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.
Recent studies have reported altered methylation levels at disorder-relevant DNA sites in people who are ill with Anorexia Nervosa (AN) compared to findings in people with no eating disorder (ED) or ...in whom AN has remitted. The preceding implies state-related influences upon gene expression in people with AN. This study further examined this notion.
We measured genome-wide DNA methylation in 145 women with active AN, 49 showing stable one-year remission of AN, and 64 with no ED.
Comparisons revealed 205 differentially methylated sites between active and no ED groups, and 162 differentially methylated sites between active and remitted groups (Q < 0.01). Probes tended to map onto genes relevant to psychiatric, metabolic and immune functions. Notably, several of the genes identified here as being differentially methylated in people with AN (e.g. SYNJ2, PRKAG2, STAT3, CSGALNACT1, NEGR1, NR1H3) have figured in previous studies on AN. Effects also associated illness chronicity and lower BMI with more pronounced DNA methylation alterations, and remission of AN with normalisation of DNA methylation.
Findings corroborate earlier results suggesting reversible DNA methylation alterations in AN, and point to particular genes at which epigenetic mechanisms may act to shape AN phenomenology.
Schizophrenia and chromosome 6p Turecki, G; Rouleau, G A; Joober, R ...
American journal of medical genetics,
18 April 1997, Volume:
74, Issue:
2
Journal Article
Peer reviewed
Several studies have recently reported genetic linkage between markers located on the short arm of chromosome 6 and schizophrenia. Valid conclusions, however, are difficult to formulate because ...chromosomal markers that yielded positive results span a relatively large region of chromosome 6, and studies did not necessarily obtain consistent results with regard to the particular loci tested. Here, we report a meta-analysis of the results of linkage studies of schizophrenia that used chromosome 6p markers. After conducting a systematic search, nine different studies were selected for the analysis using defined criteria. Pooled P values were obtained for all common markers investigated and provided additional support for a major susceptibility locus for schizophrenia in this region. In addition, two markers located 2 cM apart, D6S274 and D6S285, provided the most significant results. These findings may help narrow the chromosomal region in the search for a major gene implicated in schizophrenia.
To test for genetic linkage and association with GABAergic candidate genes in lithium-responsive bipolar disorder.
Polymorphisms located in genes that code for GABRA3, GABRA5 and GABRB3 subunits of ...the GABAA receptor were investigated using association and linkage strategies.
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.
The association between the candidate genes and patients with bipolar disorder versus that of controls and genetic linkage within families.
There was no significant association or linkage found between lithium-responsive bipolar disorder and the GABAergic candidate genes investigated.
This study does not support a major role for the GABAergic candidate genes tested in lithium-responsive bipolar disorder.
Schizophrenia is a complex disease that affects up to 1% of the general population. It is manifested by a variable number of negative, positive and disorganisation symptoms giving rise to an ...important diversity in the expression of this syndrome. The treatment of schizophrenia is mainly based on neuroleptic drugs that alleviate, to a variable extent, psychotic symptoms in the majority but not all the patients. Although its aetiology is still unknown, it is now well established that schizophrenia is a brain disease resulting from the combination of environmental and genetic risk factors. In spite of intensive research, no specific genes were convincingly associated with schizophrenia possibly because of the presence of genetic heterogeneity. In this work, it was hypothesised that schizophrenic patients with excellent long-term response (R) and those with very poor long-term response to conventional neuroleptics (NR) may differ, at least partially, with respect to the pathogenesis of their disease. In this thesis we aimed at validating this classification scheme and illustrating its usefulness for genetic studies. In accordance with this hypothesis, it was found that NR differ from R patients with respect to age at onset, premorbid social adjustment, neuropsychological profiles and family history of psychiatric disorders. Molecular genetic investigations identified 2 genes, the hGT1 and 5-HT2a-receptor genes, that were associated respectively with responsive and nonresponsive schizophrenia, thus showing the utility of categorising patients according to their therapeutic response. A third gene, called hSWI2/SNF2 was also found to be associated with schizophrenia irrespective of therapeutic response to neuroleptics. In addition, a potentially abnormal protein was detected in two schizophrenic patients but not in controls. In conclusion, the distinction of schizophrenic patients belonging to the two extremes of long-term responsiveness to neuroleptics may help in identifying susceptibility genes involved in this complex syndrome.
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.
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.
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