Evidence for a role of phospholipase C-gamma1 in the pathogenesis of bipolar disorder.

Abstract

Several studies have indicated that patients with bipolar disorder (BD) who respond well to lithium prophylaxis constitute a biologically distinct subgroup. Lithium is thought to stabilize mood by acting at the phosphoinositide cycle. We have investigated a polymorphism located in the gene (PLCG1) that codes for a gamma-1 isozyme of phospholipase (PLC), an enzyme that plays an important role in the phosphoinositide second messenger system. A population-based association study and a family-based linkage study were carried out on patients who were considered excellent responders to lithium prophylaxis. Response to lithium was evaluated prospectively with an average follow-up of 14.4 +/- 6.8 years. The PLCG1 polymorphism was investigated in 136 excellent lithium responders and 163 controls. In addition, the segregation of this marker was studied in 32 families ascertained through lithium-responsive bipolar probands. The allele distributions between lithium-responsive bipolar patients and controls were different, with a higher frequency of one of the PLCG1 polymorphisms in patients (chi2 = 8.09; empirical P = 0.033). This polymorphism, however, confers only a small risk (OR = 1.88, CI 1.19-3.00). Linkage studies with the same marker yielded modest support for the involvement of this gene in the pathogenesis of BD when unilineal families were considered (Max LOD = 1.45; empirical P = 0.004), but not in the whole sample. Our results provide preliminary evidence that a PLC isozyme may confer susceptibility to bipolar disorder, probably accounting for a fraction of the total genetic variance. Whether this polymorphism is implicated in the pathogenesis of BD or in the mechanism of lithium response remains to be determined.

• Authors: G Turecki, P Grof, P Cavazzoni, A Duffy, E Grof, B Ahrens, A Berghöfer, B Müller-Oerlinghausen, M Dvoráková, E Libigerová, M Vojtechovský, P Zvolský, R Joober, A Nilsson, H Prochazka, R W Licht, N A Rasmussen, M Schou, P Vestergaard, A Holzinger, C Schumann, K Thau, G A Rouleau, M Alda
• Journal: Molecular psychiatry (Mol Psychiatry) Vol. 3 Issue 6 Pg. 534-8 (Nov 1998) ISSN: 1359-4184 [Print] England
• PMID: 9857980 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Genetic Markers
• Isoenzymes
• Lithium
• Type C Phospholipases
• Phospholipase C gamma

Topics

• Adult
• Age of Onset
• Bipolar Disorder (drug therapy, enzymology, genetics)
• Female
• Gene Frequency
• Genes, Dominant
• Genes, Recessive
• Genetic Linkage
• Genetic Markers
• Genotype
• Humans
• Isoenzymes (genetics, metabolism)
• Lithium (therapeutic use)
• Lod Score
• Male
• Middle Aged
• Models, Statistical
• Phospholipase C gamma
• Polymorphism, Genetic
• Reference Values
• Statistics, Nonparametric
• Type C Phospholipases (genetics, metabolism)