Evidence for a role of phospholipase C-γ1 in the pathogenesis of bipolar disorder

• Published in: Molecular psychiatry Vol. 3; no. 6; pp. 534 - 538
• Main Authors: TURECKI, G, GROF, P, VOJTECHOVSKY, M, ZVOLSKY, P, JOOBER, R, NILSSON, A, PROCHAZKA, H, LICHT, R, RASMUSSEN, N, SCHOU, M, VESTERGAARD, P, HOLZINGER, A, CAVAZZONI, P, SCHUMANN, C, THAU, K, ROULEAU, G, ALDA, M, DUFFY, A, GROF, E, AHRENS, B, BERGHÖFER, A, MÜLLER-OERLINGHAUSEN, B, DVORAKOVA, M, LIBIGEROVA, E
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01-11-1998
• Subjects: Adult and adolescent clinical studies; Biological and medical sciences; Bipolar disorder; Bipolar disorders; Disease prevention; Gene polymorphism; Genetic diversity; Lithium; Medical sciences; Mood disorders; Pathogenesis; Phospholipase C; Polymorphism; Population studies; Prophylaxis; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Mood disorder; Human; Linkage; Enzyme; Pathogenesis; Bipolar disorder; Esterases; Phosphoric diester hydrolases; Genetic determinism; Phospholipase C; Gene; Risk factor; Hydrolases; Genetics; Polymorphism
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/sj.mp.4000447

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 stablize mood by acting at the phosphoinositide cycle. We have investigated a polymorphism located in the gene (PLCG1) that codes for a γ-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 (χ2 = 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.