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

Mol Psychiatry. 1998 Nov;3(6):534-8. 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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


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