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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Objectives: Lithium remains the oldest and most effective treatment for mood stabilisation in bipolar disorder (BD), even though at least half of patients are only partially responsive or do not respond. This study aimed to identify biomarkers associated with lithium response in BD, based on comparing RNA sequencing information derived from lymphoblastoid cell lines (LCLs) of lithium-responsive (LR) versus lithium non-responsive (LNR) BD patients, to assess gene expression variations that might bear on treatment outcome. Methods: RNA sequencing was carried out on 24 LCLs from female BD patients (12 LR and 12 LNR) followed by qPCR validation in two additional independent cohorts (41 and 17 BD patients, respectively). Results: Fifty-six genes showed nominal differential expression comparing LR and LNR (FC ≥ |1.3|, P ≤ 0.01). The differential expression of HDGFRP3 and ID2 was validated by qPCR in the independent cohorts. Conclusions: We observed higher expression levels of HDGFRP3 and ID2 in BD patients who favourably respond to lithium. Both of these genes are involved in neurogenesis, and HDGFRP3 has been suggested to be a neurotrophic factor. Additional studies in larger BD cohorts are needed to confirm the potential of HDGFRP3 and ID2 expression levels in blood cells as tentative favourable lithium response biomarkers.

Original languageEnglish
Pages (from-to)449-461
Number of pages13
JournalWorld Journal of Biological Psychiatry
Issue number6
StatePublished - 3 Jul 2019


FundersFunder number
Accademia delle Belle Arti Santa Giulia
Shalom and Varda Yoran Institute for Human Genome Research
United States - Israel Binational Science Foundation
United States-Israel Binational Science Foundation2013223
Bundesministerium für Bildung und Forschung01 EE 1404H
Tel Aviv University


    • Bipolar disorder
    • HDGFRP3
    • RNA sequencing
    • lithium
    • lymphoblastoid cell lines


    Dive into the research topics of 'RNA sequencing of bipolar disorder lymphoblastoid cell lines implicates the neurotrophic factor HRP-3 in lithium’s clinical efficacy'. Together they form a unique fingerprint.

    Cite this