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M Alda

Publications and source records attributed to M Alda.

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

Association and linkage studies of CRH and PENK genes in bipolar disorder: a collaborative IGSLI study.

Corticotropin-releasing hormone (CRH) and proenkephalin (PENK) are hypothalamic peptides involved in the stress response and hypothalamic-pituitary axis regulation. Previous research has implicated these peptides in the pathogenesis of affective disorders. In this study we investigated two polymorphisms located in the genes that code for CRH and PENK by means of association and linkage analyses. A total of 138 bipolar patients and 108 controls were included in the association study. In addition, 24 families were available for linkage analysis, including six families of probands with documented periodic positivity of dexamethasone suppression tests (DST) during remission. We found no association of bipolar disorder with either gene. Similarly, we did not find any evidence of linkage (P = 0.56 for CRH and 0.52 for PENK) in the entire sample or in the subsample of families of DST positive probands. In conclusion, our study does not support the hypothesis that genes coding for CRH or PENK contribute to the genetic susceptibility to bipolar disorder. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:178-181, 2000.

Adult↗
PubMed2000

Polyglutamine coding genes in bipolar disorder: lack of association with selected candidate loci.

BACKGROUND: Several studies have suggested that expanded trinucleotide repeats, particularly CAG, may have a role in the etiology of BD. Results obtained with the repeat expansion detection technique (RED) have indicated that bipolar patients have an excess of expanded CAG repeats. However, it is not clear which loci account for this difference. METHODS: Using lithium-responsive bipolar patients in order to reduce heterogeneity, we investigated five loci that are expressed in the brain and contain translated CAG repeats. A sample of 138 cases and 108 controls was studied. Genotypes were coded quantitatively or qualitatively and repeat distributions were compared. RESULTS: No difference was found in allele distribution between cases and controls for any of the loci studied. In one locus - L10378 - patients had a tendency to present shorter alleles (28.1 versus 27.9 repeats; t=2.55, df=205, P=0.011), however, this difference disappeared after correction for multiple testing. LIMITATIONS: The study has limitations common to most candidate gene association studies, that is, limited number of loci investigated and limited power to detect loci that account for a small proportion of the total genetic variability. CONCLUSIONS: Our results suggest that the loci investigated have no major role in the genetic predisposition to bipolar disorder.

Adult↗
PubMed2000

Protective effect of pregnancy in women with lithium-responsive bipolar disorder.

BACKGROUND: Recent psychiatric literature, while indicating a high incidence of postpartum depression, contains a few clinical reports which support our observations that women with episodic bipolar disorder often remain well without treatment during pregnancy. Our retrospective study statistically examines the clinical course of 28 women with RDC typical bipolar disorder, type I, who became pregnant prior to receiving successful lithium prophylaxis. METHODS: We derived all data from the International Group for the Study of Lithium-treated Patients (IGSLI) database of excellent lithium responders. Data were compared both intraindividually, using data from three 9-month periods - immediately prior to pregnancy, pregnancy and postpartum - and interindividually, using never-pregnant women as controls. RESULTS: Intraindividual data show that women with typical bipolar disorder, type I, experience significantly fewer and shorter recurrences during pregnancy than either before or after. Interindividual comparisons indicate that the recurrence risk during pregnancy is markedly lower than the clinical course would predict. Moreover, the few recurrences observed during pregnancy all took place in the last 5 weeks. LIMITATIONS: Limiting cases to lithium responsive patients could have reduced heterogeneity and perhaps generalizability. CONCLUSIONS: The findings, nonetheless, indicate a marked improvement of the clinical course of typical bipolar disorder, type I, lithium-responsive, during pregnancy. Exploring the underlying protective mechanisms may lead to new understanding of the pathophysiology of mood disorders and to new approaches to treatment and prevention.

Adult↗
PubMed2000

The implications of genetics studies of major mood disorders for clinical practice.

BACKGROUND: This article is a selective review and synthesis of relevant research findings from genetic studies of major mood disorders and the application of these to clinical practice. METHOD: The article discusses the application of genetic research findings in major mood disorders, including epidemiologic and family study risk estimates, risk modifiers, and the concepts of etiologic and phenotypic heterogeneity, to 3 clinical domains: risk counseling, diagnosis, and treatment prediction. RESULTS: Epidemiologic and family studies have provided general risk estimates useful in counseling mood-disordered patients and their relatives. A complete and accurate family pedigree provides more individualized risk estimates for specific cases and is useful in identifying the phenotypic spectrum of the disorder being transmitted in the family. Both proband course parameters and familial loading for psychiatric illnesses may be relevant for the prediction of treatment response. However, the hypothesis of inherited pharmacologic selectivity remains to be proven. CONCLUSION: Genetic studies of mood disorders have not yet provided conclusive evidence of specific susceptibility genes or their pattern of inheritance. However, they have generated information that is useful to clinical practice.

Adult↗
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

Analysis of 14 CAG repeat-containing genes in schizophrenia.

Recently, it has been suggested that trinucleotide repeat-containing genes may be involved in the etiology of schizophrenia. This study was aimed at investigating putative associations between allelic variants or expansions of CAG repeat-containing genes (CAGrCG) and schizophrenia or its variability with respect to responsiveness to conventional neuroleptics. CAG repeat allelic variants of 14 expressed sequences were compared among three groups of subjects: neuroleptic-responder (R; n = 43) and neuroleptic-nonresponder (NR; n = 63) schizophrenic patients, and a control group (C; n = 122). No CAG expansions, in the range of those observed in neurodegenerative diseases, were identified in these 14 expressed sequences. The sizes of CAG repeat for the hGT1 gene were marginally different among the three groups of subjects (Kruskal-Wallis H (2, 456) = 10.48, Bonferroni corrected P = 0.047). Comparisons among the different groups indicated that neuroleptic responders have shorter alleles compared to controls (Mann-Whitney adjusted Z = -3.23, P = 0.0012). NR patients were not different from controls. These preliminary results suggest that the hGT1 gene, or a gene in its vicinity, may be involved in the etiology of schizophrenia or in modifying the disease phenotype with regard to outcome and/or neuroleptic responsiveness. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:694-699, 1999.

Adolescent↗
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

Lack of association between the hSKCa3 channel gene CAG polymorphism and schizophrenia.

Genetic anticipation, a phenomenon characterized by increased severity of symptoms and earlier age at onset of a disease in successive generations, is believed to be present in schizophrenia. In several neurodegenerative diseases showing anticipation, the mutation causing the disease is an expanded trinucleotide repeat. Therefore, genes containing trinucleotide repeats prone to expansion have become a suitable family of candidate genes in schizophrenia. A human calcium-activated potassium channel gene (hSKCa3), possibly mapping to chromosome 22q11-13, a region previously linked to schizophrenia, was recently described. This gene contains two contiguous expressed CAG repeat stretches. Recently, long allelic variants of one of these CAG repeats were found to be overrepresented in schizophrenic patients compared to normal controls. In this study we attempted to replicate this result and to study the relationship between the length of this CAG repeat on the one hand and the severity and age at onset of the disease on the other hand. No association with the disease or correlation with the severity of schizophrenia was identified. In addition, hSKCa3 was mapped to chromosome 1. Our results do not support the involvement of this particular CAG repeat-containing gene in schizophrenia.

Adult↗
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

Family density of alcoholism and linkage information in the analysis of the COGA data.

In this study of GAW11 Problem 1, we analyzed the genome scan data in families weighted according to the density of alcoholism among the probands' siblings. We hypothesized that certain disease-predisposing alleles may be common in the general population, rendering high-density sibships less informative for linkage. Three types of families were found in the data, with the prevalence of alcoholism of 1.0, 0.78, and 0.24 in the probands' sibships. The linkage results showed several peak lod scores on chromosomes 1, 2, 4, 8, 11, 19, and 21, the majority of which originated in only one or two types of families. However, for almost all markers, the maximum lod scores observed without the weights were equal to or exceeded the values obtained for any single type of family. These results indicate that although the stratification of families may be theoretically justified, in practice the best strategy is to use all available information.

Alcoholism↗
PubMed1999

Prediction of level of serotonin 2A receptor binding by serotonin receptor 2A genetic variation in postmortem brain samples from subjects who did or did not commit suicide.

OBJECTIVE: Postmortem studies have indicated that suicide victims have greater serotonin receptor 2A (5-HTR2A) binding in prefrontal brain regions. However, there remains some controversy regarding the biological specificity of these findings. The authors hypothesized that the variance observed in brain 5-HTR2A binding is genetically mediated, at least in part. METHOD: Postmortem data from 56 subjects who had committed suicide and 126 normal comparison subjects were studied; brain tissue was available from 11 subjects who committed suicide and 11 comparison subjects. Homogenate binding assays were carried out with [3H]ketanserin. Variation at the 5-HTR2A gene (HTR2A) was investigated by means of two polymorphisms: T102C and A-1438G. RESULTS: 5-HTR2A binding was greater in the prefrontal cortex of the subjects who committed suicide. In addition, the findings suggest that HTR2A variation significantly affects 5-HTR2A binding. However, no interaction between suicidal behavior and this locus was observed. CONCLUSIONS: These results confirm previous reports of greater 5-HTR2A binding in subjects who committed suicide; they also provide preliminary evidence suggesting that the number of 5-HTR2A receptors is genetically mediated.

Adult↗
PubMed1999

T102C polymorphism in the 5HT2A gene and schizophrenia: relation to phenotype and drug response variability.

Although genes play a major role in the etiology of schizophrenia, no major genes involved in this disease have been identified. However, several genes with small effect have been reported, though inconsistently, to increase the risk for schizophrenia. Recently, the 5HT2A 2 allele (T102C polymorphism) was reported to be over-represented in patients with schizophrenia. Other reports have found an excess of allele 2(C) only in schizophrenic patients who are resistant to clozapine, not in those who respond to clozapine. In this study, the 5HT2A receptor allele 2 frequencies were compared between 2 groups of patients with schizophrenia (39 responders and 63 nonresponders) based on long-term outcome and response to typical neuroleptics. A control group of 90 healthy volunteers screened for mental disorders was also included. Genotype 2/2 tended to be more frequent in patients with schizophrenia with poor long-term outcome and poor response to typical neuroleptics (Bonferroni corrected p = 0.09). This difference was significant in men (Bonferroni corrected p = 0.054) but not in women. In addition, the age at first contact with psychiatric care was significantly younger in the patients with schizophrenia with genotype 2/2 than in patients with genotype 1/1. These result suggest that the 5HT2A-receptor gene may play a role in a subset of schizophrenia characterized by poor long-term outcome and poor response to neuroleptics.

Adult↗
PubMed1999

Pharmacogenetics of lithium response in bipolar disorder.

Lithium is the first-line treatment for bipolar disorder. In the past, genetic studies have attempted to identify factors associated with positive treatment response or side effects. Several research groups have shown that familial factors, family history of primary bipolar disorder, and negative family history of schizophrenia in particular, correlate well with prophylactic lithium response. Conversely, studies of lithium responsive patients and their families can assist genetic research of bipolar disorder. Lithium responders appear to suffer from a form of bipolar disorder that is more genetically based and more homogeneous. In a series of family studies, the author and his colleagues have confirmed the differences in family histories of lithium responders and nonresponders and shown that the mode of inheritance in lithium responders is compatible with a major-gene model. Subsequently, they initiated an international collaborative study to map the gene(s) predisposing to the illness or treatment response, or both, using both linkage and association strategies. To date, a sample of 32 families, 138 unrelated patients and 163 control subjects has been studied. In these studies, they found support for the role of phospholipase C in lithium responsive bipolar disorder.

Antimanic Agents↗
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↗