Publications (25)82 Total impact
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Article: Brain Structural Signature of Familial Predisposition for Bipolar Disorder: Replicable Evidence For Involvement of the Right Inferior Frontal Gyrus.
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ABSTRACT: BACKGROUND: To translate our knowledge about neuroanatomy of bipolar disorder (BD) into a diagnostic tool, it is necessary to identify the neural signature of predisposition for BD and separate it from effects of long-standing illness and treatment. Thus, we examined the associations among genetic risk, illness burden, lithium treatment, and brain structure in BD. METHODS: This is a two-center, replication-design, structural magnetic resonance imaging study. First, we investigated neuroanatomic markers of familial predisposition by comparing 50 unaffected and 36 affected relatives of BD probands as well as 49 control subjects using modulated voxel-based morphometry. Second, we investigated effects of long-standing illness and treatment on the identified markers in 19 young participants early in the course of BD, 29 subjects with substantial burden of long-lasting BD and either minimal lifetime (n = 12), or long-term ongoing (n = 17) lithium treatment. RESULTS: Five groups, including the unaffected and affected relatives of BD probands from each center as well as participants early in the course of BD showed larger right inferior frontal gyrus (rIFG) volumes than control subjects (corrected p < .001). The rIFG volume correlated negatively with illness duration (corrected p < .01) and, relative to the controls, was smaller among BD individuals with long-term illness burden and minimal lifetime lithium exposure (corrected p < .001). Li-treated subjects had normal rIFG volumes despite substantial illness burden. CONCLUSIONS: Brain structural changes in BD may result from interplay between illness burden and compensatory processes, which may be enhanced by lithium treatment. The rIFG volume could aid in identification of subjects at risk for BD even before any behavioral manifestations.Biological psychiatry 07/2012; · 8.93 Impact Factor -
Article: Antidepressant monotherapy compared with combinations of antidepressants in the treatment of resistant depressive patients: A randomized, open-label study.
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ABSTRACT: Objective. This randomized, 6-week, open-label study compared efficacy of CAD and antidepressant monotherapies (ADM) that had been chosen according to clinical judgment of the attending psychiatrist. Methods. A total of 60 inpatients (intent-to-treat analysis) with depressive disorder (≥ 1 unsuccessful antidepressant treatment) were randomly assigned to the interventions. The responders who completed the acute phase of study, were evaluated for relapse within 2 months of follow-up treatment. The primary outcome measure was change in the Montgomery-Åsberg Depression Rating Scale (MADRS) and response was defined as a ≥ 50% reduction of MADRS score. Results. Mean changes in total MADRS score from baseline to week 6 for patients in both treatment modalities were not different (ADM = 13.2 ± 8.6 points; CAD = 14.5 ± 9.5 points; P = 0.58). The analysis of covariance performed for significantly higher value of imipramine equivalent dose in CAD group showed only a non-significant between-group difference for total MADRS change (P = 0.17). There were also no differences between groups in response rate (ADM = 48%; CAD = 58%) and number of drop-outs in acute treatment as well as proportion of responders' relapses in the follow-up. Conclusion. Both treatment modalities produced clinically relevant reduction of depressive symptomatology in acute treatment of patients with resistant depression and their effect was comparable.International Journal of Psychiatry in Clinical Practice 04/2012; · 0.43 Impact Factor -
Article: The change of QEEG prefrontal cordance as a response predictor to antidepressive intervention in bipolar depression. A pilot study.
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ABSTRACT: The aim of the study was to examine whether the change of quantitative EEG (QEEG) theta prefrontal cordance after one week of various antidepressive interventions predicts response to a 4-week treatment in patients with bipolar depression. We investigated 20 inpatients who completed a 4-week treatment. EEG data were monitored at baseline and after 1 week of treatment. QEEG cordance was computed at 3 frontal electrodes (Fp1, Fp2, Fz) in theta frequency band. Depressive symptoms and clinical status were assessed using Montgomery-Åsberg Depression Rating Scale (MADRS), Clinical Global Impression (CGI) and Young Mania Rating Scale (YMRS). Seven of 8 responders (reduction of MADRS ≥50%) and only 2 of 12 non-responders had decreased prefrontal theta cordance value after the first week of treatment (p = 0.02). The positive and negative predictive values of cordance reduction for response were 0.78 and 0.91, respectively. We also found significant differences in cordance value reductions between responders and non-responders after week 1 and higher baseline cordance in responders. Conclusion: The change in prefrontal theta cordance was associated with subsequent change in depressive symptoms and potentially might be a useful tool in the early detection of acute response to antidepressive interventions in bipolar depressed patients.Journal of psychiatric research 09/2011; 46(2):219-25. · 3.72 Impact Factor -
Article: White matter hyperintensities in affected and unaffected late teenage and early adulthood offspring of bipolar parents: a two-center high-risk study.
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ABSTRACT: White matter hyperintensities (WMHs) are among the most replicated neuroimaging findings in bipolar disorder (BD). It is not clear whether these lesions are an artifact of comorbid conditions, or whether they are directly associated with the disorder, or even represent biological risk factor for BD. To test whether WMHs meet criteria for an endophenotype of BD, we conducted a high-risk design study and recruited 35 affected, 44 unaffected relatives of bipolar probands (age range 15-30 years), matched by age and sex with 49 healthy controls without any personal or family history of psychiatric disorders. The presence of WMHs was determined from Fluid Attenuated Inversion Recovery (FLAIR) scans acquired on a 1.5 Tesla scanner using a validated semi-quantitative scale. We found mostly low grade WMHs in all groups. The proportion of WMH-positive subjects was comparable between the unaffected high-risk, affected familial and control groups. White matter hyperintensities did not meet criteria for an endophenotype of BD. Bipolar disorder in young subjects without comorbid conditions was not associated with increased rate of WMHs.Journal of psychiatric research 01/2011; 45(1):76-82. · 3.72 Impact Factor -
Article: Antidepressant monotherapy and combination of antidepressants in the treatment of resistant depression in current clinical practice: A retrospective study
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ABSTRACT: Abstract Objectives. The aim of this study was to compare efficacy of antidepressant monotherapies and combinations of antidepressants in the treatment of resistant patients in current clinical practice. Methods. We reviewed chart documents of resistant depressive inpatients treated at least 4 weeks with a new treatment. Depressive symptoms and clinical status were assessed using Montgomery and Åsberg Depression Rating Scale (MADRS), Beck Depression Inventory–Short Form and Clinical Global Impression at the baseline, week 2 and in the end of treatment. Results. We identified 81 patients (27 with combinations and 51 with monotherapies) that were suitable for analyses. The combination group achieved higher reduction of MADRS score (14.6 vs 10.2 pts., p=0.02) and response rate (≥ 50% reduction of MADRS, 67% vs 39%, p=0.03). Number needed to treat for response was 4. Conclusions. Based on our results, we suggest that combination of antidepressants might be more effective than monotherapy in clinical practice.10/2010; 14(4):303-308. -
Article: The change of prefrontal QEEG theta cordance as a predictor of response to bupropion treatment in patients who had failed to respond to previous antidepressant treatments.
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ABSTRACT: The aim of the study was to examine whether the reduction of theta prefrontal quantitative EEG (QEEG) cordance after one week of bupropion administration is a predictor of response to a 4-week treatment in patients that had failed to respond to previous antidepressant treatments. Method: EEG data of 18 inpatients were monitored at baseline and after one week. QEEG cordance was computed at 3 frontal electrodes (Fp1, Fp2, Fz). Response to treatment was defined as a >/=50% reduction of MADRS score. Results: Nine of the eleven responders and one of the seven non-responders showed decreased prefrontal cordance value after the first week of treatment (p=0.01). Positive and negative predictive values of cordance reduction for the prediction of response to the treatment were 0.9 and 0.75, respectively. Conclusion: Similar to other antidepressants, the reduction of prefrontal QEEG cordance might be helpful in the prediction of the acute outcome of bupropion treatment.European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 07/2010; 20(7):459-66. · 3.68 Impact Factor -
Article: Rare NRXN1 promoter variants in patients with schizophrenia.
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ABSTRACT: Copy number variants (CNVs) affecting the neurexin 1 (NRXN1) gene have been found in a subgroup of patients with schizophrenia (SZ). NRXN1 expression is complex, with multiple alternative splice forms generated from two major transcripts; NRXN1alpha and NRXN1beta. The majority of CNVs in SZ are deletions affecting the proximal NRXN1alpha exons and promoter region. Rare chromosomal events are useful in understanding the genetic basis of complex psychiatric disorders since affected genes become feasible targets to analyze for more subtle genetic alterations. As a first step towards this goal, we resequenced the NRXN1alpha promoter region in 170 patients with SZ and a similar number of controls. Two rare mutations were identified in the patient population. One previously unknown single nucleotide polymorphism (SNP) was found in controls. Bioinformatics analysis suggests that binding to several transcription factors may be affected by the minor alleles. The findings suggest that in addition to chromosomal alterations disrupting the NRXN1alpha promoter, rare point mutations in the region may also be involved in SZ pathogenesis.Neuroscience Letters 03/2010; 475(2):80-4. · 2.11 Impact Factor -
Article: Analysis of a promoter polymorphism in the SMDF neuregulin 1 isoform in Schizophrenia.
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ABSTRACT: Neuregulin 1 (NRG1) is a positional candidate gene in schizophrenia (SZ). Two major susceptibility loci in the NRG1 gene approximately one million nucleotides apart have been identified in genetic studies. Several candidate functional allelic variants have been described that might be involved in disease susceptibility. However, the findings are still preliminary. We recently mapped active promoters and other regulatory domains in several SZ and bipolar disorder (BD) candidate genes using ChIP-chip (chromatin immunoprecipitation hybridized to microarrays). One was the promoter for the NRG1 isoform, SMDF, which maps to the 3' end of the gene complex. Analysis of the SNP database revealed several polymorphisms within the approximate borders of the region immunoprecipitated in our ChIP-chip experiments, one of which is rs7825588. This SNP was analyzed in patients with SZ and BD and its effect on promoter function was assessed by electromobility gel shift assays and luciferase reporter constructs. A significant increase in homozygosity for the minor allele was found in patients with SZ (genotype distribution chi(2) = 7.32, p = 0.03) but not in BD (genotype distribution chi(2) = 0.52, p = 0.77). Molecular studies demonstrated modest, but statistically significant allele-specific differences in protein binding and promoter function. The findings suggest that homozygosity for rs725588 could be a risk genotype for SZ.Neuropsychobiology 07/2009; 59(4):205-12. · 2.67 Impact Factor -
Article: Low frequency (1-Hz), right prefrontal repetitive transcranial magnetic stimulation (rTMS) compared with venlafaxine ER in the treatment of resistant depression: a double-blind, single-centre, randomized study.
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ABSTRACT: Previous studies have shown effectiveness of repetitive transcranial magnetic stimulation (rTMS) in the treatment of depression. This double-blind study compared efficacy of l Hz rTMS over the right prefrontal dorsolateral cortex with venlafaxine ER in the treatment of resistant depression. A total of 60 inpatients with depressive disorder (DSM-IV criteria), who previously did not respond to at least one antidepressant treatment, were randomly assigned to 1 Hz rTMS with placebo and venlafaxine ER with sham rTMS for 4 weeks. The primary outcome measure was score change in the Montgomery-Asberg Depression Rating Scale (MADRS). We also used Clinical Global Impression (CGI) and Beck Depressive. Inventory-Short Form (BDI-SF). The response was defined as a >or=50% reduction of MADRS score. There were no significant differences between treatment groups in MADRS (p=0.38), BDI-SF (p=0.56) and CGI (p=0.17) scores from baseline to endpoint. Response rates for rTMS (33%) and venlafaxine (39%) as well as remission (MADRS score<or=10 points) rates (19% vs. 23%) and drop-out rate did not differ between treatment groups. There were significant reductions of MADRS, CGI and BDI-SF scores in both groups. Small sample size. No placebo arm was included for ethical reasons, because both treatments have previously been reported to be more effective than placebo. Relatively short duration of antidepressant treatment. The findings of this study suggest that, at least in the acute treatment, the right sided rTMS produces clinically relevant reduction of depressive symptomatology in patients with resistant depression comparable to venlafaxine ER. Larger sample sizes are required to confirm these results.Journal of affective disorders 02/2009; 118(1-3):94-100. · 3.76 Impact Factor -
Article: Analysis of protocadherin alpha gene enhancer polymorphism in bipolar disorder and schizophrenia.
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ABSTRACT: Cadherins and protocadherins are cell adhesion proteins that play an important role in neuronal migration, differentiation and synaptogenesis, properties that make them targets to consider in schizophrenia (SZ) and bipolar disorder (BD) pathogenesis. Consequently, allelic variation occurring in protocadherin and cadherin encoding genes that map to regions of the genome targeted in SZ and BD linkage studies are particularly strong candidates to consider. One such set of candidate genes is the 5q31-linked PCDH family, which consists of more than 50 exons encoding three related, though distinct family members--alpha, beta, and gamma--which can generate thousands of different protocadherin proteins through alternative promoter usage and cis-alternative splicing. In this study, we focused on a SNP, rs31745, which is located in a putative PCDHalpha enhancer mapped by ChIP-chip using antibodies to covalently modified histone H3. A striking increase in homozygotes for the minor allele at this locus was detected in patients with BD. Molecular analysis revealed that the SNP causes allele-specific changes in binding to a brain protein. The findings suggest that the 5q31-linked PCDH locus should be more thoroughly considered as a disease-susceptibility locus in psychiatric disorders.Schizophrenia Research 08/2008; 102(1-3):210-9. · 4.75 Impact Factor -
Article: Analysis of protocadherin alpha gene deletion variant in bipolar disorder and schizophrenia.
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ABSTRACT: The cell adhesion proteins protocadherins and cadherins, through their effects on guiding neurons during development, neuronal differentiation, and synaptogenesis, are feasible targets to consider in schizophrenia (SZ) and bipolar disorder (BD) pathogenesis. Thus, allelic variation occurring in protocadherin and cadherin encoding genes that map to regions of the genome targeted in SZ and BD linkage studies are particularly strong candidates to consider as underlying susceptibility factors. One such set of candidate genes is the 5q31-linked PCDH family. A polymorphic copy number variation in this locus, a 16.7-kb deletion affecting PCDH-alpha exons 8-10 (alpha 8-alpha 10 Delta), was analyzed in this study as a potential candidate variant in SZ and BD. The frequency of the alpha 8-alpha 10 Delta variant was determined in a cohort of Caucasian patients with SZ from the United States and a cohort of patients with BD from the Czech Republic, and corresponding controls by amplifying DNA with deletion specific primers followed by gel electrophoresis. No significant difference was observed in the frequency of the alpha 8-alpha 10 Delta variant in patients with SZ or BD compared with their respective controls. Although the results of this study were negative, theoretical considerations and linkage studies suggest that the 5q31-linked PCDH family should be analyzed as a potential locus underlying SZ and BD susceptibility.Psychiatric genetics 07/2008; 18(3):110-5. · 2.33 Impact Factor -
Article: Early reduction in prefrontal theta QEEG cordance value predicts response to venlafaxine treatment in patients with resistant depressive disorder.
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ABSTRACT: Previous studies of patients with unipolar depression have shown that early decrease of prefrontal EEG cordance in theta band can predict clinical response to various antidepressants. We have now examined whether decrease of prefrontal quantitative EEG (QEEG) cordance value after 1 week of venlafaxine treatment predicts clinical response to venlafaxine in resistant patients. We analyzed 25 inpatients who finished 4-week venlafaxine treatment. EEG data were monitored at baseline and after 1 week of treatment. QEEG cordance was computed at three frontal electrodes in theta frequency band. Depressive symptoms and clinical status were assessed using Montgomery-Asberg Depression Rating Scale (MADRS), Beck Depression Inventory-Short Form (BDI-S) and Clinical Global Impression (CGI). Eleven of 12 responders (reduction of MADRS >or=50%) and only 5 of 13 non-responders had decreased prefrontal QEEG cordance value after the first week of treatment (p=0.01). The decrease of prefrontal cordance after week 1 in responders was significant (p=0.03) and there was no significant change in non-responders. Positive and negative predictive values of cordance reduction for response were 0.7 and 0.9, respectively. The reduction of prefrontal theta QEEG cordance value after first week of treatment might be helpful in the prediction of response to venlafaxine.European Psychiatry 04/2008; 23(5):350-5. · 2.77 Impact Factor -
Article: Can prefrontal theta cordance differentiate between depression recovery and dissimulation?
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ABSTRACT: We present a case report of a 37-year old woman diagnosed with depressive disorder, first episode, who was admitted into a psychiatric hospital after a failed suicidal attempt. She responded to antidepressant therapy, as evidenced by a >50% reduction in MADRS total score. She was discharged after 4 weeks of treatment, denying any suicidal ideations. The following day the patient committed suicide; she burned herself to death. It is very likely that the patient dissimulated her symptoms and ideations. Subsequently, her quantitative EEG records were retrospectively analyzed. An increase of prefrontal theta cordance value after the first week of mirtazapine therapy was found. Recently three small studies have revealed that decrease of prefrontal theta cordance after 1 week of antidepressant administration can predict clinical response in patients with unipolar depression. In our previous study the absence of a decreased theta prefrontal cordance was associated with lack of treatment response with NPV 1.0 (Bares et al., 2007). Thus, we hypothesize that prefrontal theta cordance could become an objective marker of change of depressive symptoms, independent of patients' compliance and symptom dissimulation, more precise than objective and self-rated depression rating scales.Neuro endocrinology letters 08/2007; 28(4):524-6. · 1.30 Impact Factor -
Article: Increase in GSK3beta gene copy number variation in bipolar disorder.
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ABSTRACT: The analysis of submicroscopic copy number variations (CNVs), also known as copy number polymorphisms (CNPs), is emerging as a new tool for understanding the genetic basis of cancer, developmental disorders, and complex traits. One area where this may be particularly useful is in the identification of genetic variants underlying schizophrenia (SZ) and bipolar disorder (BD). Linkage analysis and pharmacological studies carried out over the past decade have implicated a number of positional and physiological candidate genes. Yet, despite extensive analysis, the underlying allelic variants responsible for disease susceptibility have remained, largely, elusive. Although the borders of most CNV have not been precisely mapped, it appears that a considerable number of SZ and BD candidate genes have their coding elements disrupted by polymorphic CNVs, suggesting that these would be good variants to consider for underlying disease susceptibility. One such gene is GSK3beta, which codes for glycogen synthase kinase, a key component of the Wnt signaling pathway and a target of lithium salts. A CNV in the GSK3beta locus at chromosome 3q13.3 appears to disrupt the gene's 3'-coding elements. The CNV also affects two other annotated genes. We now report that patients with BD have an increased frequency of this CNV-primarily the duplication variant-compared with controls (P = 0.002). The finding suggests that GSK3beta may be involved in BD susceptibility in some individuals and that CNVs in this and other candidate genes for psychiatric disorders should be analyzed as causative functional genetic variants.American Journal of Medical Genetics Part B Neuropsychiatric Genetics 05/2007; 144B(3):259-65. · 3.70 Impact Factor -
Article: Increase in GSK3β gene copy number variation in bipolar disorder
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ABSTRACT: The analysis of submicroscopic copy number variations (CNVs), also known as copy number polymorphisms (CNPs), is emerging as a new tool for understanding the genetic basis of cancer, developmental disorders, and complex traits. One area where this may be particularly useful is in the identification of genetic variants underlying schizophrenia (SZ) and bipolar disorder (BD). Linkage analysis and pharmacological studies carried out over the past decade have implicated a number of positional and physiological candidate genes. Yet, despite extensive analysis, the underlying allelic variants responsible for disease susceptibility have remained, largely, elusive. Although the borders of most CNV have not been precisely mapped, it appears that a considerable number of SZ and BD candidate genes have their coding elements disrupted by polymorphic CNVs, suggesting that these would be good variants to consider for underlying disease susceptibility. One such gene is GSK3β, which codes for glycogen synthase kinase, a key component of the Wnt signaling pathway and a target of lithium salts. A CNV in the GSK3β locus at chromosome 3q13.3 appears to disrupt the gene's 3′-coding elements. The CNV also affects two other annotated genes. We now report that patients with BD have an increased frequency of this CNV—primarily the duplication variant—compared with controls (P = 0.002). The finding suggests that GSK3β may be involved in BD susceptibility in some individuals and that CNVs in this and other candidate genes for psychiatric disorders should be analyzed as causative functional genetic variants. © 2007 Wiley-Liss, Inc.American Journal of Medical Genetics Part B Neuropsychiatric Genetics 04/2007; 144B(3):259 - 265. · 3.70 Impact Factor -
Article: Analysis of synapsin III-196 promoter mutation in schizophrenia and bipolar disorder.
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ABSTRACT: The 22q13-linked gene synapsin III is a positional candidate gene for schizophrenia (SZ). One interesting synapsin III single nucleotide polymorphism (SNP), -196G/A, has been identified in the promoter region. The -196A allele results in a 6/8 base match to the core recognition octamer sequence for Oct-1, a member of the POU family of transcription factors. To determine whether or not the -196 SNP is associated with either SZ or bipolar disorder (BD). A case control comparison was used to determine whether or not differences in allele or genotype distribution occurred in patients with SZ and BD. Electromobility gel shift assay (EMSA) was used to determine whether the -196 SNP affected protein binding. A trend towards significance was detected when the allele distribution was analyzed in Caucasian patients with SZ (n = 145; 191 controls) and a cohort of subjects from the Czech Republic with BD (n = 82; 94 controls). No association was found in bipolar patients from the United States (n = 127) or in African-American patients with SZ (n = 124; 133 controls). EMSA showed that the region encompassing the -196 SNP binds to a brain protein in an allele-specific manner. These data, while inconclusive, suggest that -196 SNP should be further investigated as a candidate for 22q13-linked SZ.Neuropsychobiology 02/2006; 53(2):57-62. · 2.67 Impact Factor -
Article: Screening of PIP5K2A promoter region for mutations in bipolar disorder and schizophrenia.
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ABSTRACT: To analyze the promoter region of PIP5K2A, a phosphatidylinositol 4-phosphate 5-kinase that maps to 10p in a region linked to both bipolar disorder and schizophrenia. The promoter region was screened by single-strand conformation polymorphism analysis and DNA sequencing. Allele frequencies were determined in a case-control study. Functional significance of a promoter variant was determined by electromobility gel shift assays. Homozygosity for a rare putative promoter variant, -1007C-->T, was found in only two patients with schizophrenia and in no controls or bipolar patients. The variant forms a 7/8 base match for the binding site of Oct-1, a member of the POU homeodomain family. Electromobility gel shift assays revealed increased binding of a brain-specific nuclear protein to the -1007T allele compared with -1007C. The data suggest that homozygosity for -1007T could be a rare genetic factor in the development of schizophrenia.Psychiatric Genetics 09/2005; 15(3):223-7. · 2.58 Impact Factor -
Article: Association of schizophrenia in African Americans to polymorphism in synapsin III gene.
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ABSTRACT: Linkage studies in families with schizophrenia have pointed to chromosome 22q12-q13 as one of several regions of the genome that may contain a susceptibility gene. The gene coding for synapsin III, an intrinsic synaptic vesicle membrane protein, maps to this target region. Two tightly linked single-nucleotide polymorphisms were recently found in a small subset of patients with SZ - a synonymous variant, L469L (469G>A), and a non-synonymous variant, S470N (470G>A) - which results in the loss of a mitogen-activated protein kinase serine phosphorylation site. We also found a slight increase in 470A in Caucasian patients from the US with schizophrenia. But, the sample size and allele frequency were too small to draw definitive conclusions. However, both single-nucleotide polymorphisms were much more polymorphic in African American controls than in Caucasian controls, thereby providing a better sample cohort to analyze for schizophrenia involvement. For the codon 469 single-nucleotide polymorphisms, a 50-fold increase was observed in the frequency of 469A in African Americans compared with Caucasians. Furthermore, there was an increase in the percentage of African American patients with schizophrenia who were homozygous for the 469A allele compared with controls who were homozygous (11 versus 5%; AA vs. all other genotypes - Fisher statistic=3.08, P=0.04, one-tailed). An increase in 470A heterozygotes was also found, but the results fell short of being statistically significant. The findings support a role for synapsin III in a subset of African American patients with schizophrenia and raises questions about selective pressure in Africa to account for the extraordinary disparity of the 469 and 470 single-nucleotide polymorphisms in different ethnic populations.Psychiatric Genetics 06/2005; 15(2):127-32. · 2.58 Impact Factor -
Article: Analysis of SYNJ1, a candidate gene for 21q22 linked bipolar disorder: a replication study.
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ABSTRACT: Linkage analysis has shown that chromosome 21q22 may contain a candidate gene for bipolar disorder (BPD). One potential 21q22 candidate gene we previously analyzed is SYNJ1, which encodes synaptojanin 1, an inositol 5-phosphatase. Previous mutation screening of SYNJ1 identified three rare functional variants, one of which is a polymorphic variant near the intron 12-oxon 12 border. The rare variants were found only in a total of four BPD patients and no controls, and a trend toward significance was found for the intron 12 polymorphism. In an analysis of a new set of 84 bipolar patients, none of the rare variants were detected. There was an increase in allele 2 for the intron 12 polymorphism, similar to our original study, but the result was not significant. The combined data from both studies continue to show a trend toward significance for allele 2 homozygotes in BPD.Psychiatry Research 07/2004; 127(1-2):157-61. · 2.52 Impact Factor -
Article: Identification of PIK3C3 promoter variant associated with bipolar disorder and schizophrenia.
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ABSTRACT: Genes involved in phosphoinositide (PI) lipid metabolism are excellent candidates to consider in the pathogenesis of bipolar disorder (BD) and schizophrenia (SZ). One is PIK3C3, a member of the phosphatidylinositide 3-kinase family that maps closely to markers on 18q linked to both BD and SZ in a few studies. The promoter region of PIK3C3 was analyzed for mutations by single-strand conformation polymorphism analysis and sequencing. A case-control association study was conducted to determine the distribution of variant alleles in unrelated patients from three cohorts. Electromobility gel shift assays (EMSA) were performed to assess the functional significance of variants. Two polymorphisms in complete linked disequilibrium with each other were identified, -432C- > T and a "C" insert at position -86. The -432T allele occurs within an octamer containing an ATTT motif resembling members of the POU family of transcription factors. In each population analyzed, an increase in -432T was found in patients. EMSAs showed that a -432T containing oligonucleotide binds to brain proteins that do not recognize -432C. A promoter mutation in a PI regulator affecting the binding of a POU-type transcription factor may be involved in BD and SZ in a subset of patients.Biological Psychiatry 06/2004; 55(10):981-8. · 8.28 Impact Factor
Top co-authors
Top Journals
Institutions
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2008–2012
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Prague Psychiatric Center
Praha, Hlavni mesto Praha, Czech Republic
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2004–2011
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Charles University in Prague
- Psychiatrické centrum Praha
Praha, Hlavni mesto Praha, Czech Republic
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2003–2010
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Albert Einstein College of Medicine
- Department of Psychiatry & Behavioral Sciences
New York City, NY, USA
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