Molecular Psychiatry (1998) 3, 534–538  1998 Stockton Press All rights reserved 1359–4184/98 $12.00 ORIGINAL RESEARCH ARTICLE Evidence for a role of phospholipase C-1 in the pathogenesis of bipolar disorder G Turecki 1 , P Grof 2 , P Cavazzoni 2 , A Duffy 2 , E Grof 2 , B Ahrens 3 , A Bergho ¨ fer 3 , B Mu ¨ ller- Oerlinghausen 3 , M Dvora ´ kova ´ 4 , E Libigerova ´ 4 , M Vojtechovsky ´ 4 , P Zvolsky ´ 4 , R Joober 1 , A Nilsson 5 , H Prochazka 5 , RW Licht 6 , NA Rasmussen 6 , M Schou 6 , P Vestergaard 6 , A Holzinger 7 , C Schumann 7 , K Thau 7 , GA Rouleau 1 and M Alda 2 1 Centre for Research in Neuroscience, The Montreal General Hospital, McGill University, Canada; 2 Department of Psychiatry, University of Ottawa, Canada; 3 Department of Psychiatry, Free University, Berlin, Germany; 4 Department of Psychiatry, Charles University, Prague and Hradec Kra ´ love ´ , Czech Republic; 5 Karsudden Hospital, Katrineholm, Sweden; 6 Psychiatric Hospital, University of Århus, Risskov, Denmark; 7 University Clinic of Vienna, Department of Psychiatry, Austria Keywords: bipolar disorder; phospholipase C; genetics; lithium; signal transduction; linkage; association 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 phosphoinosi- tide cycle. We have investigated a polymorphism located in the gene (PLCG1) that codes for a -1 iso- zyme of phospholipase (PLC), an enzyme that plays an important role in the phosphoinositide second messen- ger 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 lith- ium-responsive bipolar patients and controls were dif- ferent, with a higher frequency of one of the PLCG1 polymorphisms in patients ( 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 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 dis- order, probably accounting for a fraction of the total genetic variance. Whether this polymorphism is impli- cated in the pathogenesis of BD or in the mechanism of lithium response remains to be determined. Bipolar disorder (BD) is a major psychiatric con- dition characterized by episodes of mania and depression, affecting up to 1% of the general popu- lation. 1 Lithium has been used in the prophylaxis and treatment of BD for almost half a century, and remains the first-choice therapy for preventing recurrences. 2 Although lithium is considered specific for the treat- ment of BD, with no comparable effect in other psychi- atric disorders, its effectiveness varies widely. There is compelling evidence that lithium is more effective in forms of BD characterized by typical symptomatology and the absence of comorbidity. 3–5 There is also evi- dence that responders and nonresponders to lithium treatment differ in certain neuroendocrine responses involving the serotonergic and endorphin systems. 6 In addition, family studies indicate a higher recurrence risk for bipolar disorder among relatives of patients who respond well to lithium treatment. 5,7,8 Taken together, these findings suggest that response to lith- ium prophylaxis may help define a distinct bipolar phenotype with less genetic heterogeneity. The mechanism by which lithium acts is not exactly known. Recent findings indicate that lithium may sta- bilize mood by acting at the phosphoinositide second messenger system. 9 Cellular responses mediated by inositol phospholipids are involved in many brain pro- cesses. 10,11 They are initiated by a phospholipase C (PLC) isozyme after activation by a membrane receptor that can be coupled to a G protein, protein tyrosine kinase or several lipid-derived second messengers such as arachidonic acid. 12 Lithium is thought to inhibit the enzyme inositol monophosphatase, leading to a reduction in the availability of inositol. 9 In this study we present preliminary evidence sug- gesting that patients who have an excellent response to lithium prophylaxis have a higher frequency of a polymorphism located in the gene coding for the -1 isozyme of phospholipase C (PLCG1 ) on chromosome 20. This result was further explored in a family link- age study. Patients with bipolar disorder were recruited from six centers that collaborate in the International Group for the Study of Lithium (IGSLI) (see methods). These patients have been followed in specialized lithium clinics and their response to lithium prophylaxis has been assessed systematically and prospectively. In order to be included in the study, all patients had to meet stringent criteria of excellent lithium response, described previously 5 and summarized in Table 1. A total of 136 patients were included in the association study. The mean (± standard deviation) age of onset was 27.6 (± 9.9) years. The number of the illness epi- sodes prior to lithium treatment was 8.2 (± 10.1). Patients have been stabilized on lithium monotherapy for 14.4 (± 6.8) years. Control subjects for this study were 128 psychiatrically unaffected individuals who were collected in similar fashion by participating centres, and consisted of healthy married-in individ- uals from the linkage study, hospital staff and normal