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Biomedical subjects

P Grof

Publications and source records attributed to P Grof.

At least 37 records · Page 2Linked to original sources
PubMed2000

Association and linkage studies of candidate genes involved in GABAergic neurotransmission in lithium-responsive bipolar disorder.

OBJECTIVE: To test for genetic linkage and association with GABAergic candidate genes in lithium-responsive bipolar disorder. DESIGN: Polymorphisms located in genes that code for GABRA3, GABRA5 and GABRB3 subunits of the GABAA receptor were investigated using association and linkage strategies. PARTICIPANTS: A total of 138 patients with bipolar 1 disorder with a clear response to lithium prophylaxis, selected from specialized lithium clinics in Canada and Europe that are part of the International Group for the Study of Lithium-Treated Patients, and 108 psychiatrically healthy controls. Families of 24 probands were suitable for linkage analysis. OUTCOME MEASURES: The association between the candidate genes and patients with bipolar disorder versus that of controls and genetic linkage within families. RESULTS: There was no significant association or linkage found between lithium-responsive bipolar disorder and the GABAergic candidate genes investigated. CONCLUSIONS: This study does not support a major role for the GABAergic candidate genes tested in lithium-responsive bipolar disorder.

Alleles↗
PubMed1999

Lithium responsive bipolar disorder, unilineality, and chromosome 18: A linkage study.

Over the last three years several studies have investigated the hypothesis of linkage between bipolar disorder and markers on chromosome 18. Although independent groups have reported positive results, it is still not clear how these should be interpreted, as linkage spans a considerably large segment of the chromosome. In this study we have investigated linkage with chromosome 18 markers in 19 families of lithium-responsive bipolar patients, as a way to select a more homogeneous population. In addition, we have investigated whether there is evidence of a parent-of-origin effect as suggested by previous studies. Eleven markers spanning the whole chromosome were typed and linkage analysis was carried out using parametric and nonparametric methods. Analysis of the whole sample provided nonsignificant linkage results. However, when the sample included only unilineal families, and was further stratified according to parental origin, two chromosomal regions provided modestly positive lod scores. Maximum lod scores of 1.04 (P = 0.001) at D18S53 and 0.87 (P = 0.045) at D18S61 were observed for maternal and paternal pedigrees, respectively. Nonparametric analysis yielded similar results. In conclusion, our results are congruent with previous reports that suggest an advantage of unilineal pedigrees in linkage analysis of bipolar disorder and cannot rule out a parent-of-origin effect in this genomic region.

Adolescent↗
PubMed1999

Patterns of DST positivity in remitted affective disorders.

BACKGROUND: While the Dexamethasone Suppression Test (DST) has been extensively used in cross-sectional observations of patients with major affective disorders, studies have tended to ignore the longitudinal application of the DST in patients stabilized on long-term prophylactic medication. METHODS: Monthly DST's were performed on 19 patients, 16 with bipolar disorder and 3 with recurrent major depression. All cases had an excellent response to lithium treatment, and family history positive for bipolar disorder. The average duration of observation was 4 years. RESULTS: All patients remained clinically stable throughout the period of observation. Eleven patients showed intermittent DST positivity ranging from 10% to 60% of tests, and 2 patients exhibited no positivity. Six patients had fewer than 10% positive DST's. Females showed significantly higher positivity than males. The frequency of positivity did not correlate with current age, age of illness onset, duration of illness, duration of lithium treatment, or season. The risk of primary affective disorders in first-degree relatives was also unrelated to the frequency of positivity. CONCLUSIONS: While the highly selected and small sample population limits generalizability, our observations suggest that clinically sufficient lithium prophylaxis does not automatically prevent intermittent HPA dysregulation. We hope that a better understanding of this phenomenon will offer new approaches to the long-term management of mood disorders.

Adult↗
PubMed1999

MAOA: association and linkage studies with lithium responsive bipolar disorder.

A number of association studies have investigated the role of the monoamine oxidase A (MAOA) gene in the susceptibility to bipolar disorder. Although some studies have reported positive findings, there remains some controversy, because results from different studies have not been consistent. A common explanation for inconsistencies between studies is genetic heterogeneity. We have focused on lithium responsive bipolar disorder as a way to reduce heterogeneity. In this study, we investigated the role of MAOA in lithium responsive bipolar patients using association and linkage study designs. The investigation used 138 patients and 108 normal controls. In addition, 25 families were also studied. Our results were not supportive of a major role of MAOA in the predisposition to bipolar disorder.

Alleles↗
PubMed1998

MN blood groups and bipolar disorder: evidence of genotypic association and Hardy-Weinberg disequilibrium.

BACKGROUND: MN blood groups have been studied in the past as a genetic marker of biopolar disorder (BD). Several previous studies reported an association of the illness with lower frequency of blood group NN. METHODS: We analyzed distribution of MN blood groups in a sample of 174 patients with BD, 176 with unipolar depression, 98 with schizophrenia, and 331 healthy controls. In addition, we tested whether the inferred genotypes. conform to Hardy-Weinberg equilibrium (HWE). RESULTS: The frequency of NN phenotype was significantly lower among the bipolar patients than in any of the other three groups (p < .001). The genotype frequencies in the BD group deviated significantly from those expected under HWE (p < .01). CONCLUSIONS: These results suggest a possible locus on chromosome 4 (4q28-q31.1) associated with genetic susceptibility to bipolar illness.

Alleles↗
PubMed1998

Evidence supporting the independent inheritance of primary affective disorders and primary alcoholism in the families of bipolar patients.

BACKGROUND: This study explored the nature of the association between bipolar disorder and alcoholism. METHODS: The authors studied 814 first-degree relatives of 121 bipolar patients, divided on the basis of response to lithium prophylaxis. Logistic regression analysis was used to analyze the contribution of demographic, familial and clinical variables to the risk of primary alcoholism in the relatives. RESULTS: The risk of primary alcoholism in relatives was not related to the degree of affective loading in the family or to the proband's lithium response. CONCLUSION: This study does not support a shared genetic liability between bipolar disorder and alcoholism. LIMITATIONS: This study lacked a control group, but the analysis accounted for this. CLINICAL RELEVANCE: These disorders are not alternative forms of the same illness.

Adult↗
PubMed1998

Has the effectiveness of lithium changed? Impact of the variety of lithium's effects.

Lithium treatment, initially considered specific for bipolar disorder, has since been shown to provide additional benefits in affective and other disorders. This variety of benefits should be taken into account when interpreting recently reported lower efficacy during lithium prophylaxis, as well as early relapses and loss of efficacy after lithium discontinuation. There are particularly striking parallels between these recent reports and earlier observations of "antipsychotic" lithium effects. Other factors, such as the accumulation of atypical, treatment-resistant patients in academic centers and, in particular, the broadening of diagnoses of affective disorders, further complicate the interpretation of the recent reports. Lithium, however, continues working well for patients with typical bipolar disorders, for whom it was originally proved effective.

Antimanic Agents↗
PubMed1998

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.

Adult↗
PubMed1998

Psychiatric symptoms and syndromes among adolescent children of parents with lithium-responsive or lithium-nonresponsive bipolar disorder.

OBJECTIVE: The purpose of this pilot study was to describe the initial course of psychiatric illness in the adolescent children of parents with bipolar disorder who were divided into two groups on the basis of their response to long-term lithium monotherapy. METHOD: Proband parents met Research Diagnostic Criteria for bipolar illness and predetermined criteria for a clear response or nonresponse to lithium prophylaxis. All adolescent offspring were interviewed by a blinded interviewer using the Schedule for Affective Disorders and Schizophrenia for School-Age Children, and final diagnosis was made by blinded consensus. RESULTS: Psychiatrically ill children of lithium-responsive parents tended to have affective disorders that remitted and followed a recurrent course. Psychiatrically ill children of lithium-nonresponsive parents, however, manifested a broad range of psychopathology, had high rates of comorbid illnesses, and experienced nonremitting affective illnesses. CONCLUSIONS: These results suggest that family history and course of illness are important factors to consider in the diagnosis and pharmacological treatment of affective disorders.

Adolescent↗
PubMed1997

Autosomal recessive inheritance of affective disorders in families of responders to lithium prophylaxis?

In this paper we report the results of a study of the mode of inheritance in affective disorders responsive to lithium. Earlier we described a series of 71 families in which the genetic transmission was compatible with a single-gene model. We have now carried out an independent replication study on 25 newly recruited families in a different geographical location. The autosomal recessive model from our original study could not be rejected with the new data. In a subsequent analysis of the pooled sample of 96 families, a recessive model with a common predisposing allele (q = 0.16) and sex-specific penetrance (0.35 in males, 0.66 in females) fitted the data best. On the other hand, X-chromosome and polygenic models could be rejected. The finding of a major-gene effect represents a specific hypothesis that can be tested by molecular genetic techniques.

Adult↗
PubMed1996

Lithium-responsive affective disorders: no association with the tyrosine hydroxylase gene.

Family, adoption, and twin studies have demonstrated the involvement of genetic factors in the etiology of major affective disorders. In an attempt to identify the involved genes, several linkage and association studies have focused on the gene coding for tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis. The discrepant results to date could be explained by etiological heterogeneity, which may be substantially reduced by selecting patients according to lithium response. Therefore, we investigated 54 patients who had shown definite long-term response to lithium monotherapy in spite of a high risk of recurrence as indicated by the previous clinical course. All the subjects suffered from major affective disorder by Research Diagnostic Criteria (48 bipolar, 6 recurrent unipolar). They were compared to 94 population controls of similar ethnic background to test for association with a penta-allelic microsatellite marker found within the tyrosine hydroxylase gene. No significant differences in allele and genotype frequencies were observed between the two groups, providing further evidence against a major role for the tyrosine hydroxylase gene in the etiology of major affective disorders.

Adult↗
PubMed1996

How to interpret findings on mortality of long-term lithium treated manic-depressive patients?! Critique of different methodological approaches.

Many studies have shown that patients with affective disorders have a mortality markedly higher than that of the general population. Studies of manic-depressive patients given prophylactic lithium treatment have yielded varying results. Some authors have reported mortalities which were more than four times that of the general population. Others have found mortalities which did not differ significantly from that of the general population. In order to examine these discrepancies we re-analysed the data of a previous study by IGSLI, using three different methods to calculate the Standardised Mortality Ratio (SMR). The data base was enlarged by adding mortality data from two additional centres. The results indicate that the discrepancies may result from the common use of a 'cumulative' approach which produces a distortion of the data if the treatment duration is not taken into consideration properly. An analysis which eliminates this artefact and takes the treatment duration into account ('year-by-year' approach) provides the strongest evidence that the mortality of lithium treated patients is not significantly different from that of the general population.

Adult↗
PubMed1996

No association between chromosome-18 markers and lithium-responsive affective disorders.

An allelic association study of excellent responders to lithium was conducted with a candidate gene (Golf, a G-protein receptor gene) and five other chromosome-18p markers. Golf is of special interest because it maps to a region of chromosome 18 where two independent groups (Berrettini et al., 1994; Stine et al., 1995) have found linkage to bipolar disorder. It has been proposed that G proteins are involved in the pathogenesis of bipolar disorder, and lithium, an effective prophylactic agent, is known to impair G-protein activation. To reduce heterogeneity--a common obstacle to genetic investigation--only patients who showed excellent response to lithium prophylaxis were studied. Fifty-five genetically unrelated excellent responders to lithium prophylaxis were compared with 94 normal subjects of similar ethnic background. The groups did not differ in either allele or genotype frequency for the tested markers. The data do not support the hypothesis that the tested loci confer a major susceptibility for affective disorders.

Adult↗