EVIDENCE FOR A ROLE OF PHOSPHOLIPASE C-GAMMA-1 IN THE PATHOGENESIS OFBIPOLAR DISORDER

Several studies have indicated that patients with bipolar disorder (BD ) who respond well to lithium prophylaxis constitute a biologically di stinct 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 gamma-1 isozyme of phospholipase (P LC), an enzyme that plays an important role in the phosphoinositide se cond messenger system. A population-based association study and a fami ly-based linkage study were carried out on patients who were considere d 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 res ponders and 163 controls. In addition, the segregation of this marker was studied in 32 families ascertained through lithium-responsive bipo lar probands. The allele distributions between lithium-responsive bipo lar patients and controls were different, with a higher frequency of o ne of the PLCG1 polymorphisms in patients (chi(2) = 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 mode st support for the involvement of this gene in the pathogenesis of ED 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 disor der, probably accounting for a fraction of the total genetic variance. Whether this polymorphism is implicated in the pathogenesis of ED or in the mechanism of lithium response remains to be determined.