This research aimed to develop a machine learning algorithm to predict suicide risk in bipolar disorder (BD) patients using RNA sequencing analysis of lymphoblastoid cell lines (LCLs). By identifying differentially expressed genes (DEGs) between high and low risk patients and their enrichment in relevant pathways, we gained insights into the molecular mechanisms underlying suicide risk. LCL gene expression analysis revealed pathway enrichment related to primary immunodeficiency, ion channels, and cardiovascular defects. Notably, genes such as LCK, KCNN2, and GRIA1 emerged as pivotal, suggesting their potential roles as biomarkers. Machine learning algorithms trained on a subset of the patients and tested on others demonstrated high accuracy in distinguishing low and high risk of suicide in BD patients. Additionally, the study explored the genetic overlap between suicide-related genes and several psychiatric disorders. Our study enhances the understanding of the complex interplay between genetics and suicidal behaviour, providing a foundation for prevention strategies.

Department of Biomedical Sciences University of Cagliari Cagliari Italy

Department of Psychiatry Dalhousie University Halifax NS Canada

National Institute of Mental Health Klecany Czech Republic

Sagol Department of Neurobiology University of Haifa Haifa Israel

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World Health Organization. Suicide. (n.d.). https://www.who.int/news-room/fact-sheets/detail/suicide. Accessed 25 Mar 2025

Bachmann S. Epidemiology of suicide and the psychiatric perspective. Int J Env Res Public Health. 2018;15:1425. PubMed DOI PMC

Pinals DA. Liability and patient suicide. Focus. 2019;17:349–54. PubMed DOI PMC

Cavanagh JT, Carson AJ, Sharpe M, Lawrie SM. Psychological autopsy studies of suicide: a systematic review. Psychol Med. 2003;33:395–405. PubMed DOI

Arsenault-Lapierre G, Kim C, Turecki G. Psychiatric diagnoses in 3275 suicides: a meta-analysis. BMC Psychiatry. 2004;4:37. PubMed DOI PMC

Harris EC, Barraclough B. Suicide as an outcome for mental disorders. A meta-analysis. Br J Psychiatry. 1997;170:205–28. PubMed DOI

Jones S, Riste L, Barrowclough C, Bartlett P, Clements C, Davies L, et al. Reducing relapse and suicide in bipolar disorder: practical clinical approaches to identifying risk, reducing harm and engaging service users in planning and delivery of care - the PARADES (Psychoeducation, Anxiety, Relapse, Advance Directive Evaluation and Suicidality) programme. Programme Grants for Applied Research. Southampton (UK) 2018. 10.3310/pgfar06060 PubMed

da Silva Costa L, Alencar AP, Nascimento Neto PJ, do Socorro Vieira dos Santos M, da Silva CG, de França Lacerda Pinheiro S, et al. Risk factors for suicide in bipolar disorder: a systematic review. J Affect Disord. 2015;170:237–54. PubMed DOI

Costa Lda SAÁ, Nascimento Neto PJ, dos Santos Mdo S, da Silva CG, Pinheiro Sde F, Silveira RT, et al. Bipolar disorder and suicide. J Psychiatry Neurological Sci. 2013;26:139–47.

Simon NM, Zalta AK, Otto MW, Ostacher MJ, Fischmann D, Chow CW, et al. The association of comorbid anxiety disorders with suicide attempts and suicidal ideation in outpatients with bipolar disorder. J Psychiatr Res. 2007;41:255–64. PubMed DOI

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. PubMed DOI

Zhu R, Tian S, Wang H, Jiang H, Wang X, Shao J, et al. Discriminating suicide attempters and predicting suicide risk using altered frontolimbic resting-state functional connectivity in patients with bipolar II disorder. Front Psychiatry. 2020;11:597770. PubMed DOI PMC

Strakowski SM, McElroy SL, Keck PE Jr, West SA. Suicidality among patients with mixed and manic bipolar disorder. Am J Psychiatry. 1996;153:674–6. PubMed DOI

Dome P, Rihmer Z, Gonda X. Suicide risk in bipolar disorder: a brief review. Medicina. 2019;55:403. PubMed DOI PMC

Lee S, Tsang A, Kessler RC, Jin R, Sampson N, Andrade L, et al. Rapid-cycling bipolar disorder: cross-national community study. Br J Psychiatry. 2010;196:217–25. PubMed DOI PMC

Berardelli I, Rogante E, Sarubbi S, Erbuto D, Cifrodelli M, Concolato C, et al. Is lethality different between males and females? Clinical and gender differences in inpatient suicide attempters. Int J Env Res Public Health. 2022;19:13309. PubMed DOI PMC

Monnin J, Thiemard E, Vandel P, Nicolier M, Tio G, Courtet P, et al. Sociodemographic and psychopathological risk factors in repeated suicide attempts: gender differences in a prospective study. J Affect Disord. 2012;136:35–43. PubMed DOI

Miller JN, Black DW. Bipolar disorder and suicide: a review. Curr Psychiatry Rep. 2020;22:6. PubMed DOI

Isometsa ET, Lonnqvist JK. Suicide attempts preceding completed suicide. Br J Psychiatry. 1998;173:531–5. PubMed DOI

Bostwick JM, Pankratz VS. Affective disorders and suicide risk: a reexamination. Am J Psychiatry. 2000;157:1925–32. PubMed DOI

Conwell Y, Duberstein PR, Cox C, Herrmann J, Forbes N, Caine ED. Age differences in behaviors leading to completed suicide. Am J Geriatr Psychiatry. 1998;6:122–6. PubMed DOI

Ribeiro JD, Franklin JC, Fox KR, Bentley KH, Kleiman EM, Chang BP, et al. Self-injurious thoughts and behaviors as risk factors for future suicide ideation, attempts, and death: a meta-analysis of longitudinal studies. Psychol Med. 2016;46:225–36. PubMed DOI PMC

Antypa N, Serretti A. Family history of a mood disorder indicates a more severe bipolar disorder. J Affect Disord. 2014;156:178–86. PubMed DOI

Antypa N, Antonioli M, Serretti A. Clinical, psychological and environmental predictors of prospective suicide events in patients with bipolar disorder. J Psychiatr Res. 2013;47:1800–8. PubMed DOI

Guillaume S, Jaussent I, Jollant F, Rihmer Z, Malafosse A, Courtet P. Suicide attempt characteristics may orientate toward a bipolar disorder in attempters with recurrent depression. J Affect Disord. 2010;122:53–9. PubMed DOI

Maniglio R. The impact of child sexual abuse on the course of bipolar disorder: a systematic review. Bipolar Disord. 2013;15:341–58. PubMed DOI

Etain B, Aas M, Andreassen OA, Lorentzen S, Dieset I, Gard S, et al. Childhood trauma is associated with severe clinical characteristics of bipolar disorders. J Clin Psychiatry. 2013;74:991–8. PubMed DOI

Erten E, Funda Uney A, Saatcioglu O, Ozdemir A, Fistikci N, Cakmak D. Effects of childhood trauma and clinical features on determining quality of life in patients with bipolar I disorder. J Affect Disord. 2014;162:107–13. PubMed DOI

Aas M, Etain B, Bellivier F, Henry C, Lagerberg T, Ringen A, et al. Additive effects of childhood abuse and cannabis abuse on clinical expressions of bipolar disorders. Psychol Med. 2014;44:1653–62. PubMed DOI

Tsai SY, Lee JC, Chen CC. Characteristics and psychosocial problems of patients with bipolar disorder at high risk for suicide attempt. J Affect Disord. 1999;52:145–52. PubMed DOI

Chiba T, Ide K, Murakami M, Kobayashi N, Oka T, Nakai F, et al. Event-related PTSD symptoms as a high-risk factor for suicide: longitudinal observational study. Nat Ment Health. 2023;1:1013–22. DOI

Hatoum AS, Colbert SMC, Johnson EC, Huggett SB, Deak JD, Pathak G, et al. Multivariate genome-wide association meta-analysis of over 1 million subjects identifies loci underlying multiple substance use disorders. Nat Ment Health. 2023;1:210–23. PubMed DOI PMC

Choudhary A, Peles D, Nayak R, Mizrahi L, Stern S. Current progress in understanding schizophrenia using genomics and pluripotent stem cells: a meta-analytical overview. Schizophr Res. 2024;273:24–38. PubMed DOI

Antypa N, Serretti A, Rujescu D. Serotonergic genes and suicide: a systematic review. Eur Neuropsychopharmacol. 2013;23:1125–42. PubMed DOI

Brezo J, Klempan T, Turecki G. The genetics of suicide: a critical review of molecular studies. Psychiatr Clin North Am. 2008;31:179–203. PubMed DOI

Courtet P, Jollant F, Castelnau D, Buresi C, Malafosse A. Suicidal behavior: relationship between phenotype and serotonergic genotype. Am J Med Genet C Semin Med Genet. 2005;133C:25–33. PubMed DOI

Brezo J, Bureau A, Merette C, Jomphe V, Barker ED, Vitaro F, et al. Differences and similarities in the serotonergic diathesis for suicide attempts and mood disorders: a 22-year longitudinal gene-environment study. Mol Psychiatry. 2010;15:831–43. PubMed DOI

Mann JJ. The serotonergic system in mood disorders and suicidal behaviour. Philos Trans R Soc Lond B Biol Sci. 2013;368:20120537. PubMed DOI PMC

Bigdeli TB, Barr PB, Rajeevan N, Graham DP, Li Y, Meyers JL, et al. Correlates of suicidal behaviors and genetic risk among United States veterans with schizophrenia or bipolar I disorder. Mol Psychiatry. 2024;29:2399–407. PubMed DOI

Rozanov V, Mazo G. Using the strategy of genome-wide association studies to identify genetic markers of suicidal behavior: a narrative review. Consort Psychiatr. 2024;5:63–77. PubMed PMC

Ceja Z, van Velzen LS, Campos AI, Jahanshad N, Medland SE, Edwards AC, et al. Recent breakthroughs in genetic and brain structural correlates of suicidal behaviors: a short review. Biol Psychiatry. 2025;97:775–85. PubMed DOI

Dwivedi Y. Brain-derived neurotrophic factor and suicide pathogenesis. Ann Med. 2010;42:87–96. PubMed DOI PMC

Banerjee R, Ghosh AK, Ghosh B, Bhattacharyya S, Mondal AC. Decreased mRNA and protein expression of BDNF, NGF, and their receptors in the hippocampus from suicide: an analysis in human postmortem brain. Clin Med Insights Pathol. 2013;6:1–11. PubMed DOI PMC

Kohli MA, Salyakina D, Pfennig A, Lucae S, Horstmann S, Menke A, et al. Association of genetic variants in the neurotrophic receptor-encoding gene NTRK2 and a lifetime history of suicide attempts in depressed patients. Arch Gen Psychiatry. 2010;67:348–59. PubMed DOI PMC

Pivac N, Pregelj P, Nikolac M, Zupanc T, Nedic G, Muck Seler D, et al. The association between catechol-O-methyl-transferase Val108/158Met polymorphism and suicide. Genes Brain Behav. 2011;10:565–9. PubMed DOI

Antypa N, Souery D, Tomasini M, Albani D, Fusco F, Mendlewicz J, et al. Clinical and genetic factors associated with suicide in mood disorder patients. Eur Arch Psychiatry Clin Neurosci. 2016;266:181–93. PubMed DOI

Isayeva U, Manchia M, Collu R, Primavera D, Deriu L, Caboni E, et al. Exploring the association between brain-derived neurotrophic factor levels and longitudinal psychopathological and cognitive changes in Sardinian psychotic patients. Eur Psychiatry. 2022;65:e71. PubMed DOI PMC

Magno LA, Miranda DM, Neves FS, Pimenta GJ, Mello MP, De Marco LA, et al. Association between AKT1 but not AKTIP genetic variants and increased risk for suicidal behavior in bipolar patients. Genes Brain Behav. 2010;9:411–8. PubMed DOI

Ekinci O, Albayrak Y, Ekinci AE, Caykoylu A. Relationship of trait impulsivity with clinical presentation in euthymic bipolar disorder patients. Psychiatry Res. 2011;190:259–64. PubMed DOI

Jimenez E, Arias B, Mitjans M, Goikolea JM, Roda E, Saiz PA, et al. Genetic variability at IMPA2, INPP1 and GSK3beta increases the risk of suicidal behavior in bipolar patients. Eur Neuropsychopharmacol. 2013;23:1452–62. PubMed DOI

Sequeira A, Mamdani F, Lalovic A, Anguelova M, Lesage A, Seguin M, et al. Alpha 2A adrenergic receptor gene and suicide. Psychiatry Res. 2004;125:87–93. PubMed DOI

Zai CC, Goncalves VF, Tiwari AK, Gagliano SA, Hosang G, de Luca V, et al. A genome-wide association study of suicide severity scores in bipolar disorder. J Psychiatr Res. 2015;65:23–9. PubMed DOI

Mizrahi L, Choudhary A, Ofer P, Goldberg G, Milanesi E, Kelsoe JR, et al. Immunoglobulin genes expressed in lymphoblastoid cell lines discern and predict lithium response in bipolar disorder patients. Mol Psychiatry. 2023;28:4280–93. PubMed DOI PMC

Docherty AR, Mullins N, Ashley-Koch AE, Qin X, Coleman JRI, Shabalin A, et al. GWAS meta-analysis of suicide attempt: identification of 12 genome-wide significant loci and implication of genetic risks for specific health factors. Am J Psychiatry. 2023;180:723–38. PubMed DOI PMC

Breen MS, White CH, Shekhtman T, Lin K, Looney D, Woelk CH, et al. Lithium-responsive genes and gene networks in bipolar disorder patient-derived lymphoblastoid cell lines. Pharmacogenomics J. 2016;16:446–53. PubMed DOI

Hunsberger JG, Chibane FL, Elkahloun AG, Henderson R, Singh R, Lawson J, et al. Novel integrative genomic tool for interrogating lithium response in bipolar disorder. Transl Psychiatry. 2015;5:e504. PubMed DOI PMC

Morag A, Pasmanik-Chor M, Oron-Karni V, Rehavi M, Stingl JC, Gurwitz D. Genome-wide expression profiling of human lymphoblastoid cell lines identifies CHL1 as a putative SSRI antidepressant response biomarker. Pharmacogenomics. 2011;12:171–84. PubMed DOI

Squassina A, Costa M, Congiu D, Manchia M, Angius A, Deiana V, et al. Insulin-like growth factor 1 (IGF-1) expression is up-regulated in lymphoblastoid cell lines of lithium responsive bipolar disorder patients. Pharmacol Res. 2013;73:1–7. PubMed DOI

Milanesi E, Voinsky I, Hadar A, Srouji A, Maj C, Shekhtman T, et al. RNA sequencing of bipolar disorder lymphoblastoid cell lines implicates the neurotrophic factor HRP-3 in lithium’s clinical efficacy. World J Biol Psychiatry. 2019;20:449–61. PubMed DOI

Squassina A, Niola P, Lopez JP, Cruceanu C, Pisanu C, Congiu D, et al. MicroRNA expression profiling of lymphoblasts from bipolar disorder patients who died by suicide, pathway analysis and integration with postmortem brain findings. Eur Neuropsychopharmacol. 2020;34:39–49. PubMed DOI

Spitzer RL, Endicott J, Robins E. Research diagnostic criteria: rationale and reliability. Arch Gen Psychiatry. 1978;35:773–82. PubMed DOI

Endicott J, Spitzer RL. A diagnostic interview: the schedule for affective disorders and schizophrenia. Arch Gen Psychiatry. 1978;35:837–44. PubMed DOI

Squassina A, Manchia M, Chillotti C, Deiana V, Congiu D, Paribello F, et al. Differential effect of lithium on spermidine/spermine N1-acetyltransferase expression in suicidal behaviour. Int J Neuropsychopharmacol. 2013;16:2209–18. PubMed DOI

Darlington GJ. Epstein-barr virus transformation of lymphoblasts. CSH Protoc. 2006;2006:pdb.prot4481. PubMed

Simon Andrews. FastQC: a quality control tool for high throughput sequence data. Babraham Bioinformatics 2010.

Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15–21. PubMed DOI PMC

Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550. PubMed DOI PMC

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. DOI

Gao M, Wong NML, Lin C, Huang C‐M, Liu H‐L, Toh C-H, et al. Multimodal brain connectome-based prediction of suicide risk in people with late-life depression. Nat Ment Health. 2023;1:100–13. DOI

Sharma O, Sahoo NC, Puhan NB. Highway lane-changing prediction using a hierarchical software architecture based on support vector machine and continuous hidden Markov model. Int J Intell Transp Syst Res. 2022;20:519–39.

Lalvani S, Bari S, Vike NL, Stefanopoulos L, Kim B-W, Block M, et al. Predicting suicidality with small sets of interpretable reward behavior and survey variables. Nat Ment Health. 2024;2:773–86. DOI

Tripathi U, Mizrahi L, Alda M, Falkovich G, Stern S. Information theory characteristics improve the prediction of lithium response in bipolar disorder patients using a support vector machine classifier. Bipolar Disord. 2023;25:110–27. PubMed DOI

Madanlal D, Guinard C, Nunez VP, Becker S, Garnham J, Khayachi A, et al. A pilot study examining the impact of lithium treatment and responsiveness on mnemonic discrimination in bipolar disorder. J Affect Disord. 2024;351:49–57. PubMed DOI

Singh S. The effects of bipolar disorder granule cell hyperexcitability and lithium therapy on pattern separation in a computational model of the dentate gyrus. bioRxiv. [Preprint]. 2024. Available from: https://www.biorxiv.org/content/10.1101/2024.04.09.588764v1. DOI

Santos R, Linker SB, Stern S, Mendes APD, Shokhirev MN, Erikson G, et al. Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients. Mol Psychiatry. 2021;26:2440–56. PubMed DOI PMC

Trivedi D, Sharma O, Pattnaik S, Hazra V, Punhan NB. Improving rainfall forecast at the district scale over the eastern Indian region using deep neural network. Theor Appl Climatol. 2024;155:761–77. DOI

Stern S, Linker S, Vadodaria KC, Marchetto MC, Gage FH. Prediction of response to drug therapy in psychiatric disorders. Open Biol. 2018;8:180031. PubMed DOI PMC

Buniello A, MacArthur JAL, Cerezo M, Harris LW, Hayhurst J, Malangone C, et al. The NHGRI-EBI GWAS catalog of published genome-wide association studies, targeted arrays and summary statistics 2019. Nucleic Acids Res. 2019;47:D1005–D12. PubMed DOI PMC

Jeremian R, Malinowski A, Chaudhary Z, Srivastava A, Qian J, Zai C, et al. Epigenetic age dysregulation in individuals with bipolar disorder and schizophrenia. Psychiatry Res. 2022;315:114689. PubMed DOI

Lima CNC, Kovacs EHC, Mirza S, Del Favero-Campbell A, Diaz AP, Quevedo J, et al. Association between the epigenetic lifespan predictor GrimAge and history of suicide attempt in bipolar disorder. Neuropsychopharmacology. 2023;48:954–62. PubMed DOI PMC

Martinez D, Lavebratt C, Millischer V, de Jesus RdPV, Pires T, Michelon L, et al. Shorter telomere length and suicidal ideation in familial bipolar disorder. PLoS One. 2022;17:e0275999. PubMed DOI PMC

Herrera-Rivero M, Gutierrez-Fragoso K, International Consortium on Lithium G, Kurtz J, Baune BT. Immunogenetics of lithium response and psychiatric phenotypes in patients with bipolar disorder. Transl Psychiatry. 2024;14:174. PubMed DOI PMC

Nielsen RE, Banner J, Jensen SE. Cardiovascular disease in patients with severe mental illness. Nat Rev Cardiol. 2021;18:136–45. PubMed DOI

Quraishi IH, Stern S, Mangan KP, Zhang Y, Ali SR, Mercier MR, et al. An epilepsy-associated KCNT1 mutation enhances excitability of human iPSC-Derived neurons by increasing slack K(Na) currents. J Neurosci. 2019;39:7438–49. PubMed DOI PMC

Gananca L, Oquendo MA, Tyrka AR, Cisneros-Trujillo S, Mann JJ, Sublette ME. The role of cytokines in the pathophysiology of suicidal behavior. Psychoneuroendocrinology. 2016;63:296–310. PubMed DOI PMC

Xu Y, Liang J, Gao W, Sun Y, Zhang Y, Shan F, et al. Peripheral blood cytokines as potential diagnostic biomarkers of suicidal ideation in patients with first-episode drug-naive major depressive disorder. Front Public Health. 2022;10:1021309. PubMed DOI PMC

Hoprekstad GE, Skrede S, Bartz-Johannessen C, Joa I, Reitan SK, Steen VM, et al. Association between cytokines and suicidality in patients with psychosis: a multicentre longitudinal analysis. Brain Behav Immun Health. 2024;37:100756. PubMed DOI PMC

Weigent DA. High molecular weight isoforms of growth hormone in cells of the immune system. Cell Immunol. 2011;271:44–52. PubMed DOI PMC

Alrfooh A, Casten LG, Gringer Richards J, Wemmie JA, Magnotta VA, Fiedorowicz JG, et al. Investigating the relationship between DNA methylation, genetic variation, and suicide attempt in bipolar disorder. Arch Suicide Res. 2025. 10.1080/13811118.2025.2511264 PubMed DOI PMC

Delgado-Sequera A, Perez-Revuelta JI, Caballero-Garcia A, Duran-Ruiz M, Romero-Lopez-Alberca C, Garcia-Mompo C, et al. Distinct patterns of cell adhesion, migration, and morphology in olfactory neuroepithelium cells of bipolar disorder patients. Mol Med. 2024;30:271. PubMed DOI PMC

Chaves-Filho A, Eyres C, Blobaum L, Landwehr A, Tremblay ME. The emerging neuroimmune hypothesis of bipolar disorder: an updated overview of neuroimmune and microglial findings. J Neurochem. 2024;168:1780–816. PubMed DOI

Garcia-Ruiz B, Jimenez E, Aranda S, Verdolini N, Gutierrez-Zotes A, Saez C, et al. Associations of altered leukocyte DDR1 promoter methylation and childhood trauma with bipolar disorder and suicidal behavior in euthymic patients. Mol Psychiatry. 2024;29:2478–86. PubMed DOI

Naggan L, Robinson E, Dinur E, Goldenberg H, Kozela E, Yirmiya R. Suicide in bipolar disorder patients is associated with hippocampal microglia activation and reduction of lymphocytes-activation gene 3 (LAG3) microglial checkpoint expression. Brain Behav Immun. 2023;110:185–94. PubMed DOI

Roy B, Ochi S, Dwivedi Y. Potential of circulating miRNAs as molecular markers in mood disorders and associated suicidal behavior. Int J Mol Sci. 2023;24:4664. PubMed DOI PMC

Sandberg JV, Hansson C, Goteson A, Joas E, Jakobsson J, Palsson E, et al. Proteins associated with future suicide attempts in bipolar disorder: a large-scale biomarker discovery study. Mol Psychiatry. 2022;27:3857–63. PubMed DOI PMC

Jiang X, Guo Y, Jia L, Zhu Y, Sun Q, Kong L, et al. Altered levels of plasma inflammatory cytokines and white matter integrity in bipolar disorder patients with suicide attempts. Front Psychiatry. 2022;13:861881. PubMed DOI PMC

Huang MH, Chen MH, Chan YE, Li CT, Tsai SJ, Bai YM, et al. Pro-inflammatory cytokines and suicidal behavior among patients with bipolar I disorder. J Psychiatr Res. 2022;150:346–52. PubMed DOI

Loo JL, Mohamad Kamal NA, Goon JA, Ahmad Damanhuri H, Tan JAC, Abdul Murad NA, et al. The role of oxidative stress in suicidal behaviour among bipolar patients: a cross-sectional study in a malaysian sample. Front Psychiatry. 2021;12:698911. PubMed DOI PMC

Aytac HM, Oyaci Y, Yazar MS, Erol A, Pehlivan S. Association of MIF and MBL2 gene polymorphisms with attempted suicide in patients diagnosed with schizophrenia or bipolar disorder. J Clin Neurosci. 2020;78:264–8. PubMed DOI

Shah K, Al-Haidari A, Sun J, Kazi JU. T cell receptor (TCR) signaling in health and disease. Signal Transduct Target Ther. 2021;6:412. PubMed DOI PMC

Ting JP, Trowsdale J. Genetic control of MHC class II expression. Cell. 2002;109(Suppl):S21–33. PubMed DOI

Park SR. Activation-induced cytidine deaminase in B cell immunity and cancers. Immune Netw. 2012;12:230–9. PubMed DOI PMC

Koh CH, Lee S, Kwak M, Kim BS, Chung Y. CD8 T-cell subsets: heterogeneity, functions, and therapeutic potential. Exp Mol Med. 2023;55:2287–99. PubMed DOI PMC

Sheng L, Leshchyns’ka I, Sytnyk V. Cell adhesion and intracellular calcium signaling in neurons. Cell Commun Signal. 2013;11:94. PubMed DOI PMC

Brown DA. Neurons, receptors, and channels. Annu Rev Pharmacol Toxicol. 2020;60:9–30. PubMed DOI

Dean C, Scholl FG, Choih J, DeMaria S, Berger J, Isacoff E, et al. Neurexin mediates the assembly of presynaptic terminals. Nat Neurosci. 2003;6:708–16. PubMed DOI PMC

Zheng M, Chen R, Chen H, Zhang Y, Chen J, Lin P, et al. Netrin-1 promotes synaptic formation and axonal regeneration via JNK1/c-Jun pathway after the middle cerebral artery occlusion. Front Cell Neurosci. 2018;12:13. PubMed DOI PMC

Berselli A, Benfenati F, Maragliano L, Alberini G. Multiscale modelling of claudin-based assemblies: a magnifying glass for novel structures of biological interfaces. Comput Struct Biotechnol J. 2022;20:5984–6010. PubMed DOI PMC

Kim HG, Kishikawa S, Higgins AW, Seong IS, Donovan DJ, Shen Y, et al. Disruption of neurexin 1 associated with autism spectrum disorder. Am J Hum Genet. 2008;82:199–207. PubMed DOI PMC

Gregor A, Albrecht B, Bader I, Bijlsma EK, Ekici AB, Engels H, et al. Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1. BMC Med Genet. 2011;12:106. PubMed DOI PMC

Chen J, Dong B, Feng X, Jiang D, Chen G, Long C, et al. Aberrant mPFC GABAergic synaptic transmission and fear behavior in neuroligin-2 R215H knock-in mice. Brain Res. 2020;1730:146671. PubMed DOI

Jesudas BR, Nandeesha H, Menon V, Allimuthu P. Relationship of elevated neural cell adhesion molecule 1 with interleukin-10 and disease severity in bipolar disorder. Asian J Psychiatr. 2020;47:101849. PubMed DOI

Dai G. Signaling by ion channels: pathways, dynamics and channelopathies. Mo Med. 2023;120:367–73. PubMed PMC

Stern S, Segal M, Moses E. Involvement of potassium and cation channels in hippocampal abnormalities of embryonic Ts65Dn and Tc1 trisomic mice. EBioMedicine. 2015;2:1048–62. PubMed DOI PMC

Catterall WA. Voltage-gated calcium channels. Cold Spring Harb Perspect Biol. 2011;3:a003947. PubMed DOI PMC

Bouza AA, Isom LL. Voltage-gated sodium channel beta subunits and their related diseases. Handb Exp Pharmacol. 2018;246:423–50. PubMed DOI PMC

Kim DM, Nimigean CM. Voltage-gated potassium channels: a structural examination of selectivity and gating. Cold Spring Harb Perspect Biol. 2016;8:a029231. PubMed DOI PMC

Frank B, Niesler B, Nothen MM, Neidt H, Propping P, Bondy B, et al. Investigation of the human serotonin receptor gene HTR3B in bipolar affective and schizophrenic patients. Am J Med Genet B Neuropsychiatr Genet. 2004;131B:1–5. PubMed DOI

Wang L, Wang M, Zhao C, Jian J, Qiao D. Association of HTR3B gene polymorphisms with depression and its executive dysfunction: a case-control study. BMC Psychiatry. 2023;23:128. PubMed DOI PMC

Vadodaria KC, Stern S, Marchetto MC, Gage FH. Serotonin in psychiatry: in vitro disease modeling using patient-derived neurons. Cell Tissue Res. 2018;371:161–70. PubMed DOI

Kim JB. Channelopathies. Korean J Pediatr. 2014;57:1–18. PubMed DOI PMC

Bernardi J, Aromolaran KA, Aromolaran AS. Neurological disorders and risk of arrhythmia. Int J Mol Sci. 2020;22:188. PubMed DOI PMC

Pekny M, Nilsson M. Astrocyte activation and reactive gliosis. Glia. 2005;50:427–34. PubMed DOI

Park H, Poo MM. Neurotrophin regulation of neural circuit development and function. Nat Rev Neurosci. 2013;14:7–23. PubMed DOI

Nagappan PG, Chen H, Wang DY. Neuroregeneration and plasticity: a review of the physiological mechanisms for achieving functional recovery postinjury. Mil Med Res. 2020;7:30. PubMed PMC

Sun Z, Costell M, Fassler R. Integrin activation by talin, kindlin and mechanical forces. Nat Cell Biol. 2019;21:25–31. PubMed DOI

Plow EF, Meller J, Byzova TV. Integrin function in vascular biology: a view from 2013. Curr Opin Hematol. 2014;21:241–7. PubMed DOI PMC

Wang CS, Kavalali ET, Monteggia LM. BDNF signaling in context: from synaptic regulation to psychiatric disorders. Cell. 2022;185:62–76. PubMed DOI PMC

Zou Y, Zhang Y, Tu M, Ye Y, Li M, Ran R, et al. Brain-derived neurotrophic factor levels across psychiatric disorders: a systemic review and network meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2024;131:110954. PubMed DOI

Blacker CJ, Lewis CP, Frye MA, Veldic M. Metabotropic glutamate receptors as emerging research targets in bipolar disorder. Psychiatry Res. 2017;257:327–37. PubMed DOI

Hu VW, Frank BC, Heine S, Lee NH, Quackenbush J. Gene expression profiling of lymphoblastoid cell lines from monozygotic twins discordant in severity of autism reveals differential regulation of neurologically relevant genes. BMC Genom. 2006;7:118. PubMed DOI PMC

Scheinfeldt LB, Hodges K, Pevsner J, Berlin D, Turan N, Gerry NP. Genetic and genomic stability across lymphoblastoid cell line expansions. BMC Res Notes. 2018;11:558. PubMed DOI PMC

Annesley SJ, Fisher PR. Lymphoblastoid Cell Lines as Models to Study Mitochondrial Function in Neurological Disorders. Int J Mol Sci. 2021;22:4536. PubMed PMC

Romanovsky E, Choudhary A, Peles D, Abu-Akel A, Stern S. Uncovering convergence and divergence between autism and schizophrenia using genomic tools and patients’ neurons. Mol Psychiatry. 2025;30:1019–28. PubMed DOI PMC

Peykov S, Berkel S, Schoen M, Weiss K, Degenhardt F, Strohmaier J, et al. Identification and functional characterization of rare SHANK2 variants in schizophrenia. Mol Psychiatry. 2015;20:1489–98. PubMed DOI PMC

Guilmatre A, Huguet G, Delorme R, Bourgeron T. The emerging role of SHANK genes in neuropsychiatric disorders. Dev Neurobiol. 2014;74:113–22. PubMed DOI

Chen RS, Deng TC, Garcia T, Sellers ZM, Best PM. Calcium channel gamma subunits: a functionally diverse protein family. Cell Biochem Biophys. 2007;47:178–86. PubMed DOI

Guan F, Zhang T, Liu X, Han W, Lin H, Li L, et al. Evaluation of voltage-dependent calcium channel gamma gene families identified several novel potential susceptible genes to schizophrenia. Sci Rep. 2016;6:24914. PubMed DOI PMC

Cunha SR, Mohler PJ. Ankyrin protein networks in membrane formation and stabilization. J Cell Mol Med. 2009;13:4364–76. PubMed DOI PMC

Wirgenes KV, Tesli M, Inderhaug E, Athanasiu L, Agartz I, Melle I, et al. ANK3 gene expression in bipolar disorder and schizophrenia. Br J Psychiatry. 2014;205:244–5. PubMed DOI

Falls DL. Neuregulins: functions, forms, and signaling strategies. Exp Cell Res. 2003;284:14–30. PubMed DOI

Meier S, Strohmaier J, Breuer R, Mattheisen M, Degenhardt F, Muhleisen TW, et al. Neuregulin 3 is associated with attention deficits in schizophrenia and bipolar disorder. Int J Neuropsychopharmacol. 2013;16:549–56. PubMed DOI

Osete JR, Akkouh IA, Ievglevskyi O, Vandenberghe M, de Assis DR, Ueland T, et al. Transcriptional and functional effects of lithium in bipolar disorder iPSC-derived cortical spheroids. Mol Psychiatry. 2023;28:3033–43. PubMed DOI PMC

Nayak R, Rosh I, Kustanovich I, Stern S. Mood stabilizers in psychiatric disorders and mechanisms learnt from in vitro model systems. Int J Mol Sci. 2021;22:9315. PubMed DOI PMC

Tobe BTD, Crain AM, Winquist AM, Calabrese B, Makihara H, Zhao WN, et al. Probing the lithium-response pathway in hiPSCs implicates the phosphoregulatory set-point for a cytoskeletal modulator in bipolar pathogenesis. Proc Natl Acad Sci USA. 2017;114:E4462–E71. PubMed DOI PMC

Stern S, Santos R, Marchetto MC, Mendes APD, Rouleau GA, Biesmans S, et al. Neurons derived from patients with bipolar disorder divide into intrinsically different sub-populations of neurons, predicting the patients’ responsiveness to lithium. Mol Psychiatry. 2018;23:1453–65. PubMed DOI PMC

Stern S, Sarkar A, Stern T, Mei A, Mendes APD, Stern Y, et al. Mechanisms underlying the hyperexcitability of CA3 and dentate gyrus hippocampal neurons derived from patients with bipolar disorder. Biol Psychiatry. 2020;88:139–49. PubMed DOI PMC

Stern S, Sarkar A, Galor D, Stern T, Mei A, Stern Y, et al. A physiological instability displayed in hippocampal neurons derived from lithium-nonresponsive bipolar disorder patients. Biol Psychiatry. 2020;88:150–8. PubMed DOI PMC

Nayak R, Rosh I, Rabinski T, Falik D, Mendel Percia M, Stern S. Generation and characterization of iPSC lines (UOHi003-A, UOHi002-A) from a patient with SHANK3 mutation and her healthy mother. Stem Cell Res. 2022;64:102899. PubMed DOI