| 1. |
- Andreou, Dimitrios, et al.
(författare)
-
d-amino acid oxidase activator gene (DAOA) variation affects cerebrospinal fluid homovanillic acid concentrations in healthy Caucasians
- 2012
-
Ingår i: European Archives of Psychiatry and Clinical Neuroscience. - : Springer Science and Business Media LLC. - 0940-1334 .- 1433-8491. ; 262:7, s. 549-556
-
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.
|
|
| 2. |
- Andreou, Dimitrios, et al.
(författare)
-
Dystrobrevin-binding protein 1 gene (DTNBP1) variants associated with cerebrospinal fluid homovanillic acid and 5-hydroxyindoleacetic acid concentrations in healthy volunteers
- 2011
-
Ingår i: European Neuropsychopharmacology. - : Elsevier BV. - 0924-977X .- 1873-7862. ; 21:9, s. 700-704
-
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.
|
|
| 3. |
- Andreou, Dimitrios, et al.
(författare)
-
Tryptophan hydroxylase gene 1 (TPH1) variants associated with cerebrospinal fluid 5-hydroxyindole acetic acid and homovanillic acid concentrations in healthy volunteers
- 2010
-
Ingår i: Psychiatry Research. - : Elsevier BV. - 0165-1781 .- 1872-7123. ; 180:2-3, s. 63-67
-
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.
|
|
| 4. |
- Baussan, E., et al.
(författare)
-
A very intense neutrino super beam experiment for leptonic CP violation discovery based on the European spallation source linac
- 2014
-
Ingår i: Nuclear Physics B. - : Elsevier BV. - 0550-3213 .- 1873-1562. ; 885, s. 127-149
-
Tidskriftsartikel (refereegranskat)abstract
- Very intense neutrino beams and large neutrino detectors will be needed in order to enable the discovery of CP violation in the leptonic sector. We propose to use the proton linac of the European Spoliation Source currently under construction in Lund, Sweden, to deliver, in parallel with the spoliation neutron production, a very intense, cost effective and high performance neutrino beam. The baseline program for the European Spoliation Source linac is that it will be fully operational at 5 MW average power by 2022, producing 2 GeV 2.86 ms long proton pulses at a rate of 14 Hz. Our proposal is to upgrade the linac to 10 MW average power and 28 Hz, producing 14 pulses/s for neutron production and 14 pulses/s for neutrino production. Furthermore, because of the high current required in the pulsed neutrino horn, the length of the pulses used for neutrino production needs to be compressed to a few mu s with the aid of an accumulator ring. A long baseline experiment using this Super Beam and a megaton underground Water Cherenkov detector located in existing mines 300-600 km from Lund will make it possible to discover leptonic CP violation at 5 sigma significance level in up to 50% of the leptonic Dirac CP-violating phase range. This experiment could also determine the neutrino mass hierarchy at a significance level of more than 3 sigma if this issue will not already have been settled by other experiments by then. The mass hierarchy performance could be increased by combining the neutrino beam results with those obtained from atmospheric neutrinos detected by the same large volume detector. This detector will also be used to measure the proton lifetime, detect cosmological neutrinos and neutrinos from supernova explosions. Results on the sensitivity to leptonic CP violation and the neutrino mass hierarchy are presented.
|
|
| 5. |
|
|
| 6. |
- Bergman, Sara, et al.
(författare)
-
Synthesis and Labelling of a Piperazine-Based Library of 11C-Labeled Ligands for Imaging of the Vesicular Acetylcholine Transporter
- 2014
-
Ingår i: Journal of labelled compounds & radiopharmaceuticals. - : Wiley. - 0362-4803 .- 1099-1344. ; 57:8, s. 525-532
-
Tidskriftsartikel (refereegranskat)abstract
- The cholinergic system is involved in neurodegenerative diseases, and visualization of cholinergic innervations with positron emission tomography (PET) would be a useful tool in understanding these diseases. A ligand for the vesicular acetylcholine transporter (VAChT), acknowledged as a marker for cholinergic neurons, could serve as such a PET tracer. The aim was to find a VAChT PET tracer using a library concept to create a small but diverse library of labeled compounds. From the same precursor and commercially available aryl iodides 6a-f, six potential VAChT PET tracers, [C-11]-(+/-)5a-f, were C-11-labeled by a palladium (0)-mediated aminocarbonylation, utilizing a standard protocol. The labeled compounds [C-11]-(+/-)5a-f were obtained in radiochemical purities >95% with decay-corrected radiochemical yields and specific radioactivities between 4-25% and 124-597 GBq/mu mol, respectively. Autoradiography studies were then conducted to assess the compounds binding selectivity for VAChT. Labeled compounds [C-11]-(+/-)5d and [C-11]-(+/-)5e showed specific binding but not enough to permit further preclinical studies. To conclude, a general method for a facile synthesis and labeling of a small piperazine-based library of potential PET tracers for imaging of VAChT was shown, and in upcoming work, another scaffold will be explored using this approach.
|
|
| 7. |
- Blom, Elisabeth, et al.
(författare)
-
68Ga-Labeling of RGD peptides and biodistribution
- 2012
-
Ingår i: International Journal of Clinical and Experimental Medicine. - 1940-5901. ; 5:2, s. 165-172
-
Tidskriftsartikel (refereegranskat)abstract
- Several peptides comprising Arg-Gly-Asp (RGD) domain and macrocyclic chelator were labeled with 68Ga for the imaging of angiogenesis. The analogues varied in peptide constitution, linker and chelator type. The labeling efficiency did not vary with the peptide constitution and linker type, but depended on the chelator type. Four of the compounds containing 2,2',2'',2'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA) chelator were labeled at 90 ± 5°C using conventional or microwave heating reaching 90% of 68Ga incorporation after 5 and 2 min respectively, when the concentration of the precursor was 2.5 μM. The compound having 2,2',2''-(1,4,7-triazonane-1,4,7-triyl)triacetic acid (NOTA) as the chelator could be labeled at room temperature within 5 min using 2.5 μM peptide precursor. Two of the compounds contained a poly (ethylene glycol) (PEG) linker to the chelator. The biodistribution of the analogues was studied in male rats.
|
|
| 8. |
- Blom, Elisabeth, et al.
(författare)
-
Ga-68-Labeling of RGD peptides and biodistribution
- 2012
-
Ingår i: International Journal of Clinical and Experimental Medicine. - 1940-5901. ; 5:2, s. 165-172
-
Tidskriftsartikel (refereegranskat)abstract
- Several peptides comprising Arg-Gly-Asp (RGD) domain and macrocyclic chelator were labeled with Ga-68 for the imaging of angiogenesis. The analogues varied in peptide constitution, linker and chelator type. The labeling efficiency did not vary with the peptide constitution and linker type, but depended on the chelator type. Four of the compounds containing 2,2', 2 '', 2'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl) tetraacetic acid (DOTA) chelator were labeled at 90 +/- 5 degrees C using conventional or microwave heating reaching 90% of Ga-68 incorporation after 5 and 2 min respectively, when the concentration of the precursor was 2.5 mu M. The compound having 2,2', 2 ''-(1,4,7-triazonane1,4,7-triyl)triacetic acid (NOTA) as the chelator could be labeled at room temperature within 5 min using 2.5 mu M peptide precursor. Two of the compounds contained a poly (ethylene glycol) (PEG) linker to the chelator. The biodistribution of the analogues was studied in male rats.
|
|
| 9. |
- Burgess, S., et al.
(författare)
-
Bayesian methods for meta-analysis of causal relationships estimated using genetic instrumental variables
- 2010
-
Ingår i: Statistics in medicine. - : Wiley. - 1097-0258 .- 0277-6715. ; 29:12, s. 1298-311
-
Tidskriftsartikel (refereegranskat)abstract
- Genetic markers can be used as instrumental variables, in an analogous way to randomization in a clinical trial, to estimate the causal relationship between a phenotype and an outcome variable. Our purpose is to extend the existing methods for such Mendelian randomization studies to the context of multiple genetic markers measured in multiple studies, based on the analysis of individual participant data. First, for a single genetic marker in one study, we show that the usual ratio of coefficients approach can be reformulated as a regression with heterogeneous error in the explanatory variable. This can be implemented using a Bayesian approach, which is next extended to include multiple genetic markers. We then propose a hierarchical model for undertaking a meta-analysis of multiple studies, in which it is not necessary that the same genetic markers are measured in each study. This provides an overall estimate of the causal relationship between the phenotype and the outcome, and an assessment of its heterogeneity across studies. As an example, we estimate the causal relationship of blood concentrations of C-reactive protein on fibrinogen levels using data from 11 studies. These methods provide a flexible framework for efficient estimation of causal relationships derived from multiple studies. Issues discussed include weak instrument bias, analysis of binary outcome data such as disease risk, missing genetic data, and the use of haplotypes.
|
|
| 10. |
- Crosby, Jacy, et al.
(författare)
-
Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease
- 2014
-
Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 371:1, s. 22-31
-
Tidskriftsartikel (refereegranskat)abstract
- Background Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype. Methods We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons. Results An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G -> A and IVS3+1G -> T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39% lower than levels in noncarriers (P<1x10(-20)), and circulating levels of APOC3 in carriers were 46% lower than levels in noncarriers (P = 8x10(-10)). The risk of coronary heart disease among 498 carriers of any rare APOC3 mutation was 40% lower than the risk among 110,472 noncarriers (odds ratio, 0.60; 95% confidence interval, 0.47 to 0.75; P = 4x10(-6)). Conclusions Rare mutations that disrupt APOC3 function were associated with lower levels of plasma triglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease. (Funded by the National Heart, Lung, and Blood Institute and others.)
|
|
