RNA sequencing of bipolar disorder lymphoblastoid cell lines implicates the neurotrophic factor HRP-3 in lithium’s clinical efficacy

Milanesi, Elena; Voinsky, Irena; Hadar, Adva; Srouji, Ala; Maj, Carlo; Shekhtman, Tatyana; Gershovits, Michael; Gilad, Shlomit; Chillotti, Caterina; Squassina, Alessio; Potash, James B.; Schulze, Thomas G.; Goes, Fernando S.; Zandi, Peter P.; Kelsoe, John R.; Genevieve, David

doi:10.1080/15622975.2017.1372629

Cited by 13 publications

(28 citation statements)

References 78 publications

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“…However, ID2 expression was higher in PBMC from LNR compared with LR BD patients (Figure a; FD = 4.5, p = .0297). This finding is the opposite of what we expected based on our RNA‐sequencing study in LCLs (Milanesi et al, ). The reasons for this difference are unclear, and may reflect the fact that the majority of cells in the PBMC fraction are T lymphocytes while LCLs are derived from B lymphocytes (Ryan et al, ).…”

Section: Resultscontrasting

confidence: 99%

“…We recently reported, based on a genome‐wide RNA‐sequencing study, that two protein coding genes, the transcription factor ID2 (inhibitor of DNA binding 2) and HDGFRP3 (hepatoma‐derived growth factor, related protein 3), showed differential expression when comparing the transcriptome of lymphoblastoid cell lines (LCLs) from LR and LNR BD patients (Milanesi et al, ). Both genes had higher expression in LCLs from BD patients who favorably responded to lithium (Alda scale >6).…”

Section: Resultsmentioning

confidence: 99%

“…Despite many years of research, including several large genome‐wide association studies (Pagani et al, ), no established genomic biomarkers for predicting a favorable response to lithium in BD patients are available. We recently reported that the expression levels of ID2 (inhibitor of DNA binding 2) and HDGFRP3 (hepatoma‐derived growth factor, related protein 3) might represent tentative biomarkers for distinguishing LR and nonresponder BD patients (Milanesi et al, ). Thus, in the current retrospective study we explored, in addition to SCN11A , the PBMC expression levels of ID2 and HDGFRP3 as tentative biomarkers for distinct BD phenotypes.…”

Section: Introductionmentioning

confidence: 99%

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SCN11A mRNA levels in female bipolar disorder PBMCs as tentative biomarker for distinct patient sub‐phenotypes

Voinsky

McCarthy

Shekhtman

et al. 2019

Drug Development Research

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Bipolar disorder (BD) is a complex neuropsychiatric disorder characterized by recurrent mania and depression episodes and requiring lifelong treatment with mood stabilizing drugs. Several lines of evidence, including with BD patient iPSC‐derived neurons, suggest that neuronal hyperexcitability may underlie the key clinical symptoms of BD. Indeed, higher mRNA levels of SCN11A, coding for the voltage‐gated sodium channel NaV1.9 implicated in nociception, were detected in iPSC‐derived neurons from BD patients, and were normalized by in vitro lithium. Here we studied SCN11A expression in peripheral blood mononuclear cells (PBMCs) from well‐phenotyped female BD patients and controls and evaluated their association with several clinical sub‐phenotypes. We observed higher mRNA levels of SCN11A in PBMCs from female BD patients with no records of alcohol dependence (p = .0050), no records of psychosis (p = .0097), or no records of suicide attempts (p = .0409). A trend was observed for higher SCN11A expression (FD = 1.91; p = .052) in BD PBMCs compared with controls. Datamining of published postmortem gene expression datasets indicated higher SCN11A expression in dorsolateral prefrontal cortex and orbitofrontal cortex tissues from BD patients compared with controls. Higher phenotype‐associated expression levels in PBMC from BD patients were also observed for ID2 (alcohol dependence, suicide attempts) and HDGFRP3 (seasonal BD pattern). Our findings suggest that higher PBMC SCN11A expression levels may be associated with certain behavioral BD sub‐phenotypes, including lack of alcohol dependence and psychosis, among BD patients. The NaV1.9 voltage‐gated sodium channel thus deserves consideration as a tentative phenotype modifier in BD.

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Section: Resultscontrasting

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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SCN11A mRNA levels in female bipolar disorder PBMCs as tentative biomarker for distinct patient sub‐phenotypes

Voinsky

McCarthy

Shekhtman

et al. 2019

Drug Development Research

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“…Isolation of a neuronally-relevant module (Magenta) is notable because LCLs are non-neuronal cells. While other LCL-based studies of psychiatric disease identified individual genes of potential neuronal relevance [ 26 – 29 ], with others leveraging WGCNA to implicate non-specific cellular or immunologic modules [ 30 – 32 ], this is the first study using LCLs to implicate a neuronally-relevant module in psychiatric disease. In a preliminary analysis, Magenta hub genes were enriched for targets of REST , a repressor of neuronal genes in non-neuronal cells [ 17 ], suggesting that despite mechanisms limiting neuronal gene expression such as REST -mediated transcriptional repression, potentially meaningful differences in aggregate expression could still be detected, perhaps due to careful phenotyping and appropriate clinical stratification.…”

Section: Discussionmentioning

confidence: 99%

Altered estradiol-dependent cellular Ca2+ homeostasis and endoplasmic reticulum stress response in Premenstrual Dysphoric Disorder

Goff

Rudzinskas

et al. 2021

Mol Psychiatry

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Premenstrual Dysphoric Disorder (PMDD) is characterized by debilitating mood symptoms in the luteal phase of the menstrual cycle. Prior studies of affected women have implicated a differential response to ovarian steroids. However, the molecular basis of these patients’ differential response to hormone remains poorly understood. We performed transcriptomic analyses of lymphoblastoid cell lines (LCLs) derived from women with PMDD and asymptomatic controls cultured under untreated (steroid-free), estradiol-treated (E2), and progesterone-treated (P4) conditions. Weighted gene correlation network analysis (WGCNA) of transcriptomes identified four gene modules with significant diagnosis x hormone interactions, including one enriched for neuronal functions. Next, in a gene-level analysis comparing transcriptional response to hormone across diagnoses, a generalized linear model identified 1522 genes differentially responsive to E2 (E2-DRGs). Among the top 10 E2-DRGs was a physically interacting network (NUCB1, DST, GCC2, GOLGB1) involved in endoplasmic reticulum (ER)-Golgi function. qRT-PCR validation reproduced a diagnosis x E2 interaction (F(1,24)=7.01, p = 0.014) for NUCB1, a regulator of cellular Ca2+ and ER stress. Finally, we used a thapsigargin (Tg) challenge assay to test whether E2 induces differences in Ca2+ homeostasis and ER stress response in PMDD. PMDD LCLs had a 1.36-fold decrease in Tg-induced XBP1 splicing response compared to controls, and a 1.62-fold decreased response (p = 0.005), with a diagnosis x treatment interaction (F(3,33)=3.51, p = 0.026) in the E2-exposed condition. Altered hormone-dependent in cellular Ca2+ dynamics and ER stress may contribute to the pathophysiology of PMDD.

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“…The data for the second cohort were taken from the published work of Milanesi et al 37 and consisted of 12 BD LR and 12 BD NR patients.…”

Section: Second Cohortmentioning

confidence: 99%

Immunoglobulin genes expressed in lymphoblast cell lines discern and predict lithium response in bipolar disorder patients

Mizrahi

Choudhary

Ofer

et al. 2022

Preprint

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Bipolar disorder (BD) is a neuropsychiatric mood disorder manifested by recurrent episodes of mania and depression. More than half of BD patients are non-responsive to lithium, the first-line treatment drug, complicating BD clinical management. Given its unknown etiology, it is pertinent to understand the genetic signatures that lead to variability in lithium treatment. We discovered a set of differentially expressed genes from the LCLs of 10 controls and 19 BD patients belonging mainly to the immunoglobulin gene family that can be used as potential biomarkers to diagnose and treat BD. Importantly, we trained a machine learning algorithm on our datasets that predicted the lithium response of BD subtypes with no errors, even when used on a different cohort of 24 BD patients acquired by a different laboratory. This proves the scalability of our methodology for predicting lithium response in BD and for a prompt and suitable decision on therapeutic interventions.

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RNA sequencing of bipolar disorder lymphoblastoid cell lines implicates the neurotrophic factor HRP-3 in lithium’s clinical efficacy

Cited by 13 publications

References 78 publications

SCN11A mRNA levels in female bipolar disorder PBMCs as tentative biomarker for distinct patient sub‐phenotypes

SCN11A mRNA levels in female bipolar disorder PBMCs as tentative biomarker for distinct patient sub‐phenotypes

Altered estradiol-dependent cellular Ca2+ homeostasis and endoplasmic reticulum stress response in Premenstrual Dysphoric Disorder

Immunoglobulin genes expressed in lymphoblast cell lines discern and predict lithium response in bipolar disorder patients

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