Selena Aranda, Alfonso Gutiérrez-Zotes, Cristina Sáez & Elisabet Vilella

  3. Universitat Rovira i Virgili (URV), Reus, Spain

    Beatriz Garcia-Ruiz, Selena Aranda, Alfonso Gutiérrez-Zotes & Elisabet Vilella

  4. Centro de investigación biomédica en red en salud mental (CIBERSAM)-Instituto de Salud Carlos III, Madrid, Spain

    Esther Jiménez, Selena Aranda, Norma Verdolini, Alfonso Gutiérrez-Zotes, Cristina Sáez, Silvia Alonso-Lana, Mar Fatjó-Vilas, Salvador Sarró, Caterina del Mar Bonnin, Edith Pomarol-Clotet, Eduard Vieta & Elisabet Vilella

  5. Bipolar and Depressive Disorders Unit, Hospital Clínic de Barcelona, Barcelona, Spain

    Esther Jiménez, Norma Verdolini, Caterina del Mar Bonnin & Eduard Vieta

  6. Departament de Medicina, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), Barcelona, Spain

    Esther Jiménez, Norma Verdolini, Caterina del Mar Bonnin & Eduard Vieta

  7. Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Esther Jiménez, Norma Verdolini, Caterina del Mar Bonnin & Eduard Vieta

  8. Institute of Neurosciences (UBNeuro), Universitat de Barcelona, Barcelon, Spain

    Esther Jiménez, Norma Verdolini, Caterina del Mar Bonnin & Eduard Vieta

  9. FIDMAG Research Foundation, Germanes Hospitalàries, Barcelona, Spain

    Norma Verdolini, Silvia Alonso-Lana, Mar Fatjó-Vilas, Salvador Sarró & Edith Pomarol-Clotet

  10. Research Center and Memory Clinic Fundació ACE, Barcelona, Spain

    Silvia Alonso-Lana

  11. Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain

    Silvia Alonso-Lana

  12. Departament de Biologia Evolutiva, Ecologia i Ciències Ambientals, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain

    Mar Fatjó-Vilas

  13. Hospital Mare de Déu de la Mercè, Unitat Polivalent, Germanes Hospitalàries, Barcelona, Spain

    Llanos Torres

  14. Benito Menni Complex Assistencial en Salut Mental, Germanes Hospitalàries, Sant Boi de Llobregat, Barcelona, Spain

    Francesco Panicalli

Authors
  1. Beatriz Garcia-Ruiz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Esther Jiménez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Selena Aranda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Norma Verdolini
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alfonso Gutiérrez-Zotes
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Cristina Sáez
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Elisa Losantos
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Silvia Alonso-Lana
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mar Fatjó-Vilas
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Salvador Sarró
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Llanos Torres
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Francesco Panicalli
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Caterina del Mar Bonnin
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Edith Pomarol-Clotet
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Eduard Vieta
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Elisabet Vilella
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

ElV, EP-C, and EdV conceptualized and designed the study and provided funding acquisition, ethics approval, project administration, and resources. BG-R conceptualized and designed the study, performed DNA extraction, computed the statistical analyses, interpreted the results, produced the display items, and wrote the manuscript draft. ElV supervised the statistical analyses, interpreted the results, and wrote the manuscript draft. BG-R, EJ, SA, NV, AG-Z, CS, EL, SA-L, MF-V, SS, LlT, FP, and CM-B contributed to the recruitment of patients, collection and handling of blood samples, and acquisition and curation of research data. All the authors discussed the results, commented on the manuscript, and approved the final version for publication.

Corresponding author

Correspondence to Elisabet Vilella.

Ethics declarations

Competing interests

EdV has received grants and served as consultant, advisor, or CME speaker (unrelated to this work) for the following entities: AB-Biotics, Abbott, AbbVie, Angelini, Biogen, Compass, Dainippon Sumitomo Pharma, Ferrer, Gedeon Richter, Glaxo Smith-Kline, GH Research, Janssen, Lundbeck, Otsuka, Sage, Sanofi-Aventis, Sunovion, Takeda, and Viatris. The other authors have no conflicts of interest to disclose.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

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.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Garcia-Ruiz, B., Jiménez, E., Aranda, S. et al. Associations of altered leukocyte DDR1 promoter methylation and childhood trauma with bipolar disorder and suicidal behavior in euthymic patients. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02522-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41380-024-02522-8

Search

Advanced search

Quick links