Evidence for a role of phospholipase C-gamma1 in the pathogenesis of bipolar disorder.
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.
Turecki
G
G
Centre for Research in Neuroscience, The Montreal General Hospital, McGill University, Canada.
Grof
P
P
Cavazzoni
P
P
Duffy
A
A
Grof
E
E
Ahrens
B
B
Berghöfer
A
A
Müller-Oerlinghausen
B
B
Dvoráková
M
M
Libigerová
E
E
Vojtechovský
M
M
Zvolský
P
P
Joober
R
R
Nilsson
A
A
Prochazka
H
H
Licht
R W
RW
Rasmussen
N A
NA
Schou
M
M
Vestergaard
P
P
Holzinger
A
A
Schumann
C
C
Thau
K
K
Rouleau
G A
GA
Alda
M
M
D000328:Adult; D017668:Age of Onset; D001714:Bipolar Disorder / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005799:Genes, Dominant; D005808:Genes, Recessive; D008040:Genetic Linkage; D005819:Genetic Markers; D005838:Genotype; D006801:Humans; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism*; D008094:Lithium / Q000627:therapeutic use; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D051966:Phospholipase C gamma; D011110:Polymorphism, Genetic; D012016:Reference Values; D018709:Statistics, Nonparametric; D010738:Type C Phospholipases / Q000235:genetics* / Q000378:metabolism*
D005819:Genetic Markers; D007527:Isoenzymes; D008094:Lithium; D010738:Type C Phospholipases; D051966:Phospholipase C gamma