| 21. |
- Andreou, Dimitrios, et al.
(författare)
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Cerebrospinal fluid monoamine metabolite concentrations as intermediate phenotypes between glutamate-related genes and psychosis
- 2015
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Ingår i: Psychiatry Research. - : Elsevier BV. - 0165-1781 .- 1872-7123. ; 229:1-2, s. 497-504
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Tidskriftsartikel (refereegranskat)abstract
- 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 (DADA) 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.
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| 22. |
- Andreou, Dimitrios, et al.
(författare)
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d-amino acid oxidase activator gene (DAOA) variation affects cerebrospinal fluid homovanillic acid concentrations in healthy Caucasians
- 2012
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Ingår i: European Archives of Psychiatry and Clinical Neuroscience. - : Springer Science and Business Media LLC. - 0940-1334 .- 1433-8491. ; 262:7, s. 549-556
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Tidskriftsartikel (refereegranskat)abstract
- The d-amino acid oxidase activator (DAOA) protein regulates the function of d-amino oxidase (DAO), an enzyme that catalyzes the oxidative deamination of d-3,4-dihydroxyphenylalanine (D-DOPA) and d-serine. D-DOPA is converted to l-3,4-DOPA, a precursor of dopamine, whereas d-serine participates in glutamatergic transmission. We hypothesized that DAOA polymorphisms are associated with dopamine, serotonin and noradrenaline turnover in the human brain. Four single-nucleotide polymorphisms, previously reported to be associated with schizophrenia, were genotyped. Cerebrospinal fluid (CSF) samples were drawn by lumbar puncture, and the concentrations of the major dopamine metabolite homovanillic acid (HVA), the major serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) and the major noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured. Two of the investigated polymorphisms, rs3918342 and rs1421292, were significantly associated with CSF HVA concentrations. Rs3918342 was found to be nominally associated with CSF 5-HIAA concentrations. None of the polymorphisms were significantly associated with MHPG concentrations. Our results indicate that DAOA gene variation affects dopamine turnover in healthy individuals, suggesting that disturbed dopamine turnover is a possible mechanism behind the observed associations between genetic variation in DAOA and behavioral phenotypes in humans.
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| 23. |
- Andreou, Dimitrios, et al.
(författare)
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Dystrobrevin-binding protein 1 gene (DTNBP1) variants associated with cerebrospinal fluid homovanillic acid and 5-hydroxyindoleacetic acid concentrations in healthy volunteers
- 2011
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Ingår i: European Neuropsychopharmacology. - : Elsevier BV. - 0924-977X .- 1873-7862. ; 21:9, s. 700-704
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Tidskriftsartikel (refereegranskat)abstract
- The dystrobrevin binding protein-1 (DTNBP1) gene encodes dysbindin-1, a protein involved in neurodevelopmental and neurochemical processes related mainly to the monoamine dopamine. We investigated possible associations between eleven DTNBP1 polymorphisms and cerebrospinal fluid (CSF) concentrations of the major dopamine metabolite homovanillic acid (HVA), the major serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), and the major noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in healthy human subjects (n=132). Two polymorphisms, rs2619538 and rs760666, were nominally associated with CSF HVA and 5-HIAA concentrations, whereas a third polymorphism, rs909706, showed association only with HVA. After correction for multiple testing only the associations between rs2619538 and HVA and 5-HIAA concentrations remained significant. No significant association was found between any of the investigated DTNBP1 polymorphisms and CSF MHPG concentrations. The results suggest that genetic variation in DTNBP1 gene affects the regulation of dopamine and serotonin turnover in the central nervous system of healthy volunteers.
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| 24. |
- Andreou, Dimitrios, et al.
(författare)
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Polymorphisms in genes implicated in dopamine, serotonin and noradrenalin metabolism suggest association with cerebrospinal fluid monoamine metabolite concentrations in psychosis
- 2014
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Ingår i: Behavioral and Brain Functions. - : Springer Science and Business Media LLC. - 1744-9081. ; 10, s. 26-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) are the major monoamine metabolites in the central nervous system (CNS). Their cerebrospinal fluid (CSF) concentrations, reflecting the monoamine turnover rates in CNS, are partially under genetic influence and have been associated with schizophrenia. We have hypothesized that CSF monoamine metabolite concentrations represent intermediate steps between single nucleotide polymorphisms (SNPs) in genes implicated in monoaminergic pathways and psychosis.METHODS: We have searched for association between 119 SNPs in genes implicated in monoaminergic pathways [tryptophan hydroxylase 1 (TPH1), TPH2, tyrosine hydroxylase (TH), DOPA decarboxylase (DDC), dopamine beta-hydroxylase (DBH), catechol-O-methyltransferase (COMT), monoamine oxidase A (MAOA) and MAOB] and monoamine metabolite concentrations in CSF in 74 patients with psychotic disorder.RESULTS: There were 42 nominally significant associations between SNPs and CSF monoamine metabolite concentrations, which exceeded the expected number (20) of nominal associations given the total number of tests performed. The strongest association (p = 0.0004) was found between MAOB rs5905512, a SNP previously reported to be associated with schizophrenia in men, and MHPG concentrations in men with psychotic disorder. Further analyses in 111 healthy individuals revealed that 41 of the 42 nominal associations were restricted to patients with psychosis and were absent in healthy controls.CONCLUSIONS: The present study suggests that altered monoamine turnover rates in CNS reflect intermediate steps in the associations between SNPs and psychosis.
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| 25. |
- Andreou, Dimitrios, et al.
(författare)
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Tryptophan hydroxylase gene 1 (TPH1) variants associated with cerebrospinal fluid 5-hydroxyindole acetic acid and homovanillic acid concentrations in healthy volunteers
- 2010
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Ingår i: Psychiatry Research. - : Elsevier BV. - 0165-1781 .- 1872-7123. ; 180:2-3, s. 63-67
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Tidskriftsartikel (refereegranskat)abstract
- Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in serotonin synthesis. We investigated possible relationships between five TPH1 gene polymorphisms and cerebrospinal fluid (CSF) concentrations of the major serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), the major dopamine metabolite homovanillic acid (HVA), and the major norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in healthy volunteers (n = 132). The G-allele of the TPH1 rs4537731 (A-6526G) polymorphism was associated with 5-HIM and HVA, but not MHPG concentrations. None of the other four TPH1 polymorphisms (rs211105, rs1800532, rs1799913 and rs7933505) were significantly associated with any of the monoamine metabolite concentrations. Two (rs4537731G/rs211105T/rs1800532C/rs1799913C/rs7933505G and rs4537731A/rs211105T/rs1800532C/rs1799913C/rs7933505G) of five common TPH1 five-allele haplotypes were associated with 5-HIAA and HVA concentrations in opposite directions. None of the common haplotypes was associated with MHPG concentrations in the CSF. The results suggest that TPH1 gene variation participates in the regulation of serotonin and dopamine turnover rates in the central nervous system of healthy human subjects.
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| 26. |
- Arnborg, Stefan, et al.
(författare)
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Data Mining in Schizophrenia Research - preliminary analysis
- 2002
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Konferensbidrag (refereegranskat)abstract
- We describe methods used and some results in a study of schizophrenia in a population of affected and unaffected participants, called patients and controls. The subjects are characterized by diagnosis, genotype, brain anatomy (MRI), laboratory tests on blood samples, and basic demographic data. The long term goal is to identify the causal chains of processes leading to disease. We describe a number of preliminary findings, which confirm earlier results on deviations of brain tissue volumes in schizophrenia patients, and also indicate new effects that are presently under further investigation. More importantly, we discuss a number of issues in selection of methods from the very large set of tools in data mining and statistics.
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| 27. |
- Barth, Claudia, et al.
(författare)
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In vivo white matter microstructure in adolescents with early-onset psychosis : a multi-site mega-analysis
- 2023
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Ingår i: Molecular Psychiatry. - : Springer Nature. - 1359-4184 .- 1476-5578. ; 28, s. 1159-1169
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Tidskriftsartikel (refereegranskat)abstract
- Emerging evidence suggests brain white matter alterations in adolescents with early-onset psychosis (EOP; age of onset <18 years). However, as neuroimaging methods vary and sample sizes are modest, results remain inconclusive. Using harmonized data processing protocols and a mega-analytic approach, we compared white matter microstructure in EOP and healthy controls using diffusion tensor imaging (DTI). Our sample included 321 adolescents with EOP (median age=16.6 years, interquartile range (IQR)=2.14, 46.4% females) and 265 adolescent healthy controls (median age=16.2 years, IQR=2.43, 57.7% females) pooled from nine sites. All sites extracted mean fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) for 25 white matter regions of interest per participant. ComBat harmonization was performed for all DTI measures to adjust for scanner differences. Multiple linear regression models were fitted to investigate case-control differences and associations with clinical variables in regional DTI measures. We found widespread lower FA in EOP compared to healthy controls, with the largest effect sizes in the superior longitudinal fasciculus (Cohen's d=0.37), posterior corona radiata (d=0.32), and superior fronto-occipital fasciculus (d=0.31). We also found widespread higher RD and more localized higher MD and AD. We detected significant effects of diagnostic subgroup, sex, and duration of illness, but not medication status. Using the largest EOP DTI sample to date, our findings suggest a profile of widespread white matter microstructure alterations in adolescents with EOP, most prominently in male individuals with early-onset schizophrenia and individuals with a shorter duration of illness.
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| 28. |
- Boen, Rune, et al.
(författare)
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Beyond the global brain differences : intraindividual variability differences in 1q21.1 distal and 15q11.2 bp1-bp2 deletion carriers
- 2024
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Ingår i: Biological Psychiatry. - 0006-3223 .- 1873-2402. ; 95:2, s. 147-160
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Tidskriftsartikel (refereegranskat)abstract
- Background: Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure.Methods: Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individual's regional difference and global difference, were used to test for regional differences that diverge from the global difference.Results: For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differed more than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thickness in regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal and somatosensory cortex differed more than the global difference in cortical thickness.Conclusions: We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanisms involved in altered neurodevelopment.
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| 29. |
- Bohman, Hannes, 1965-, et al.
(författare)
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Preclinical atherosclerosis in adolescents with psychotic or bipolar disorders investigated with carotid high-frequency ultrasound.
- 2020
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Ingår i: Brain and Behavior. - : Wiley. - 2162-3279. ; 10:12
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Early-onset psychosis (EOP) and bipolar disorder (EOBP) (at <18 years of age), are associated with an increased future risk of cardiovascular disease (CVD) and premature death. Yet it is unknown whether the arteries show visible signs of atherosclerosis in EOP and EOBP. This study investigated whether having EOP or EOBP was associated with detectable signs of preclinical atherosclerosis.METHOD: By using 22 MHz high-frequency ultrasound, different layers of the arterial wall of the left common carotid artery (LCCA) were assessed in 77 individuals with EOP (n = 25), EOBP (n = 22), and in age-matched healthy controls (n = 30). Conventional CVD confounders were included in the analyses.RESULTS: Adolescents with EOP and EOBP, compared to controls, had a significantly thicker LCCA intima thickness (0.132 vs. 0.095 mm, p < .001) and intima/media ratio (0.24 vs. 0.17 p < .001). There was a nonsignificant intima difference between EOP and EOBP. Conventional CVD risk factors did not explain the association between EOP/EOBP and intima thickness. In the group of EOP/EOBP, there was a significant correlation between the dose of current antipsychotic medication and intima thickness; however, the correlation was attenuated to a nonsignificant level when adjusted for global function.CONCLUSIONS: Adolescents with EOP or EOBP had an increased LCCA intima thickness, interpreted as a sign of preclinical atherosclerosis. Global function of the disorders was the strongest determinant of intima thickness. The findings, if replicated, might have implications for long-term treatment of EOP and EOBP in order to reduce a future risk of CVD.
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| 30. |
- Comasco, Erika, 1982-, et al.
(författare)
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Genetic and Functional Study of L-Type Amino Acid Transporter 1 in Schizophrenia
- 2017
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Ingår i: Neuropsychobiology. - Basel : S. Karger. - 0302-282X .- 1423-0224. ; 74:2, s. 96-103
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Tidskriftsartikel (refereegranskat)abstract
- Schizophrenia involves neural catecholaminergic dysregulation. Tyrosine is the precursor of catecholamines, and its major transporter, according to studies on fibroblasts, in the brain is the L-type amino acid transporter 1 (LAT1). The present study assessed haplotype tag single-nucleotide polymorphisms (SNPs) of the SLC7A5/LAT1 gene in 315 patients with psychosis within the schizophrenia spectrum and 233 healthy controls to investigate genetic vulnerability to the disorder as well as genetic relationships to homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), the major catecholamine metabolites in the cerebrospinal fluid (CSF). Moreover, the involvement of the different isoforms of the system L in tyrosine uptake and LAT1 tyrosine kinetics were studied in fibroblast cell lines of 10 patients with schizophrenia and 10 healthy controls. The results provide suggestive evidence of individual vulnerability to schizophrenia related to the LAT1 SNP rs9936204 genotype. A number of SNPs were nominally associated with CSF HVA and MHPG concentrations but did not survive correction for multiple testing. The LAT1 isoform was confirmed as the major tyrosine transporter in patients with schizophrenia. However, the kinetic parameters (maximal transport capacity, affinity of the binding sites, and diffusion constant of tyrosine transport through the LAT1 isoform) did not differ between patients with schizophrenia and controls. The present genetic findings call for independent replication in larger samples, while the functional study seems to exclude a role of LAT1 in the aberrant transport of tyrosine in fibroblasts of patients with schizophrenia.
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