Evidence for a Role of Phospholipase C- 1 in the Pathogenesis of Bipolar
Total Page：16
File Type：pdf, Size：1020Kb
Molecular Psychiatry (1998) 3, 534–538 1998 Stockton Press All rights reserved 1359–4184/98 $12.00 cated in the pathogenesis of BD or in the mechanism of ORIGINAL RESEARCH ARTICLE lithium response remains to be determined. Bipolar disorder (BD) is a major psychiatric con- Evidence for a role of dition characterized by episodes of mania and ␥ depression, affecting up to 1% of the general popu- phospholipase C- 1 in the lation.1 Lithium has been used in the prophylaxis and treatment of BD for almost half a century, and remains pathogenesis of bipolar the first-choice therapy for preventing recurrences.2 disorder Although lithium is considered specific for the treat- ment of BD, with no comparable effect in other psychi- G Turecki1, P Grof2, P Cavazzoni2, A Duffy2, atric disorders, its effectiveness varies widely. There is E Grof2, B Ahrens3, A Bergho¨fer3,BMu¨ller- compelling evidence that lithium is more effective in 3 4 4 forms of BD characterized by typical symptomatology Oerlinghausen , M Dvora´kova´ , E Libigerova´ , 3–5 M Vojtechovsky´4, P Zvolsky´4, R Joober1, and the absence of comorbidity. There is also evi- A Nilsson5, H Prochazka5, RW Licht6, dence that responders and nonresponders to lithium 6 6 6 treatment differ in certain neuroendocrine responses NA Rasmussen , M Schou , P Vestergaard , 6 7 7 7 involving the serotonergic and endorphin systems. In A Holzinger , C Schumann , K Thau , addition, family studies indicate a higher recurrence 1 2 GA Rouleau and M Alda risk for bipolar disorder among relatives of patients who respond well to lithium treatment.5,7,8 Taken 1Centre for Research in Neuroscience, The Montreal together, these findings suggest that response to lith- General Hospital, McGill University, Canada; 2Department ium prophylaxis may help define a distinct bipolar of Psychiatry, University of Ottawa, Canada; 3Department phenotype with less genetic heterogeneity. of Psychiatry, Free University, Berlin, Germany; The mechanism by which lithium acts is not exactly 4Department of Psychiatry, Charles University, Prague and known. Recent findings indicate that lithium may sta- Hradec Kra´love´, Czech Republic; 5Karsudden Hospital, bilize mood by acting at the phosphoinositide second Katrineholm, Sweden; 6Psychiatric Hospital, University of messenger system.9 Cellular responses mediated by Århus, Risskov, Denmark; 7University Clinic of Vienna, inositol phospholipids are involved in many brain pro- Department of Psychiatry, Austria cesses.10,11 They are initiated by a phospholipase C (PLC) isozyme after activation by a membrane receptor Keywords: bipolar disorder; phospholipase C; genetics; that can be coupled to a G protein, protein tyrosine lithium; signal transduction; linkage; association kinase or several lipid-derived second messengers such as arachidonic acid.12 Lithium is thought to inhibit the Several studies have indicated that patients with bipolar enzyme inositol monophosphatase, leading to a disorder (BD) who respond well to lithium prophylaxis reduction in the availability of inositol.9 constitute a biologically distinct subgroup. Lithium is thought to stablize mood by acting at the phosphoinosi- In this study we present preliminary evidence sug- tide cycle. We have investigated a polymorphism gesting that patients who have an excellent response located in the gene (PLCG1) that codes for a ␥-1 iso- to lithium prophylaxis have a higher frequency of a zyme of phospholipase (PLC), an enzyme that plays an polymorphism located in the gene coding for the ␥-1 important role in the phosphoinositide second messen- isozyme of phospholipase C (PLCG1) on chromosome ger system. A population-based association study and 20. This result was further explored in a family link- a family-based linkage study were carried out on age study. patients who were considered excellent responders to Patients with bipolar disorder were recruited from lithium prophylaxis. Response to lithium was evaluated six centers that collaborate in the International Group ± prospectively with an average follow-up of 14.4 6.8 for the Study of Lithium (IGSLI) (see methods). These years. The PLCG1 polymorphism was investigated in 136 excellent lithium responders and 163 controls. In patients have been followed in specialized lithium addition, the segregation of this marker was studied in clinics and their response to lithium prophylaxis has 32 families ascertained through lithium-responsive been assessed systematically and prospectively. In bipolar probands. The allele distributions between lith- order to be included in the study, all patients had to ium-responsive bipolar patients and controls were dif- meet stringent criteria of excellent lithium response, ferent, with a higher frequency of one of the PLCG1 described previously5 and summarized in Table 1. A polymorphisms in patients (2 = 8.09; empirical total of 136 patients were included in the association P = 0.033). This polymorphism, however, confers only a study. The mean (± standard deviation) age of onset = small risk (OR 1.88, CI 1.19–3.00). Linkage studies with was 27.6 (± 9.9) years. The number of the illness epi- the same marker yielded modest support for the sodes prior to lithium treatment was 8.2 (± 10.1). involvement of this gene in the pathogenesis of BD Patients have been stabilized on lithium monotherapy when unilineal families were considered (Max ± LOD = 1.45; empirical P = 0.004), but not in the whole for 14.4 ( 6.8) years. Control subjects for this study sample. Our results provide preliminary evidence that a were 128 psychiatrically unaffected individuals who PLC isozyme may confer susceptibility to bipolar dis- were collected in similar fashion by participating order, probably accounting for a fraction of the total centres, and consisted of healthy married-in individ- genetic variance. Whether this polymorphism is impli- uals from the linkage study, hospital staff and normal Phospholipase C-␥1 in the pathogenesis of BD G Turecki et al 535 Table 1 Criteria used to diagnose bipolar patients as excel- together (PLCG1/5 ± 1: 2 = 10.35; d.f. = 1, P = 0.007* lent lithium responders and PLCG1/5 ± 2: 2 = 7.59; d.f. = 1, P = 0.019*). Fur- thermore, patients and controls also differed when Each patient must meet criteria A, B and C. alleles were grouped according to size, with patients presenting an excess of long (CA) repeats (PLCG/1– A. Diagnosis of primary episodic bipolar disorder based n on the SADS-L (lifetime version) interview and PLCG/7), whereas controls have predominantly short 2 = = Research Diagnostic Criteria (RDC). (PLCG1/8–PLCG1/18) variants ( 8.30; d.f. 1, P = 0.007*) (see Figure 1). B. High Recurrence Risk Parametric linkage results using the PLCG1 marker either B1: five or more episodes prior to lithium gave non significant maximum lod scores when results treatment from all families were considered (see Table 3). Indi- or B2: four episodes prior to lithium; of these two or viduals were considered affected when they met RDC more during the 2 years preceding lithium criteria for bipolar disorder, schizoaffective disorder or treatment recurrent major disorder. Three major genetic models or B3: three episodes prior to lithium, plus one more were explored in order to maximize the evidence for with 12 months after lithium discontinuation linkage. These models were: (a) dominant (allele fre- quency (q) 0.012, male penetrance (fM) 0.4, female pen- C. Unequivocal Lithium Response etrance (fF) 0.7, and normal penetrance 0.005 for males C1: No recurrence requiring additional biological (fM0) and 0.009 for females (fF0)); (b) intermediate intervention (ECT, antidepressants, (q = 0.024, fM = 0.4/0.2, fF = 0.7/0.35, fM0 = 0.005, neuroleptics) during the entire observation fF0 = 0.009); (c) recessive (q = 0.16, fM = 0.35, fF = 0.65, time on lithium monotherapy fM0 = 0.005, fF0 = 0.009). As previous findings sug- and C2: Minimum period of observation of 3 years gested that the study of unilineal pedigrees may pro- vide an advantage to overcome part of the complexity and C3: Average plasma lithium concentration over 0.6 13–14 mEq L−1 of BD, we further analyzed the data according to lineality. Among all pedigrees, 13 were clearly unili- neal (six of paternal and seven of maternal origin). The largest lod score observed among unilineal families = volunteers. Thirty-five more control subjects were was 1.45 (P 0.004) under the dominant model. Simi- included without assessment of psychiatric status. All lar results in these families were found using a nar- rower diagnostic definition, which excluded recurrent cases and controls were of similar ethnic background = = and were, whenever possible, matched for geographi- major depression (Zmax 1.02, P 0.006). There was no cal origin. The mean age (± standard deviation) and sex difference between maternal and paternal pedigrees. ratio (M : F) were 50.0 (± 14.4) years, 0.87 for patients Nonparametric linkage analysis provided similar and 51.45 (± 14.8), 0.86 for controls. results (see Table 3). Thirty-two of the Canadian probands had families An increasing body of evidence supports the hypoth- available for linkage analysis. The family sample con- esis that alterations in the phosphoinositide signal transduction system may be implicated in the patho- sisted of 224 interviewed and genotyped individuals, 9,15 of whom 95 were affected. physiology of bipolar disorder. Studies of postmor- Allele distributions in individuals from different tem brains from patients with BD and suicide victims centers were similar, both for cases (2 = 11.95; with major depression have shown a marked reduction d.f. = 12, P Ͼ0.4), and controls (2 = 19.61; d.f. = 13, in phosphatidylinositol hydrolysis by G protein Ͼ coupled to phospholipase C stimulation, when com- P 0.1). This allowed pooling of the Canadian and Eur- 15,16 opean samples (patients as well as controls) for all pared to normal controls. Furthermore, recent mag- comparisons. netic resonance spectroscopy studies have indicated The distributions of alleles in patients and controls that lithium reduces myoinositol levels in critical brain regions in bipolar patients.17 The phosphoinositide- are shown in Table 2.