Investigation of genetic loci shared between bipolar disorder and risk-taking propensity: potential implications for pharmacological interventions

Patients with bipolar disorder (BD) often show increased risk-taking propensity, which may contribute to poor clinical outcome. While these two phenotypes are genetically correlated, there is scarce knowledge on the shared genetic determinants. Using GWAS datasets on BD (41,917 BD cases and 371,549 controls) and risk-taking (n = 466,571), we dissected shared genetic determinants using conjunctional false discovery rate (conjFDR) and local genetic covariance analysis. We investigated specificity of identified targets using GWAS datasets on schizophrenia (SCZ) and attention-deficit hyperactivity disorder (ADHD). The putative functional role of identified targets was evaluated using different tools and GTEx v. 8. Target druggability was evaluated using DGIdb and enrichment for drug targets with genome for REPositioning drugs (GREP). Among 102 loci shared between BD and risk-taking, 87% showed the same direction of effect. Sixty-two were specifically shared between risk-taking propensity and BD, while the others were also shared between risk-taking propensity and either SCZ or ADHD. By leveraging pleiotropic enrichment, we reported 15 novel and specific loci associated with BD and 22 with risk-taking. Among cross-disorder genes, CACNA1C (a known target of calcium channel blockers) was significantly associated with risk-taking propensity and both BD and SCZ using conjFDR (p = 0.001 for both) as well as local genetic covariance analysis, and predicted to be differentially expressed in the cerebellar hemisphere in an eQTL-informed gene-based analysis (BD, Z = 7.48, p = 3.8E-14; risk-taking: Z = 4.66, p = 1.6E-06). We reported for the first time shared genetic determinants between BD and risk-taking propensity. Further investigation into calcium channel blockers or development of innovative ligands of calcium channels might form the basis for innovative pharmacotherapy in patients with BD with increased risk-taking propensity

A systematic review of calcium channel antagonists in bipolar disorder and some considerations for their future development

L-type calcium channel (LTCC) antagonists have been used in bipolar disorder for over 30 years, without becoming an established therapeutic approach. Interest in this class of drugs has been rekindled by the discovery that LTCC genes are part of the genetic aetiology of bipolar disorder and related phenotypes. We have therefore conducted a systematic review of LTCC antagonists in the treatment and prophylaxis of bipolar disorder. We identified 23 eligible studies, with six randomised, double-blind, controlled clinical trials, all of which investigated verapamil in acute mania, and finding no evidence that it is effective. Data for other LTCC antagonists (diltiazem, nimodipine, nifedipine, methyoxyverapamil and isradipine) and for other phases of the illness are limited to observational studies, and therefore no robust conclusions can be drawn. Given the increasingly strong evidence for calcium signalling dysfunction in bipolar disorder, the therapeutic candidacy of this class of drugs has become stronger, and hence we also discuss issues relevant to their future development and evaluation. In particular, we consider how genetic, molecular and pharmacological data can be used to improve the selectivity, efficacy and tolerability of LTCC antagonists. We suggest that a renewed focus on LTCCs as targets, and the development of ”brain-selective” LTCC ligands, could be one fruitful approach to innovative pharmacotherapy for bipolar disorder and related phenotypes