title: Extracting a needle from a haystack: reanalysis of whole genome data reveals a readily translatable finding.
abstract: There is significant unmet need for more effective treatments for bipolar disorder. The drug discovery process is becoming prohibitively expensive. Hence, biomarker clues to assist or shortcut this process are now widely sought. Using the publicly available data from the whole genome association study conducted by the Wellcome Trust Case Control Consortium, we sought to identify groups of genetic markers (single nucleotide polymorphisms) in which each marker was independently associated with bipolar disorder, with a less stringent threshold than that set by the original investigators (p< or =1 x 10(-4)). We identified a group of markers occurring within the CACNA1C gene (encoding the alpha subunit of the calcium channel Cav1.2). We then ascertained that this locus had been previously associated with the disorder in both a smaller and a whole genome study, and that a number of drugs blocking this channel (including verapamil and diltiazem) had been trialled in the treatment of bipolar disorder. The dihydropyridine-based blockers such as nimodipine that bind specifically to Cav1.2 and are more penetrant to the central nervous system have shown some promising early results; however, further trials are indicated. In addition, migraine is commonly seen in affective disorder, and calcium channel antagonists are successfully used in the treatment of migraine. One such agent, flunarizine, is structurally related to other first-generation derivatives of antihistamines such as antipsychotics. This implies that flunarizine could be useful in the treatment of bipolar disorder, and, furthermore, that other currently licensed drugs should be investigated for antagonism of Cav1.2.
authors.affiliation: MRC SGDP Centre, Institute of Psychiatry at King's College London, 16 De Crespigny Park, Denmark Hill, London, UK. robert.keers@iop.kcl.ac.uk
authors.forename: R
authors.initials: R
authors.lastname: Keers
authors.forename: A E
authors.initials: AE
authors.lastname: Farmer
authors.forename: K J
authors.initials: KJ
authors.lastname: Aitchison
mesh_terms: D000818:Animals; D018692:Antimanic Agents / Q000627:therapeutic use; D001714:Bipolar Disorder / Q000188:drug therapy / Q000235:genetics* / Q000523:psychology; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D020746:Calcium Channels, L-Type / Q000235:genetics*; D005444:Flunarizine / Q000627:therapeutic use; D005787:Gene Frequency / Q000235:genetics; D015894:Genome, Human / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D051379:Mice; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D018692:Antimanic Agents; C079146:CACNA1C protein, human; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D005444:Flunarizine