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G Turecki

Publications and source records attributed to G Turecki.

At least 19 recordsLinked to original sources
PubMed2001

Dopaminergic neurotransmission and restless legs syndrome: a genetic association analysis.

In order to examine the genetic substrate of the dopamine hypothesis in restless legs syndrome, we analyzed eight genes coding for receptors and enzymes related to dopaminergic transmission, using a population of 92 patients with restless legs syndrome and 182 controls matched for ethnic background. No significant differences were found in the genotypic or allelic distributions between groups. Furthermore, no effect of the loci examined was observed with stratification using clinical parameters such as age at onset or periodic leg movements during sleep index.

Adult↗
PubMed2001

Identification of three polymorphisms in the translated region of PLC-gamma1 and their investigation in lithium responsive bipolar disorder.

Recently, we have found an association between bipolar disorder patients who are excellent responders to lithium prophylaxis and a polymorphic marker located in the first intron of the phospholipase C-gamma1 gene (PLC-gamma1) [Turecki et al., 1998: Mol Psychiatry 3:534-538]. As this variant is not known to be functional, we searched for other markers within the coding region, using single-strand conformational polymorphism (SSCP) analysis. We have identified three polymorphic sites localized in three different exons of the PLC-gamma1 gene (exons 9, 26, 31). Variation studies of these potentially functional sites in a group of 133 bipolar patients with an excellent response to lithium prophylaxis and a comparison group of 99 healthy controls showed no difference in genotype distributions for exon 9 (chi-square = 1.41, df = 2, P = 0.49), exon 26 (chi-square = 2.26, df = 2, P = 0.13), or exon 31 (chi-square = 1.41, df = 2, P = 0.49). Similar results were observed for allele distributions. These results suggest that our previous findings were not the result of linkage disequilibrium with these variants.

Bipolar Disorder↗
PubMed2001

Is lithium response related to G(s)alpha levels in transformed lymphoblasts from subjects with bipolar disorder?

BACKGROUND: A series of studies from independent laboratories have found increased levels of G(s)alpha in bipolar disorder in postmortem brain and peripheral blood cells. Long-term lithium administration blunts G-protein coupled cAMP signaling and may regulate G(s)alpha levels. METHODS: We measured G(s)alpha in transformed lymphoblasts obtained from subjects with bipolar disorder and compared the findings with 23 age- and sex-matched controls. To reduce patient heterogeneity, we included only patients with an excellent response to lithium prophylaxis. RESULTS: We found no differences in G(s)alpha protein levels measured with immunoblotting. G(s)alpha levels did not correlate with age, age of onset or duration of lithium therapy. LIMITATIONS: This study made use of transformed lymphoblasts, which may not fully represent changes that occur in regionalized brain tissue. Furthermore, the transformed lymphoblasts used in this study were acquired from a select group of bipolar disorder subjects that responded to lithium treatment. Lastly, consideration has to be given to the small sample size of the study. CONCLUSIONS: These results are consistent with recent observations suggesting that mood state and treatment effects may account at least in part for increased G(s)alpha levels in bipolar disorder. CLINICAL RELEVANCE: This study suggests a need to further characterize biological phenotypes in subjects with mood disorders to enhance genetic studies.

Adult↗
PubMed2001

TPH and suicidal behavior: a study in suicide completers.

An association between the gene that codes for tryptophan hydroxylase (TPH)-the rate-limiting enzyme in the synthesis of serotonin-and suicidal behavior has been investigated with some detail in samples of living subjects who attempted suicide. In this study, we investigated TPH and suicide completion, the most severe form of suicidal behavior. A relatively large sample of suicide completers (n = 101) was genotyped at three TPH loci (two polymorphisms in the promoter region, A-6526G and G-5806T, and one in intron 7, A218C) and compared to psychiatrically normal living controls (n = 129). Although no significant differences were found between groups for genetic variation at single loci, haplotype analysis revealed that one haplotype (-6526G -5806T 218C) was significantly more frequent among suicide cases than in normal controls (chi(2) = 11.30, df = 2, P = 0.0008; OR = 2.0 CI: 1.30-3.6). Further analyses suggested that this haplotype is particularly more frequent among subjects who committed suicide using violent methods. Similar results were observed in recent haplotype analyses in suicide attempters, which found that the equivalent of haplotype -6526G -5806T 218C was more frequent in impulsive attempters (Rotondo et al, Mol Psychiatry 1999; 4: 360-368). Our results replicate in suicide completers previous data observed in suicide attempters. These and other results continue to point to the substantial role that the gene that codes for TPH may play in the neurobiology of suicidal behavior.

Genetic Predisposition to Disease↗
PubMed2001

Mapping susceptibility genes for bipolar disorder: a pharmacogenetic approach based on excellent response to lithium.

Genetic mapping studies in bipolar disorder (BD) have been hampered by the unclear boundaries of the phenotypic spectrum, and possibly, by the complexity of the underlying genetic mechanisms, and heterogeneity. Among the suggested approaches to circumvent these problems, a pharmacogenetic strategy has been increasingly proposed. Several studies have indicated that patients with BD who respond well to lithium prophylaxis constitute a biologically distinct subgroup. In this study we have conducted a complete genome scan using 378 markers spaced at an average distance of 10 cM in 31 families ascertained through excellent lithium responders. Response to lithium was evaluated prospectively with an average follow-up of 12 years. Evidence for linkage was found with a locus on chromosome 15q14 (ACTC, lod score = 3.46, locus-specific P-value = 0.000014) and suggestive results were observed for another marker on chromosome 7q11.2 (D7S1816, lod score = 2.68, locus-specific P-value = 0.00011). Other interesting findings were obtained with markers on chromosomes 6 and 22, namely D6S1050 (lod score = 2.0, locus-specific P-value = 0.00004) and D22S420 (lod score = 1.91). Nonparametric linkage analysis provided additional support for the role of these loci. Further analyses of these results suggested that the locus on chromosome 15q14 may be implicated in the etiology of BD, whereas the 7q11.2 locus may be relevant for lithium response. In conclusion, our results provide original evidence suggesting that loci on 15q14 and 7q11.2 may be implicated in the pathogenesis of BD responsive to lithium.

Adult↗
PubMed2001

A functional myeloperoxidase polymorphic variant is associated with coronary artery disease in French-Canadians.

BACKGROUND: One of the enzymes involved in the production of free radicals in atherosclerotic plaques is myeloperoxidase (MPO). There is a functional G/A polymorphism 463 bp upstream of the transcription start site of the enzyme with the G allele associated with a higher level of MPO expression than the A allele. Considering the potential role of MPO in the process of atherosclerosis, studying the relationship between this polymorphism and the incidence of coronary artery disease (CAD) seems reasonable. METHOD: We performed a case-control study. The case group consisted of 229 patients who had angiographically proved atherosclerotic plaques in their coronary arteries. The control group consisted of 217 individuals who did not have a history of coronary artery disease, stroke, or peripheral vascular disease. RESULTS: We found that allele A of the MPO gene was less frequent in cases with CAD. In a recessive model patients with the AA genotype had a decreased risk of CAD (odds ratio 0.138, 95% confidence interval 0.040-0.474). In a dominant model a significant protective role for AA or AG versus GG was also detected (odds ratio 0.639, 95% confidence interval 0.436-0.937). CONCLUSION: Our findings suggest that the -463 G/A polymorphism of the MPO gene influences the risk of CAD. This effect may be mediated by the effect of this polymorphism on the transcription level of the MPO gene.

Case-Control Studies↗
PubMed2000

Erratum

Explore the source record for details and available documents.

Journal Article↗
PubMed2000

CAG repeat length in RAI1 is associated with age at onset variability in spinocerebellar ataxia type 2 (SCA2).

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant disorder caused by the expansion of a polymorphic (CAG)(n) tract, which is translated into an expanded polyglutamine tract in the ataxin-2 protein. Although repeat length and age at disease onset are inversely related, approximately 50% of the age at onset variance in SCA2 remains unexplained. Other familial factors have been proposed to account for at least part of this remaining variance in the polyglutamine dis-orders. The ability of polyglutamine tracts to interact with each other, as well as the presence of intra-nuclear inclusions in other polyglutamine disorders, led us to hypothesize that other CAG-containing proteins may interact with expanded ataxin-2 and affect the rate of protein accumulation, and thus influence age at onset. To test this hypothesis, we used step-wise multiple linear regression to examine 10 CAG-containing genes for possible influences on SCA2 age at onset. One locus, RAI1, contributed an additional 4.1% of the variance in SCA2 age at onset after accounting for the effect of the SCA2 expanded repeat. This locus was further studied in SCA3/Machado-Joseph disease (MJD), but did not have an effect on SCA3/MJD age at onset. This result implicates RAI1 as a possible contributor to SCA2 neurodegeneration and raises the possibility that other CAG-containing proteins may play a role in the pathogenesis of other polyglutamine disorders.

Age of Onset↗
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

Association between the methylenetetrahydrofolate reductase 677C-->T missense mutation and schizophrenia.

The schizophrenia phenotype is heterogeneous with respect to clinical presentation, long-term response to medication, and outcome, possibly reflecting genetic heterogeneity and/or the presence of modifier genes. Compared to non-responders, schizophrenic patients who are responders to neuroleptic medications are characterized by a high female/male ratio, a better long-term outcome and more frequently disturbed dopamine neurotransmission. In this study, we compared two groups of schizophrenic patients selected on the basis of their long-term response to neuroleptics (excellent responders and non-responders) and a group of healthy volunteers, with regard to a missense mutation (677C-->T) in the methylenetetrahydrofolate reductase (MTHFR) gene. This polymorphism was chosen because it is functional and was previously associated with schizophrenia. The present study revealed a significant association between schizophrenia and allele T of this gene. This association was entirely due to an over-representation of allele T in responder patients compared to controls; nonresponder patients did not differ from controls. Genotype TT was more frequent in responder patients compared to controls, thus replicating the findings of Arinami et al. These results strongly suggest that the MTHFR gene is involved in the pathogenesis of schizophrenia characterized by a rapid and sustained therapeutic response to typical neuroleptics and/or a good long-term prognosis/favorable therapeutic outcome.

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↗