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Erik Jönsson

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University of Ottawa | Université d'Ottawa

Galal H Galal-Edeen

Cairo University

University of Salford

National College of Business Administration and Economics

Universidade Federal do Paraná

University of Cologne

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Paul Benjamin Lowry

Virginia Tech

Seda Arslan Durmuş

Cukurova University

D.D.U. Gorakhpur University

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Papers by Erik Jönsson

A Regulatory Monoamine Oxidase A Promoter Polymorphism and Personality Traits

by Jonas Ekblom, Håkan Garpenstrand, and Erik Jönsson

Neuropsychobiology, 2002

Monoamine oxidase type A (MAOA) has been implicated to be part of mechanisms underlying human tem... more Monoamine oxidase type A (MAOA) has been implicated to be part of mechanisms underlying human temperament and psychiatric disorders. We hypothesised that a functional polymorphism in the 5&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; untranslated region of the MAOA gene is associated with specific personality traits. In 371 healthy Caucasians, we estimated personality traits by the use of the Karolinska Scales of Personality (KSP), Scandinavian Universities Scales of Personality, Health-Relevant 5-Factor Personality inventory, Temperament and Character Inventory and the revised NEO Personality Inventory. In the same subjects, we analysed the genotype of a polymorphic region consisting of a variable number of a 30-bp repeat sequence located approximately 1.2 kb upstream of the MAOA gene. After correction for multiple testing, no statistically significant differences between MAOA genotype and personality were observed in men (n = 206) nor in women (n = 165). We conclude that the structure of this MAOA promoter region does not have a large impact on the expression of personality characteristics in the present Swedish population.

The HP5 inventory: definition and assessment of five health-relevant personality traits from a five-factor model perspective

Personality and …, 2003

... Openness). The new HP5 inventory Scales manifested a meaningful pattern of correlations with ... more

Cerebrospinal fluid kynurenic acid in male and female controls – Correlation with monoamine metabolites and influences of confounding factors

Journal of Psychiatric Research, 2007

The concentrations of the tryptophan metabolite kynurenic acid (KYNA) and the monoamine metabolit... more The concentrations of the tryptophan metabolite kynurenic acid (KYNA) and the monoamine metabolites homovanillic acid (HVA), 5-hydroxy-indoleacetic acid (5-HIAA) and 4-hydroxy-3-methoxyphenylglycol (HMPG) were determined in the cerebrospinal fluid (CSF) from 43 healthy volunteers (30 males and 13 females). Healthy female controls displayed higher CSF concentration of KYNA (1.91nM+/-0.20) compared to healthy male controls (1.06nM+/-0.07) and lower CSF levels of HMPG (39.2nM+/-2.0 and 43.4+/-1.2, respectively). CSF levels of HVA and 5-HIAA did not differ between females (181.3nM+/-21.9 and 93.7nM+/-11.4, respectively) and males (138.9nM+/-12.6 and 74.8nM+/-5.9, respectively). Positive intercorrelations were found between CSF KYNA, HVA and 5-HIAA while CSF content of HMPG did not correlate with KYNA or the other monoamine metabolites in CSF. A negative correlation was found between back length and CSF concentrations of KYNA, HVA and 5-HIAA and also between CSF KYNA levels and body height. The results of the present study suggest that concentrations of KYNA and the monoamine metabolites in CSF from healthy controls are dependent on gender and back length, which must be taken in consideration when analysing mixed groups of men and women. The higher KYNA concentration found in female controls compared to male might be attributed to a shorter back in women compared to men. Furthermore, these findings suggest that increased KYNA formation is associated with an increased dopamine and serotonin turnover.

Psychological Masculinity-Femininity via the Gender Diagnosticity Approach: Heritability and Consistency Across Ages and Populations

Journal of Personality, 2005

Cerebrospinal fluid kynurenic acid in male patients with schizophrenia ? correlation with monoamine metabolites

Acta Neuropsychiatrica, 2007

Cerebrospinal fluid kynurenic acid in male patients with schizophrenia -correlation with monoamin... more

Cerebrospinal fluid monoamine metabolite concentrations as intermediate phenotypes between glutamate-related genes and psychosis

Psychiatry Research, 2015

Glutamate-related genes have been associated with schizophrenia, but the results have been ambigu... more Glutamate-related genes have been associated with schizophrenia, but the results have been ambiguous and difficult to replicate. Homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) are the major degradation products of the monoamines dopamine, serotonin and noradrenaline, respectively, and their concentrations in the cerebrospinal fluid (CSF), mainly HVA, have been associated with schizophrenia. In the present study, we hypothesized that CSF HVA, 5-HIAA and MHPG concentrations represent intermediate phenotypes in the association between glutamate-related genes and psychosis. To test this hypothesis, we searched for association between 238 single nucleotide polymorphisms (SNPs) in ten genes shown to be directly or indirectly implicated in glutamate transmission and CSF HVA, 5-HIAA and MHPG concentrations in 74 patients with psychotic disease. Thirty-eight nominally significant associations were found. Further analyses in 111 healthy controls showed that 87% of the nominal associations were restricted to the patients with psychosis. Some of the psychosis-only-associated SNPs found in the d-amino acid oxidase activator (DAOA) and the kynurenine 3-monooxygenase (KMO) genes have previously been reported to be associated with schizophrenia. The present results suggest that CSF monoamine metabolite concentrations may represent intermediate phenotypes in the association between glutamate-related genes and psychosis.

DRD4 polymorphisms and personality traits in a Swedish sample of healthy volunteers

Psychiatric Genetics, 1996

Brain Expressed microRNAs Implicated in Schizophrenia

Background. Protein encoding genes have long been the major targets for research in schizophrenia... more Background. Protein encoding genes have long been the major targets for research in schizophrenia genetics. However, with the identification of regulatory microRNAs (miRNAs) as important in brain development and function, miRNAs genes have emerged as candidates for schizophrenia-associated genetic factors. Indeed, the growing understanding of the regulatory properties and pleiotropic effects that miRNA have on molecular and cellular mechanisms, suggests that alterations in the interactions between miRNAs and their mRNA targets may contribute to phenotypic variation. Methodology/Principal Findings. We have studied the association between schizophrenia and genetic variants of miRNA genes associated with brainexpression using a case-control study design on three Scandinavian samples. Eighteen known SNPs within or near brainexpressed miRNAs in three samples (Danish, Swedish and Norwegian: 420/163/257 schizophrenia patients and 1006/177/293 control subjects), were analyzed. Subsequently, joint analysis of the three samples was performed on SNPs showing marginal association. Two SNPs rs17578796 and rs1700 in hsa-mir-206 (mir-206) and hsa-mit-198 (mir-198) showed nominal significant allelic association to schizophrenia in the Danish and Norwegian sample respectively (P = 0.0021 & p = 0.038), of which only rs17578796 was significant in the joint sample. In-silico analysis revealed that 8 of the 15 genes predicted to be regulated by both mir-206 and mir-198, are transcriptional targets or interaction partners of the JUN, ATF2 and TAF1 connected in a tight network. JUN and two of the miRNA targets (CCND2 and PTPN1) in the network have previously been associated with schizophrenia. Conclusions/Significance. We found nominal association between brain-expressed miRNAs and schizophrenia for rs17578796 and rs1700 located in mir-206 and mir-198 respectively. These two miRNAs have a surprising large number (15) of targets in common, eight of which are also connected by the same transcription factors.

Quantitative analysis of 18F-FE-PE2I binding to the dopamine transporter in Parkinson's disease

Journal of nuclear medicine : official publication, Society of Nuclear Medicine, Jan 19, 2015

(18)F-(E)-N-(3-iodoprop-2-enyl)-2β-carbofluoroethoxy-3β-(4&amp;amp;amp;amp;amp;amp;amp;amp;am... more (18)F-(E)-N-(3-iodoprop-2-enyl)-2β-carbofluoroethoxy-3β-(4&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-methyl-phenyl) nortropane ((18)F-FE-PE2I) is a recently developed radioligand for in vivo quantification of the dopamine transporter (DAT) in striatum and substantia nigra (SN). The aim of this study was to examine the suitability of (18)F-FE-PE2I as tool for imaging the nigrostriatal pathway in Parkinson&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (PD) with positron emission tomography (PET). Ten PD patients (9M/1F, 60±9y, Hoehn&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;Yahr: 1-2; Unified Parkinson&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s Disease Rating Scale motor: 18.9±6.7) and 10 controls (9M/1F, 60±7y) were included. PET measurements with (18)F-FE-PE2I were conducted for 93 min using the High Resolution Research Tomograph. Venous blood was drawn to compare protein binding, parent fraction and radiometabolite composition in PD patients and controls. Regions of interest for caudate, putamen, ventral striatum, SN and cerebellum were drawn on co-registered magnetic resonance images. The outcome measure was the binding potential (BPND) estimated with the simplified reference tissue model (SRTM) and the Logan graphical analysis (LoganRef), using the cerebellum as reference region. Time stability of BPND was examined to define the shortest acquisition protocol for quantitative studies. The wavelet-aided parametric imaging method was used to obtain high-resolution BPND images to compare DAT availability in striatum and SN in PD patients and control subjects. Group differences were assessed with unpaired t-test (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05). Parent, radiometabolite fractions, plasma concentration and cerebellar uptake of (18)F-FE-PE2I did not differ significantly between PD patients and controls. Stable estimates of BPND (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;8% of the 93-min value) were obtained with SRTM using ̴ 66 min of data. BPND values in PD patients were significantly lower than controls (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05) in caudate (2.54±0.79 vs 3.68±0.56), putamen (1.39±1.04 vs 4.41±0.54), ventral striatum (2.26±0.93 vs 3.30±0.46) and SN (0.46±0.20 vs 0.68±0.15). (18)F-FE-PE2I is clearly a suitable radioligand for DAT quantification and imaging of the nigrostriatal pathway in PD. Similar metabolism in controls and PD patients, suitability of cerebellum as reference region and accuracy of quantification using approximately 66 min of PET data are advantages for non-invasive and simplified imaging protocols for PD studies. Finally, DAT loss in PD can be measured in both striatum and SN, supporting the utility of (18)F-FE-PE2I as imaging tool of the nigrostriatal pathway.

Lack of association between dopamine D4 receptor gene and personality traits

Psychological medicine, 1998

Personality traits have shown considerable heritable components. Association between alleles of a... more Personality traits have shown considerable heritable components. Association between alleles of a polymorphism in the third exon of the dopamine D4 receptor gene (DRD4) and the personality trait Novelty Seeking has been reported. Recently, in a sample of Swedish non-psychiatric subjects we could not detect any significant relationships between the same polymorphism and Novelty Seeking related scales in the Karolinska Scales of Personality (KSP). However, there was a tendency in the direction of the proposed association. There were also tentative associations between an exon I 13 bp deletion polymorphism and the personality traits Socialization and Guilt. We investigated a new Swedish population-based sample (N = 167) investigated with the KSP for three DRD4 polymorphisms. Neither of the previous results were replicated. Combining the previous and the present samples did not give rise to any significant association between DRD4 polymorphisms and personality scales. The dopamine D4 re...

Monoamine related functional gene variants and relationships to monoamine metabolite concentrations in CSF of healthy volunteers

Bmc Psychiatry, 2004

Background: Concentrations of monoamine metabolites in human cerebrospinal fluid (CSF) have been ... more

Morphological correlates to cognitive dysfunction in schizophrenia as studied with Bayesian regression

Background: Relationships between cognitive deficits and brain morphological changes observed in ... more Background: Relationships between cognitive deficits and brain morphological changes observed in schizophrenia are alternately explained by less gray matter in the brain cerebral cortex, by alterations in neural circuitry involving the basal ganglia, and by alteration in cerebellar structures and related neural circuitry. This work explored a model encompassing all of these possibilities to identify the strongest morphological relationships to cognitive skill in schizophrenia.

DTNBP1, NRG1, DAOA, DAO and GRM3 polymorphisms and schizophrenia: an association study

Several studies of the dystrobrevin-binding protein 1 gene (DTNBP1), neuregulin 1 (NRG1), D-amino... more Several studies of the dystrobrevin-binding protein 1 gene (DTNBP1), neuregulin 1 (NRG1), D-amino-acid oxidase (DAO), DAO activator (DAOA, G72), and metabotropic glutamate receptor 3 (GRM3) genes have suggested an association between variants of these genes and schizophrenia. In a replication attempt, single-nucleotide polymorphisms of the DTNBP1, NRG1, DAO, DAOA, and GRM3 genes were analyzed in three independent Scandinavian schizophrenia case-control samples. One DTNBP1 and three GRM3 single-nucleotide polymorphisms showed nominal significant associations to the disease. However, after correction for multiple testing, there were no statistically significant allele, genotype or haplotype case-control differences. The present Scandinavian results do not verify previous associations between the analyzed DTNBP1, NRG1, DAO, DAOA, and GRM3 gene polymorphisms and schizophrenia. Additional studies and meta-analyses are warranted to shed further light on these relationships.

Common genetic variants influence human subcortical brain structures

Nature, 2015

5HT2a receptor T102C polymorphism and schizophrenia

The Lancet, 1996

2 Ak Malhotra, D. Goldman, N. Ozaki, et al., Lack of association between polymorphisms in the 5HT... more

Potential genetic variants in schizophrenia: A Bayesian analysis

World Journal of Biological Psychiatry, 2007

Medication and suicide risk in schizophrenia: A nested case–control study

Schizophrenia Research, 2013

Patients with schizophrenia are at increased risk of suicide, but data from controlled studies of... more Patients with schizophrenia are at increased risk of suicide, but data from controlled studies of pharmacotherapy in relation to suicide risk is limited. To explore suicide risk in schizophrenia in relation to medication with antipsychotics, antidepressants, and lithium. Of all patients with a first clinical discharge diagnosis of schizophrenia or schizoaffective disorder in Stockholm County between 1984 and 2000 (n=4000), patients who died by suicide within five years from diagnosis were defined as cases (n=84; 54% male). Individually matched controls were identified from the same population. Information on prescribed medication was retrieved from psychiatric records in a blinded way. Adjusted odds ratios [OR] of the association between medication and suicide were calculated by conditional logistic regression. Lower suicide risk was found in patients who had been prescribed a second generation antipsychotic (clozapine, olanzapine, risperidone, or ziprasidone; 12 cases and 20 controls): OR 0.29 (95% confidence interval [CI], 0.09-0.97). When the 6 cases and 8 controls who had been prescribed clozapine were excluded, the OR was 0.23 (95% CI 0.06-0.89). No significant association was observed between suicide and prescription of any antipsychotic, depot injection antipsychotics, antidepressants, SSRI, or lithium. Lower suicide risk for patients who had been prescribed second generation antipsychotics may be related to a pharmacological effect of these drugs, to differences in adherence, or to differences in other patient characteristics associated with lower suicide risk.

Regional thinning of the cerebral cortex in schizophrenia: Effects of diagnosis, age and antipsychotic medication

Schizophrenia Research, 2008

Morphological abnormalities of the cerebral cortex have been reported in a number of MRI-studies ... more Morphological abnormalities of the cerebral cortex have been reported in a number of MRI-studies in schizophrenia. Uncertainty remains regarding cause, mechanism and progression of the alterations. It has been suggested that antipsychotic medication reduces total gray matter volumes, but results are inconsistent. In the present study differences in regional cortical thickness between 96 patients with a DSM-IV diagnosis of schizophrenia (n = 81) or schizoaffective disorder (n = 15) and 107 healthy subjects (mean age 42 years, range 17-57 years) were investigated using MRI and computer image analysis. Cortical thickness was estimated as the shortest distance between the gray/white matter border and the pial surface at numerous points across the entire cortical mantle. The influence of age and antipsychotic medication on variation in global and regional cortical thickness was explored. Thinner cortex among patients than controls was found in prefrontal and temporal regions of both hemispheres, while parietal and occipital regions were relatively spared. Some hemispheric specificity was noted, as regions of the prefrontal cortex were more affected in the right hemisphere, and regions of the temporal cortex in the left hemisphere. No significant interaction effect of age and diagnostic group on variation in cortical thickness was demonstrated. Among patients, dose or type of antipsychotic medication did not affect variation in cortical thickness. The results from this hitherto largest study on the topic show that prefrontal and temporal cortical thinning in patients with schizophrenia compared to controls is as pronounced in older as in younger subjects. The lack of significant influence from antipsychotic medication supports that regional cortical thinning is an inherent feature of the neurobiological disease process in schizophrenia.

Association between a promoter variant in the monoamine oxidase A gene and schizophrenia

Schizophrenia Research, 2003

Monoaminergic transmission has been implicated in the pathophysiology of schizophrenia. We invest... more Monoaminergic transmission has been implicated in the pathophysiology of schizophrenia. We investigated a putative functional promoter polymorphism in the monoamine oxidase A (MAOA) gene in schizophrenic patients (n=133) and control subjects (n=377). In men, there was an association between the less efficiently transcribed alleles and schizophrenia (chi(2)=4.01, df=1, p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05). In women, no significant differences were found. The present results support the involvement of the MAOA gene in men with schizophrenia in the investigated Swedish population but should be interpreted with caution until replicated.

Diagnostic profile and suicide risk in schizophrenia spectrum disorder

Schizophrenia Research, 2010

Earlier studies of patients with schizophrenia have investigated suicide risk in relation to spec... more Earlier studies of patients with schizophrenia have investigated suicide risk in relation to specific psychiatric symptoms, but it remains to be better understood how suicide risk relates to the diagnostic profile in these patients. We identified all patients with a first clinical ICD-diagnosis of schizophrenia, schizophreniform or schizoaffective disorder in Stockholm County between 1984 and 2000. Patients who died by suicide within five years from diagnosis were defined as cases (n=84) and were individually matched with a similar number of living controls from the same population. Sociodemographic and clinical variables were retrieved from hospital records through a blind process. DSM-IV lifetime diagnoses for cases and controls were derived using the OPCRIT algorithm. A schizophrenia spectrum diagnosis (i.e. schizophrenia, schizophreniform or schizoaffective disorder) was assigned by OPCRIT to 50% of the suicide cases and 62% of the controls. Criteria for schizophrenia were met by 41% of the cases and 51% of the controls; for schizoaffective disorder by 8% of the cases and 10% of the controls; for other psychosis by 23% of the cases and 25% of the controls; and for mood disorder by 26% of the cases and 12% of the controls. Using the schizophrenia diagnosis as a reference, suicide risk was significantly higher in patients meeting criteria for a mood disorder diagnosis with an adjusted odds ratio of 3.3 (95% CI 1.2-9.0). In patients with a clinical schizophrenia spectrum diagnosis, a DSM-IV mood disorder diagnosis increases the suicide risk more than three-fold.

A Regulatory Monoamine Oxidase A Promoter Polymorphism and Personality Traits

by Jonas Ekblom, Håkan Garpenstrand, and Erik Jönsson

Neuropsychobiology, 2002

Monoamine oxidase type A (MAOA) has been implicated to be part of mechanisms underlying human tem... more Monoamine oxidase type A (MAOA) has been implicated to be part of mechanisms underlying human temperament and psychiatric disorders. We hypothesised that a functional polymorphism in the 5&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; untranslated region of the MAOA gene is associated with specific personality traits. In 371 healthy Caucasians, we estimated personality traits by the use of the Karolinska Scales of Personality (KSP), Scandinavian Universities Scales of Personality, Health-Relevant 5-Factor Personality inventory, Temperament and Character Inventory and the revised NEO Personality Inventory. In the same subjects, we analysed the genotype of a polymorphic region consisting of a variable number of a 30-bp repeat sequence located approximately 1.2 kb upstream of the MAOA gene. After correction for multiple testing, no statistically significant differences between MAOA genotype and personality were observed in men (n = 206) nor in women (n = 165). We conclude that the structure of this MAOA promoter region does not have a large impact on the expression of personality characteristics in the present Swedish population.

The HP5 inventory: definition and assessment of five health-relevant personality traits from a five-factor model perspective

Personality and …, 2003

... Openness). The new HP5 inventory Scales manifested a meaningful pattern of correlations with ... more

Cerebrospinal fluid kynurenic acid in male and female controls – Correlation with monoamine metabolites and influences of confounding factors

Journal of Psychiatric Research, 2007

The concentrations of the tryptophan metabolite kynurenic acid (KYNA) and the monoamine metabolit... more The concentrations of the tryptophan metabolite kynurenic acid (KYNA) and the monoamine metabolites homovanillic acid (HVA), 5-hydroxy-indoleacetic acid (5-HIAA) and 4-hydroxy-3-methoxyphenylglycol (HMPG) were determined in the cerebrospinal fluid (CSF) from 43 healthy volunteers (30 males and 13 females). Healthy female controls displayed higher CSF concentration of KYNA (1.91nM+/-0.20) compared to healthy male controls (1.06nM+/-0.07) and lower CSF levels of HMPG (39.2nM+/-2.0 and 43.4+/-1.2, respectively). CSF levels of HVA and 5-HIAA did not differ between females (181.3nM+/-21.9 and 93.7nM+/-11.4, respectively) and males (138.9nM+/-12.6 and 74.8nM+/-5.9, respectively). Positive intercorrelations were found between CSF KYNA, HVA and 5-HIAA while CSF content of HMPG did not correlate with KYNA or the other monoamine metabolites in CSF. A negative correlation was found between back length and CSF concentrations of KYNA, HVA and 5-HIAA and also between CSF KYNA levels and body height. The results of the present study suggest that concentrations of KYNA and the monoamine metabolites in CSF from healthy controls are dependent on gender and back length, which must be taken in consideration when analysing mixed groups of men and women. The higher KYNA concentration found in female controls compared to male might be attributed to a shorter back in women compared to men. Furthermore, these findings suggest that increased KYNA formation is associated with an increased dopamine and serotonin turnover.

Psychological Masculinity-Femininity via the Gender Diagnosticity Approach: Heritability and Consistency Across Ages and Populations

Journal of Personality, 2005

Cerebrospinal fluid kynurenic acid in male patients with schizophrenia ? correlation with monoamine metabolites

Acta Neuropsychiatrica, 2007

Cerebrospinal fluid kynurenic acid in male patients with schizophrenia -correlation with monoamin... more

Cerebrospinal fluid monoamine metabolite concentrations as intermediate phenotypes between glutamate-related genes and psychosis

Psychiatry Research, 2015

Glutamate-related genes have been associated with schizophrenia, but the results have been ambigu... more Glutamate-related genes have been associated with schizophrenia, but the results have been ambiguous and difficult to replicate. Homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) are the major degradation products of the monoamines dopamine, serotonin and noradrenaline, respectively, and their concentrations in the cerebrospinal fluid (CSF), mainly HVA, have been associated with schizophrenia. In the present study, we hypothesized that CSF HVA, 5-HIAA and MHPG concentrations represent intermediate phenotypes in the association between glutamate-related genes and psychosis. To test this hypothesis, we searched for association between 238 single nucleotide polymorphisms (SNPs) in ten genes shown to be directly or indirectly implicated in glutamate transmission and CSF HVA, 5-HIAA and MHPG concentrations in 74 patients with psychotic disease. Thirty-eight nominally significant associations were found. Further analyses in 111 healthy controls showed that 87% of the nominal associations were restricted to the patients with psychosis. Some of the psychosis-only-associated SNPs found in the d-amino acid oxidase activator (DAOA) and the kynurenine 3-monooxygenase (KMO) genes have previously been reported to be associated with schizophrenia. The present results suggest that CSF monoamine metabolite concentrations may represent intermediate phenotypes in the association between glutamate-related genes and psychosis.

DRD4 polymorphisms and personality traits in a Swedish sample of healthy volunteers

Psychiatric Genetics, 1996

Brain Expressed microRNAs Implicated in Schizophrenia

Background. Protein encoding genes have long been the major targets for research in schizophrenia... more Background. Protein encoding genes have long been the major targets for research in schizophrenia genetics. However, with the identification of regulatory microRNAs (miRNAs) as important in brain development and function, miRNAs genes have emerged as candidates for schizophrenia-associated genetic factors. Indeed, the growing understanding of the regulatory properties and pleiotropic effects that miRNA have on molecular and cellular mechanisms, suggests that alterations in the interactions between miRNAs and their mRNA targets may contribute to phenotypic variation. Methodology/Principal Findings. We have studied the association between schizophrenia and genetic variants of miRNA genes associated with brainexpression using a case-control study design on three Scandinavian samples. Eighteen known SNPs within or near brainexpressed miRNAs in three samples (Danish, Swedish and Norwegian: 420/163/257 schizophrenia patients and 1006/177/293 control subjects), were analyzed. Subsequently, joint analysis of the three samples was performed on SNPs showing marginal association. Two SNPs rs17578796 and rs1700 in hsa-mir-206 (mir-206) and hsa-mit-198 (mir-198) showed nominal significant allelic association to schizophrenia in the Danish and Norwegian sample respectively (P = 0.0021 & p = 0.038), of which only rs17578796 was significant in the joint sample. In-silico analysis revealed that 8 of the 15 genes predicted to be regulated by both mir-206 and mir-198, are transcriptional targets or interaction partners of the JUN, ATF2 and TAF1 connected in a tight network. JUN and two of the miRNA targets (CCND2 and PTPN1) in the network have previously been associated with schizophrenia. Conclusions/Significance. We found nominal association between brain-expressed miRNAs and schizophrenia for rs17578796 and rs1700 located in mir-206 and mir-198 respectively. These two miRNAs have a surprising large number (15) of targets in common, eight of which are also connected by the same transcription factors.

Quantitative analysis of 18F-FE-PE2I binding to the dopamine transporter in Parkinson's disease

Journal of nuclear medicine : official publication, Society of Nuclear Medicine, Jan 19, 2015

(18)F-(E)-N-(3-iodoprop-2-enyl)-2β-carbofluoroethoxy-3β-(4&amp;amp;amp;amp;amp;amp;amp;amp;am... more (18)F-(E)-N-(3-iodoprop-2-enyl)-2β-carbofluoroethoxy-3β-(4&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-methyl-phenyl) nortropane ((18)F-FE-PE2I) is a recently developed radioligand for in vivo quantification of the dopamine transporter (DAT) in striatum and substantia nigra (SN). The aim of this study was to examine the suitability of (18)F-FE-PE2I as tool for imaging the nigrostriatal pathway in Parkinson&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (PD) with positron emission tomography (PET). Ten PD patients (9M/1F, 60±9y, Hoehn&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;Yahr: 1-2; Unified Parkinson&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s Disease Rating Scale motor: 18.9±6.7) and 10 controls (9M/1F, 60±7y) were included. PET measurements with (18)F-FE-PE2I were conducted for 93 min using the High Resolution Research Tomograph. Venous blood was drawn to compare protein binding, parent fraction and radiometabolite composition in PD patients and controls. Regions of interest for caudate, putamen, ventral striatum, SN and cerebellum were drawn on co-registered magnetic resonance images. The outcome measure was the binding potential (BPND) estimated with the simplified reference tissue model (SRTM) and the Logan graphical analysis (LoganRef), using the cerebellum as reference region. Time stability of BPND was examined to define the shortest acquisition protocol for quantitative studies. The wavelet-aided parametric imaging method was used to obtain high-resolution BPND images to compare DAT availability in striatum and SN in PD patients and control subjects. Group differences were assessed with unpaired t-test (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05). Parent, radiometabolite fractions, plasma concentration and cerebellar uptake of (18)F-FE-PE2I did not differ significantly between PD patients and controls. Stable estimates of BPND (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;8% of the 93-min value) were obtained with SRTM using ̴ 66 min of data. BPND values in PD patients were significantly lower than controls (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05) in caudate (2.54±0.79 vs 3.68±0.56), putamen (1.39±1.04 vs 4.41±0.54), ventral striatum (2.26±0.93 vs 3.30±0.46) and SN (0.46±0.20 vs 0.68±0.15). (18)F-FE-PE2I is clearly a suitable radioligand for DAT quantification and imaging of the nigrostriatal pathway in PD. Similar metabolism in controls and PD patients, suitability of cerebellum as reference region and accuracy of quantification using approximately 66 min of PET data are advantages for non-invasive and simplified imaging protocols for PD studies. Finally, DAT loss in PD can be measured in both striatum and SN, supporting the utility of (18)F-FE-PE2I as imaging tool of the nigrostriatal pathway.

Lack of association between dopamine D4 receptor gene and personality traits

Psychological medicine, 1998

Personality traits have shown considerable heritable components. Association between alleles of a... more Personality traits have shown considerable heritable components. Association between alleles of a polymorphism in the third exon of the dopamine D4 receptor gene (DRD4) and the personality trait Novelty Seeking has been reported. Recently, in a sample of Swedish non-psychiatric subjects we could not detect any significant relationships between the same polymorphism and Novelty Seeking related scales in the Karolinska Scales of Personality (KSP). However, there was a tendency in the direction of the proposed association. There were also tentative associations between an exon I 13 bp deletion polymorphism and the personality traits Socialization and Guilt. We investigated a new Swedish population-based sample (N = 167) investigated with the KSP for three DRD4 polymorphisms. Neither of the previous results were replicated. Combining the previous and the present samples did not give rise to any significant association between DRD4 polymorphisms and personality scales. The dopamine D4 re...

Monoamine related functional gene variants and relationships to monoamine metabolite concentrations in CSF of healthy volunteers

Bmc Psychiatry, 2004

Background: Concentrations of monoamine metabolites in human cerebrospinal fluid (CSF) have been ... more

Morphological correlates to cognitive dysfunction in schizophrenia as studied with Bayesian regression

Background: Relationships between cognitive deficits and brain morphological changes observed in ... more Background: Relationships between cognitive deficits and brain morphological changes observed in schizophrenia are alternately explained by less gray matter in the brain cerebral cortex, by alterations in neural circuitry involving the basal ganglia, and by alteration in cerebellar structures and related neural circuitry. This work explored a model encompassing all of these possibilities to identify the strongest morphological relationships to cognitive skill in schizophrenia.

DTNBP1, NRG1, DAOA, DAO and GRM3 polymorphisms and schizophrenia: an association study

Several studies of the dystrobrevin-binding protein 1 gene (DTNBP1), neuregulin 1 (NRG1), D-amino... more Several studies of the dystrobrevin-binding protein 1 gene (DTNBP1), neuregulin 1 (NRG1), D-amino-acid oxidase (DAO), DAO activator (DAOA, G72), and metabotropic glutamate receptor 3 (GRM3) genes have suggested an association between variants of these genes and schizophrenia. In a replication attempt, single-nucleotide polymorphisms of the DTNBP1, NRG1, DAO, DAOA, and GRM3 genes were analyzed in three independent Scandinavian schizophrenia case-control samples. One DTNBP1 and three GRM3 single-nucleotide polymorphisms showed nominal significant associations to the disease. However, after correction for multiple testing, there were no statistically significant allele, genotype or haplotype case-control differences. The present Scandinavian results do not verify previous associations between the analyzed DTNBP1, NRG1, DAO, DAOA, and GRM3 gene polymorphisms and schizophrenia. Additional studies and meta-analyses are warranted to shed further light on these relationships.

Common genetic variants influence human subcortical brain structures

Nature, 2015

5HT2a receptor T102C polymorphism and schizophrenia

The Lancet, 1996

2 Ak Malhotra, D. Goldman, N. Ozaki, et al., Lack of association between polymorphisms in the 5HT... more

Potential genetic variants in schizophrenia: A Bayesian analysis

World Journal of Biological Psychiatry, 2007

Medication and suicide risk in schizophrenia: A nested case–control study

Schizophrenia Research, 2013

Patients with schizophrenia are at increased risk of suicide, but data from controlled studies of... more Patients with schizophrenia are at increased risk of suicide, but data from controlled studies of pharmacotherapy in relation to suicide risk is limited. To explore suicide risk in schizophrenia in relation to medication with antipsychotics, antidepressants, and lithium. Of all patients with a first clinical discharge diagnosis of schizophrenia or schizoaffective disorder in Stockholm County between 1984 and 2000 (n=4000), patients who died by suicide within five years from diagnosis were defined as cases (n=84; 54% male). Individually matched controls were identified from the same population. Information on prescribed medication was retrieved from psychiatric records in a blinded way. Adjusted odds ratios [OR] of the association between medication and suicide were calculated by conditional logistic regression. Lower suicide risk was found in patients who had been prescribed a second generation antipsychotic (clozapine, olanzapine, risperidone, or ziprasidone; 12 cases and 20 controls): OR 0.29 (95% confidence interval [CI], 0.09-0.97). When the 6 cases and 8 controls who had been prescribed clozapine were excluded, the OR was 0.23 (95% CI 0.06-0.89). No significant association was observed between suicide and prescription of any antipsychotic, depot injection antipsychotics, antidepressants, SSRI, or lithium. Lower suicide risk for patients who had been prescribed second generation antipsychotics may be related to a pharmacological effect of these drugs, to differences in adherence, or to differences in other patient characteristics associated with lower suicide risk.

Regional thinning of the cerebral cortex in schizophrenia: Effects of diagnosis, age and antipsychotic medication

Schizophrenia Research, 2008

Morphological abnormalities of the cerebral cortex have been reported in a number of MRI-studies ... more Morphological abnormalities of the cerebral cortex have been reported in a number of MRI-studies in schizophrenia. Uncertainty remains regarding cause, mechanism and progression of the alterations. It has been suggested that antipsychotic medication reduces total gray matter volumes, but results are inconsistent. In the present study differences in regional cortical thickness between 96 patients with a DSM-IV diagnosis of schizophrenia (n = 81) or schizoaffective disorder (n = 15) and 107 healthy subjects (mean age 42 years, range 17-57 years) were investigated using MRI and computer image analysis. Cortical thickness was estimated as the shortest distance between the gray/white matter border and the pial surface at numerous points across the entire cortical mantle. The influence of age and antipsychotic medication on variation in global and regional cortical thickness was explored. Thinner cortex among patients than controls was found in prefrontal and temporal regions of both hemispheres, while parietal and occipital regions were relatively spared. Some hemispheric specificity was noted, as regions of the prefrontal cortex were more affected in the right hemisphere, and regions of the temporal cortex in the left hemisphere. No significant interaction effect of age and diagnostic group on variation in cortical thickness was demonstrated. Among patients, dose or type of antipsychotic medication did not affect variation in cortical thickness. The results from this hitherto largest study on the topic show that prefrontal and temporal cortical thinning in patients with schizophrenia compared to controls is as pronounced in older as in younger subjects. The lack of significant influence from antipsychotic medication supports that regional cortical thinning is an inherent feature of the neurobiological disease process in schizophrenia.

Association between a promoter variant in the monoamine oxidase A gene and schizophrenia

Schizophrenia Research, 2003

Monoaminergic transmission has been implicated in the pathophysiology of schizophrenia. We invest... more Monoaminergic transmission has been implicated in the pathophysiology of schizophrenia. We investigated a putative functional promoter polymorphism in the monoamine oxidase A (MAOA) gene in schizophrenic patients (n=133) and control subjects (n=377). In men, there was an association between the less efficiently transcribed alleles and schizophrenia (chi(2)=4.01, df=1, p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05). In women, no significant differences were found. The present results support the involvement of the MAOA gene in men with schizophrenia in the investigated Swedish population but should be interpreted with caution until replicated.

Diagnostic profile and suicide risk in schizophrenia spectrum disorder

Schizophrenia Research, 2010

Earlier studies of patients with schizophrenia have investigated suicide risk in relation to spec... more Earlier studies of patients with schizophrenia have investigated suicide risk in relation to specific psychiatric symptoms, but it remains to be better understood how suicide risk relates to the diagnostic profile in these patients. We identified all patients with a first clinical ICD-diagnosis of schizophrenia, schizophreniform or schizoaffective disorder in Stockholm County between 1984 and 2000. Patients who died by suicide within five years from diagnosis were defined as cases (n=84) and were individually matched with a similar number of living controls from the same population. Sociodemographic and clinical variables were retrieved from hospital records through a blind process. DSM-IV lifetime diagnoses for cases and controls were derived using the OPCRIT algorithm. A schizophrenia spectrum diagnosis (i.e. schizophrenia, schizophreniform or schizoaffective disorder) was assigned by OPCRIT to 50% of the suicide cases and 62% of the controls. Criteria for schizophrenia were met by 41% of the cases and 51% of the controls; for schizoaffective disorder by 8% of the cases and 10% of the controls; for other psychosis by 23% of the cases and 25% of the controls; and for mood disorder by 26% of the cases and 12% of the controls. Using the schizophrenia diagnosis as a reference, suicide risk was significantly higher in patients meeting criteria for a mood disorder diagnosis with an adjusted odds ratio of 3.3 (95% CI 1.2-9.0). In patients with a clinical schizophrenia spectrum diagnosis, a DSM-IV mood disorder diagnosis increases the suicide risk more than three-fold.