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ABSTRACT: Up to 90% of individuals with schizophrenia suffer from nicotine dependence. Both schizophrenia and nicotine consumption have strong genetic components, which may overlap. The relationship between schizophrenia and nicotine dependence remains unclear, due in part to confounding factors. Studies of the relationship between nicotine consumption and milder schizophrenia-related phenotypes, such as schizotypy, in first-degree relatives of individuals with schizophrenia could help to better understand the relationship between smoking and schizophrenia while avoiding such confounders. We assessed the proportion of smokers, their level of nicotine dependence and their level of schizotypy in a sample of 98 first-degree relatives of schizophrenic subjects and 110 healthy controls. Partial correlation analysis was used to assess the relationship between schizotypal dimensions and smoking dependence. The prevalence of smoking and nicotine dependence levels were higher in the relatives than in the healthy control group. We found no relationship between nicotine dependence and the magnitude of schizotypal features in either group. Our results support the hypothesis that the relationship between schizophrenia and smoking is largely mediated by common familial factors, which may be genetic.
Psychiatry research. 08/2012;
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ABSTRACT: A number of epidemiological and genetic studies suggests an overlap of Schizophrenia and Bipolar disorder across the traditional binary classification. AKT1 gene variants were previously shown to be associated with schizophrenia. In this study, our aim was to determine whether AKT1 gene variants are associated with particular phenotypes for schizophrenia (SCZ) and bipolar disorder (BPD).
This study included 529 subjects of European ancestry: 364 patients suffering from SCZ, BPD or schizoaffective disorder and 165 healthy controls. BPD patients were additionally subdivided into two groups: BPD with or without psychosis. Six AKT1 variants were assessed in a case-control study and allelic associations were analyzed. Moreover, meta-analyses were performed for those variants found in case-control studies of schizophrenia and schizoaffective disorder.
Nominal associations were found for three AKT1 gene variants, namely rs3803300, rs2494732 and rs2498804, in the four phenotypes. Two SNP survived Bonferroni corrections for multiple testing: rs3803300 (p<0.001) and rs2498804 (p<0.03) in group 1 (BPD without psychosis). In group 2 (BPD with psychosis) and in group 4 (SCZ), rs3803300 was significant but did not survive multiple testing. While rs2494732 was associated with the presence of psychosis (group-2, 3 and 4), rs2498804 was associated with affective symptoms (groups-1, 2 and 3). One meta-analysis found a significant level of association between rs3803300 and schizophrenia in Asian subjects.
AKT1 gene variations appeared to impact the risk for a class of psychiatric symptoms, comprising SCZ and BPD. Our findings support the view that AKT1 genetic variants are shared by both BPD and SCZ.
Biological Psychiatry 03/2012; 135(1-3):8-14. · 8.28 Impact Factor
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Anne Dumaine,
Alexandre Maucuer,
Aurélie Barbet,
Valérie Manceau,
Jasmine Deshommes, Alexandre Méary,
Andrei Szöke,
Franck Schürhoff,
Pierre-Michel Llorca,
Christophe Lancon,
Marion Leboyer,
Stéphane Jamain
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ABSTRACT: In two recent papers, polymorphisms located in U2AF homology motif kinase 1 (UHMK1) gene have been associated to schizophrenia. This gene encodes the serine/threonine kinase, kinase interacting with Stathmin, and has been functionally related to RNA metabolism and neurite outgrowth. In this study, we explored the contribution of this gene in schizophrenia susceptibility, using a case-control association study, a mutation screening, a transcription level analysis, and by the investigation of the phosphorylation status of the splicing factor, SF1, in B-lymphoblastoid cell lines of patients and controls. No association was observed in our French cohort, and no amino acid substitution was predicted in the subsample studied for mutation screening. No difference was observed in expression level or in SF1 phosphorylation between patients and controls. Despite a slight difference persisting in the meta-analysis carried out using four European populations, these data suggest, altogether, that UHMK1 does not play a major role in susceptibility to schizophrenia.
Psychiatric genetics 03/2011; 21(6):315-8. · 2.33 Impact Factor
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F Karege,
N Perroud,
F Schürhoff, A Méary,
G Marillier,
S Burkhardt,
E Ballmann,
R Fernandez,
S Jamain,
M Leboyer,
R La Harpe,
A Malafosse
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ABSTRACT: The AKT1 gene has been associated with the genetic aetiology of schizophrenia. Following the overlap model of bipolar disorder and schizophrenia, we aimed to investigate AKT1 genetic variants and protein expression in both diseases. A total of 679 subjects with European ancestry were included: 384 with schizophrenia, 130 with bipolar disorder and 165 controls. Six single nucleotide polymorphisms (SNPs) were investigated for association with the diseases using single- and multi-locus analyses. AKT1 and AKT2 protein levels were measured in post-mortem brain tissues from ante-mortem diagnosed schizophrenia (n = 30) and bipolar disorder subjects (n = 12) and matched controls. The analysis identified a significant global distortion in schizophrenia (P = 0.0026) and a weak association in bipolar disorder (P = 0.046). A sliding window procedure showed a five-SNP haplotype (TCGAG) to be associated with schizophrenia (P = 1.22 x 10(-4)) and bipolar disorder (P = 0.0041) and a four-SNP haplotype (TCGA) with the combined sample (1.73 x 10(-5)). On the basis of selected genotypes, a significant difference in protein expression emerged between subjects (P < 0.02). In conclusion, our findings, by showing the involvement of the AKT1 gene in both schizophrenia and bipolar disorder, support the role of AKT1 in the genetics of both disorders and add support to the view that there is some genetic overlap between them.
Genes Brain and Behavior 02/2010; 9(5):503-11. · 3.48 Impact Factor
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ABSTRACT: To test if specific correlations exist between cognitive measures and psychotic dimensions in schizophrenic subjects and if similar correlations, between cognition and schizotypal dimensions, are present in non-psychotic subjects.
We administered the same battery of cognitive tests (Source Monitoring, Verbal Fluency [VF] and Stroop tests) to schizophrenic subjects (N=54), their first-degree relatives (N=37) and controls (N=41). Scores of negative, positive and disorganisation dimensions were derived from the Signs and Symptoms of Psychotic Illness scale in schizophrenic subjects, and from the Schizotypal Personality Questionnaire in relatives and controls.
In schizophrenic subjects, as hypothesised, the negative dimension correlated with performance on VF and disorganisation with performance in the Stroop test. The positive dimension did not correlate with any cognitive measure. With only one exception, the significant correlations observed in non-psychotic subjects did not match correlations seen in schizophrenic subjects. In non-psychotic subjects greater disorganisation was associated with more clustered words in VF suggesting that excessive automatic spreading of activation in semantic networks could underlie this dimension.
As a whole, data lent partial support to our hypothesis of specific cognitive-clinical correlations in schizophrenic subjects but did not support the existence of similar correlations in non-psychotic subjects.
European Psychiatry 01/2009; 24(4):244-50. · 2.77 Impact Factor
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ABSTRACT: A wide range of cognitive deficits have been demonstrated in schizophrenia, but their longitudinal course remains unclear.
To bring together all the available information from longitudinal studies of cognitive performance in people with schizophrenia.
We carried out a meta-analysis of 53 studies. Unlike previous reviewers, we included all studies (regardless of the type of medication), analysed each variable separately and compared results with data from controls.
Participants with schizophrenia showed a significant improvement in most cognitive tasks. The available data for controls showed, with one exception (the Stroop test), a similar or greater improvement. Performance in semantic verbal fluency remained stable in both individuals with schizophrenia and controls.
Participants with schizophrenia displayed improvement in most cognitive tasks, but practice was more likely than cognitive remediation to account for most of the improvements observed. Semantic verbal fluency may be the best candidate cognitive endophenotype.
The British Journal of Psychiatry 05/2008; 192(4):248-57. · 6.62 Impact Factor
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ABSTRACT: Although catechol-O-methyltransferase (COMT) has long been suggested to be implicated in the pathogenesis of schizophrenia, association studies have generated discrepant results concerning the involvement of the COMT gene in schizophrenia. As several studies have suggested that schizotypal traits might be genetically related to schizophrenia, increased statistical power to detect gene effects could be obtained by using dimensional personality traits in unaffected relatives.
We tested the hypothesis that the functional Val158Met COMT polymorphism might contribute to the variance of self-reported schizotypal scores in a sample of 106 unaffected subjects, composed of controls (N = 57), first-degree relatives of schizophrenic (N = 27) and of bipolar (N = 22) probands. We also looked for specific associations between COMT polymorphisms and the three dimensions of schizotypy (positive, negative, disorganized) assessed by the Schizotypal Personality Questionnaire (SPQ).
We found that self-reported SPQ scores are related to COMT genotype (P = 0.01), with individuals homozygous for the high activity allele having the highest scores. This association is primarily due to specific associations with the positive (P = 0.001) and negative (P = 0.04) dimensions.
Our data support the hypothesis that the functional COMT polymorphism could be involved in different psychotic dimensions. This confirms that studying specific schizotypal dimensions can help to identify the genes involved in the pathogenesis of psychosis.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 02/2007; 144B(1):64-8. · 3.70 Impact Factor
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ABSTRACT: Executive dysfunctions are considered to be putative markers of familial/genetic vulnerability to both schizophrenia and bipolar disorder. However, familial resemblance must be demonstrated before executive functions are used as a potential endophenotype. The aim of this study was to investigate familial resemblance for executive functions in families of schizophrenic and bipolar subjects. We assessed executive functions by means of two tests - the Wisconsin Card Sorting Test (WCST) and the Trail Making Test (TMT) - in 351 subjects from five populations: schizophrenic patients, bipolar patients, a group of relatives for each patient group and controls. For both tests, cognitive assessment results were consistent with previous studies: schizophrenic patients showed the greatest impairment, followed by bipolar patients and then the two groups of relatives. In families of bipolar patients we observed familial resemblance for the WCST and part A and part B of the TMT. However, by contrast with the classical point of view, considering executive measures to be markers of genetic vulnerability to schizophrenia, we did not demonstrate familial resemblance for either of the two executive tests in families of schizophrenic patients. Thus, executive measures, as assessed by the WCST or the TMT, should not be used as endophenotypes in genetic studies of schizophrenia unless confounders are identified and their effects eliminated.
Psychiatry Research 12/2006; 144(2-3):131-8. · 2.52 Impact Factor
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ABSTRACT: Family studies have suggested that schizophrenia and bipolar disorders share some susceptibility factors. Schizotypal personality disorder (SPD) may be an intermediate phenotype common both to schizophrenia and bipolar disorders. We explored the familiality of schizotypal dimensions by comparing the magnitude of schizotypal dimensions between schizophrenic and bipolar relatives. We also looked for intra-familial resemblance for these dimensions, and for an increased familial risk of schizophrenia and/or bipolar disorders associated with a particular schizotypal dimension.
We used the Schizotypal Personality Questionnaire (SPQ) to study the three schizotypal dimensions (disorganization, negative and positive) in a sample of unaffected first-degree relatives of schizophrenic (N=85), psychotic bipolar (N=63) and bipolar (N=32) probands. Differences between groups were tested using a two-tailed t-test or ANOVA for continuous variables and a chi-squared test for discrete variables. We used the intraclass correlation method to study the intra-familial correlation. Linear mixed models were used to measure the familial risk.
The disorganization dimension appears to be common to relatives of both schizophrenia and psychotic bipolar disorders, but not in the relatives of non-psychotic bipolar probands. This dimension also increases the familial risk of these two disorders. The negative dimension shows intra-familial resemblance (R=0.29), we failed to observe the expected familiality for the disorganized dimension.
The shared nature of the disorganization dimension shown by a similar familial risk for schizophrenia and psychotic bipolar disorders suggests that same genetic background may underlie psychotic disorders. Although, negative dimension is familial, it is not associated for an increased familial risk for both disorders.
Schizophrenia Research 01/2006; 80(2-3):235-42. · 4.75 Impact Factor
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ABSTRACT: In schizophrenia, clinical, familial and biological characteristics according to age at onset (AAO) suggest that AAO is a valid candidate symptom for genetic studies. However, none of the various thresholds used to define AAO subgroups in schizophrenia has been validated. We aim to define different AAO subtypes by admixture analysis in a sample of prospectively recruited subjects with schizophrenia. Consecutive inpatients and outpatients (N=141) meeting DSM IV criteria for schizophrenia were included. We used admixture analysis to investigate whether the observed AAO distribution consisted of a mixture of gaussian distributions and then compared clinical features and familial risks in the various groups of subjects. The model that best fitted the observed AAO distribution was a mixture of two gaussian distributions (mean+/-S.D.): (19.91+/-3.56 years) and (33.48+/-8.2 years), with a cutoff point at 28 years. The existence of two subgroups according to AAO was further confirmed by the different clinical and familial profiles of these subgroups. The early-onset group consisted predominantly of male patients, with non-paranoid subtypes and with a higher familial risk of schizophrenia spectrum disorders and affective disorders. The late-onset group of patients presented predominantly paranoid subtype, preponderance of females; they were more likely to be married and to have children. We identified two subgroups of schizophrenic subjects with different clinical and familial profiles. This study provides a mathematical validation of the existence of two subgroups defined by an onset of schizophrenia before or after 28 years. These results may have important implications for the search for schizophrenia susceptibility factors. Working with homogeneous subgroups defined on the basis of AAO may facilitate the identification of genetic vulnerability factors in schizophrenia.
Schizophrenia Research 12/2004; 71(1):35-41. · 4.75 Impact Factor
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ABSTRACT: Clinical, familial, and, more recently, genetic linkage studies suggest that overlapping genetic susceptibility might contribute to both schizophrenia and bipolar disorder. To identify a potential psychotic dimension common to families of both bipolar and schizophrenia probands, the authors tested if delusional proneness was observed among first-degree relatives of bipolar and schizophrenia probands.
The authors included 32 schizophrenia probands and 61 bipolar probands and their respective first-degree relatives (N=63 and N=59). They were all interviewed with the Diagnostic Interview for Genetic Studies, and delusional proneness was assessed with a self-report questionnaire, the Peters et al. Delusions Inventory. Schizophrenia and bipolar probands were subdivided into subgroups according to the intensity of delusional symptoms assessed by Peters et al. Delusions Inventory scores, and the authors compared delusional proneness in their respective first-degree relatives.
Familial aggregation of delusional proneness was demonstrated, since Peters et al. Delusions Inventory scores were higher among nonschizophrenic first-degree relatives of schizophrenia probands with productive symptoms and among first-degree relatives of bipolar probands with psychotic features during their affective episodes. The authors also found an intrafamilial correlation of delusional proneness scores in nonaffected siblings of schizophrenia and bipolar probands.
Delusional proneness appears to be an inherited predisposition common to both schizophrenia and bipolar disorder. In the future, this dimension might be valuable when used as a quantitative phenotype in linkage and association studies.
American Journal of Psychiatry 08/2003; 160(7):1313-9. · 12.54 Impact Factor
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ABSTRACT: BACKGROUND: Strong evidence supports the association between childhood trauma and psychotic disorders. In two different high-risk populations, we looked for a correlation between the magnitude of schizotypal dimensions and the importance of self-reported childhood trauma.MethodA sample of 138 unaffected first-degree relatives was recruited (67 relatives of schizophrenic probands and 71 relatives of bipolar probands). The relationship between schizotypal dimensions and childhood trauma scores was analyzed by partial correlations. RESULTS: A positive correlation was found between childhood trauma scores and total schizotypal scores in first-degree relatives of schizophrenic subjects but not in first-degree relatives of bipolar probands. This correlation was primarily due to a strong association with the positive dimension of schizotypy. CONCLUSIONS: The significant correlation between childhood trauma and schizotypal dimensions in subjects at high genetic risk for schizophrenia suggests that susceptibility genes for schizophrenia may interact with childhood trauma to induce the emergence of schizotypal dimensions, mainly positive psychotic features.
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ABSTRACT: BACKGROUND: Memory deficits have been clearly demonstrated in schizophrenic patients. However, studies of memory performances in their relatives compared to normal controls provide conflicting results. A meta-analysis was carried out to synthesize all the published data. Unlike previous meta-analyses, which were based on composite scores, we analyzed each memory test separately. This prevents theoretically questionable choices in grouping variables, leads to results with clearer implications for applied research (e.g. the best choice of a test according to its sensitivity) and is more productive in suggesting explanatory hypotheses. METHOD: We initially selected 77 potentially relevant articles, but only 19 met our inclusion criteria. These articles provided data on eight different tasks, from five different memory tests: four tests from the Wechsler Memory Scale (WMS) and the California Verbal Learning Test (CVLT). For each task, we assessed data homogeneity, identified the outliers if any and then estimated effect sizes and tested publication bias using funnel plots. RESULTS: Adult relatives of schizophrenic patients were significantly impaired on most, but not all, tasks. The largest deficits were observed for the verbal paired associates test, the logical stories the digit span forward test and the digit span backward test. We found no significant differences in tasks of delayed recall, when deficits in immediate conditions (reflecting encoding) were taken into account. CONCLUSIONS: Adult relatives of schizophrenic patients have wide but not severe memory impairments. The size of estimated effects suggests that encoding processes are impaired, whereas storage and retrieval processes are relatively unaffected.
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ABSTRACT: Abnormal dopaminergic function in the prefrontal cortex (PFC) may be a key factor in the etiopathogeny of schizophrenia and bipolar disorder. Both schizophrenic and bipolar subjects have executive functions (EF) deficits, thought to reflect abnormal PFC function. The main inactivation pathways for dopamine in the PFC are enzymatic cleavage by the Carboxy-O-Methyl-Transferase (COMT) and reuptake by the nor-epinephrine transporter (NET). Our aim in this study was to replicate previous studies that investigated influence of the COMT genotype on EF in schizophrenic subjects, their relatives and controls and extend their scope by including bipolar patients, and their relatives and by exploring NET gene polymorphisms influence on executive performances. We investigated one functional polymorphism of the COMT gene and two polymorphisms of the NET gene. EF were assessed by means of the Trail Making Test (TMT) and the Wisconsin Card Sorting Test (WCST). We assessed the effect of each of the three genotypes on EF for the whole sample (N = 318) and separately in schizophrenic (N = 66), bipolar (N = 94) and healthy subjects (i.e., relatives and controls N = 158). Separate analyses were performed because of the presence, in patients samples, of potentially confounding factors, especially medication. Genotype had no significant effect on the cognitive measures in any of the analyses (for the two EF measures, the three polymorphisms, and the four groups). In our sample we found no evidence in favor of a major effect of COMT or NET polymorphisms on the two tests of EF.
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ABSTRACT: OBJECTIVE: This report describes the psychometric evaluation of the French translation of the Signs and Symptoms of Psychotic Illness (SSPI) scale. The SSPI scale was designed to assess the five main clusters of symptoms of people suffering from psychotic disorders (psychomotor poverty, reality distortion, disorganisation, depression, and psychomotor excitation) across diagnostic entities. This new tool has been built by Liddle because, in the existing scales assessing psychotic symptoms, individual items cover symptoms that belong to different pathophysiological processes. The SSPI scale comprises 20 items. Its interview is semi-standardised and typically lasts around 25 min. The English version of this scale has shown good psychometric properties (inter-rater reliability, factor structure). METHOD: We used the SSPI ratings of 81 patients with psychotic symptoms to assess its factor structure and concurrent validity with the Clinical Global Impressions (CGI) scale. Twenty-eight videotaped ratings were used to calculate the intra-class correlation coefficient (ICC) as a measure of inter-rater reliability. RESULTS AND DISCUSSION: The sample was composed of 46 schizophrenic subjects, 14 with schizoaffective disorder, three with major depressive episode with psychotic features, nine with manic episode with psychotic features and nine with other psychotic disorders. A principal component analysis was conducted to determine the factor structure. Using the Cattell test, we retained a five-factor solution. This solution explained 56.9% of the variance. After varimax rotation, 18 items were attributed to a unique factor. The five factors were: a psychomotor poverty factor, a reality distortion factor, a disorganised factor, an anxious/depressive factor and a psychomotor excitation factor. This structure is close to the original one. The inter-rater reliability of the French version of the SSPI was satisfactory for 18 items, with a mean ICC of 0.64 for the individual items, and an ICC of 0.76 for the global scale. Only two items had an unsatisfactory ICC. This scale showed a good correlation with the CGI scale, with a correlation coefficient between CGI score and SSPI global score of 0.64. Among the factor scores, reality distortion, disorganisation and depression factor scores exhibited a significant correlation with the CGI score. CONCLUSIONS: The French version of the SSPI scale has good psychometric properties, similar to the English version. Furthermore, its factor structure is similar to the English one. This scale is a robust instrument to rate psychotic symptoms and dimensions across diagnosis entities.
