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

<p><b>Objectives:</b> 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.</p> <p><b>Methods:</b> 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).</p> <p><b>Results:</b> Fifty-six genes showed nominal differential expression comparing LR and LNR (FC ≥ |1.3|, <i>P</i> ≤ 0.01). The differential expression of <i>HDGFRP3</i> and <i>ID2</i> was validated by qPCR in the independent cohorts.</p> <p><b>Conclusions:</b> We observed higher expression levels of <i>HDGFRP3</i> and <i>ID2</i> in BD patients who favourably respond to lithium. Both of these genes are involved in neurogenesis, and <i>HDGFRP3</i> has been suggested to be a neurotrophic factor. Additional studies in larger BD cohorts are needed to confirm the potential of <i>HDGFRP3</i> and <i>ID2</i> expression levels in blood cells as tentative favourable lithium response biomarkers.</p

Frequency of the clinically actionable genotypes in the European patients analyzed using the Affymetrix DMET^™ Plus platform.

<p>Green depicts genotypes with no actionable pharmacogenomic biomarkers, yellow depicts genotypes with at least one actionable pharmacogenomic biomarker, and red depicts genotypes with at least one high-risk actionable pharmacogenomic biomarker. As stated in PharmGKB, the term “actionable” does not discuss genetic or other testing for gene/protein/chromosomal variants, but does contain information about changes in efficacy, dosage or toxicity due to such variants.</p

Comparison of the frequencies (vertical axis; %) of the 36 actionable PGx biomarkers (depicted at the horizontal axis) among European, Saudi Arabian and South African populations.

<p>Comparison of the frequencies (vertical axis; %) of the 36 actionable PGx biomarkers (depicted at the horizontal axis) among European, Saudi Arabian and South African populations.</p

Outline of the significant differences (p-values<0.05 in boldface) of the prevalence of actionable PGx biomarkers in European populations, compared to the average European.

<p>Outline of the significant differences (p-values<0.05 in boldface) of the prevalence of actionable PGx biomarkers in European populations, compared to the average European.</p

Outline of the predicted average warfarin dosage calculation for all populations.

<p>This table suggests the weekly average dosage along with the standard deviation, confidence interval (95%) and the respective upper bound and lower bound for each population.</p

Distribution of the different individuals analyzed for each population group using the Affymetrix DMET^™ Plus platform for the predicted weekly warfarin dose (mg).

<p>Distribution of the different individuals analyzed for each population group using the Affymetrix DMET^™ Plus platform for the predicted weekly warfarin dose (mg).</p

Inter-rater agreement and reliability of the assessment of lithium response in the two-stage case-vignette rating procedure: kappa and intra-class correlation analysis.

<p>TS: total score.</p><p>ICC: intra-class correlation.</p><p>CI: confidence interval.</p>*<p>Mixed and random effects models.</p>§<p>70 raters.</p>¶<p>48 raters.</p

Empirical and theoretical distributions of the total score in the Consortium on Lithium Genetics sample.

<p>Frequentist, <b>A</b>, and Bayesian minimum message length, <b>B</b>, mixture modeling identify three subpopulations of non responders (grey), partial responders (red), and full responders (blue) in total scores of 1,308 bipolar disorder patients characterized for response to lithium maintenance treatment.</p

Number of raters from the Consortium on Lithium Genetics (ConLiGen) centres participating in the two-stage case-vignette rating procedure for inter-rater reliability and agreement.

<p>ConLiGen: Consortium on Lithium Genetics.</p>*<p>Hokkaido, Osaka, Tokio, Riken Brain Science Institute.</p

Distribution of total and A scores in the Consortium on Lithium Genetics sample.

<p>Histogram plot of the scale scores in 1,308 bipolar disorder patients characterized for response to lithium maintenance treatment.</p