Werge T

References (4)

Title : Individualization of treatments with drugs metabolized by CES1: combining genetics and metabolomics - Rasmussen_2015_Pharmacogenomics_16_649
Author(s) : Rasmussen HB , Bjerre D , Linnet K , Jurgens G , Dalhoff K , Stefansson H , Hankemeier T , Kaddurah-Daouk R , Taboureau O , Brunak S , Houmann T , Jeppesen P , Pagsberg AK , Plessen K , Dyrborg J , Hansen PR , Hansen PE , Hughes T , Werge T
Ref : Pharmacogenomics , 16 :649 , 2015
Abstract : CES1 is involved in the hydrolysis of ester group-containing xenobiotic and endobiotic compounds including several essential and commonly used drugs. The individual variation in the efficacy and tolerability of many drugs metabolized by CES1 is considerable. Hence, there is a large interest in individualizing the treatment with these drugs. The present review addresses the issue of individualized treatment with drugs metabolized by CES1. It describes the composition of the gene encoding CES1, reports variants of this gene with focus upon those with a potential effect on drug metabolism and provides an overview of the protein structure of this enzyme bringing notice to mechanisms involved in the regulation of enzyme activity. Subsequently, the review highlights drugs metabolized by CES1 and argues that individual differences in the pharmacokinetics of these drugs play an important role in determining drug response and tolerability suggesting prospects for individualized drug therapies. Our review also discusses endogenous substrates of CES1 and assesses the potential of using metabolomic profiling of blood to identify proxies for the hepatic activity of CES1 that predict the rate of drug metabolism. Finally, the combination of genetics and metabolomics to obtain an accurate prediction of the individual response to CES1-dependent drugs is discussed.
ESTHER : Rasmussen_2015_Pharmacogenomics_16_649
PubMedSearch : Rasmussen_2015_Pharmacogenomics_16_649
PubMedID: 25896426

Title : Common variants conferring risk of schizophrenia - Stefansson_2009_Nature_460_744
Author(s) : Stefansson H , Ophoff RA , Steinberg S , Andreassen OA , Cichon S , Rujescu D , Werge T , Pietilainen OP , Mors O , Mortensen PB , Sigurdsson E , Gustafsson O , Nyegaard M , Tuulio-Henriksson A , Ingason A , Hansen T , Suvisaari J , Lonnqvist J , Paunio T , Borglum AD , Hartmann A , Fink-Jensen A , Nordentoft M , Hougaard D , Norgaard-Pedersen B , Bottcher Y , Olesen J , Breuer R , Moller HJ , Giegling I , Rasmussen HB , Timm S , Mattheisen M , Bitter I , Rethelyi JM , Magnusdottir BB , Sigmundsson T , Olason P , Masson G , Gulcher JR , Haraldsson M , Fossdal R , Thorgeirsson TE , Thorsteinsdottir U , Ruggeri M , Tosato S , Franke B , Strengman E , Kiemeney LA , Melle I , Djurovic S , Abramova L , Kaleda V , Sanjuan J , de Frutos R , Bramon E , Vassos E , Fraser G , Ettinger U , Picchioni M , Walker N , Toulopoulou T , Need AC , Ge D , Yoon JL , Shianna KV , Freimer NB , Cantor RM , Murray R , Kong A , Golimbet V , Carracedo A , Arango C , Costas J , Jonsson EG , Terenius L , Agartz I , Petursson H , Nothen MM , Rietschel M , Matthews PM , Muglia P , Peltonen L , St Clair D , Goldstein DB , Stefansson K , Collier DA
Ref : Nature , 460 :744 , 2009
Abstract : Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the 'genomic disorders', have not yet been characterized. Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.
ESTHER : Stefansson_2009_Nature_460_744
PubMedSearch : Stefansson_2009_Nature_460_744
PubMedID: 19571808

Title : Association analysis of schizophrenia on 18 genes involved in neuronal migration: MDGA1 as a new susceptibility gene - Kahler_2008_Am.J.Med.Genet.B.Neuropsychiatr.Genet_147B_1089
Author(s) : Kahler AK , Djurovic S , Kulle B , Jonsson EG , Agartz I , Hall H , Opjordsmoen S , Jakobsen KD , Hansen T , Melle I , Werge T , Steen VM , Andreassen OA
Ref : American Journal of Medicine Genet B Neuropsychiatr Genet , 147B :1089 , 2008
Abstract : Several lines of evidence support the theory of schizophrenia (SZ) being a neurodevelopmental disorder. The structural, cytoarchitectural and functional brain abnormalities reported in patients with SZ, might be due to aberrant neuronal migration, since the final position of neurons affects neuronal function, morphology, and formation of synaptic connections. We have investigated the putative association between SZ and gene variants engaged in the neuronal migration process, by performing an association study on 839 cases and 1,473 controls of Scandinavian origin. Using a gene-wide approach, tagSNPs in 18 candidate genes have been genotyped, with gene products involved in the neuron-to-glial cell adhesion, interactions with the DISC1 protein and/or rearrangements of the cytoskeleton. Of the 289 markers tested, 19 markers located in genes MDGA1, RELN, ITGA3, DLX1, SPARCL1, and ASTN1, attained nominal significant P-values (P < 0.05) in either a genotypic or allelic association test. All of these genes, except transcription factor DLX1, are involved in the adhesion between neurons and radial glial cells. Eight markers obtained nominal significance in both tests, and were located in intronic or 3'UTR regions of adhesion molecule MDGA1 and previously reported SZ candidate RELN. The most significant result was attained for MDGA1 SNP rs9462341 (unadjusted association results: genotypic P = 0.00095; allelic P = 0.010). Several haplotypes within MDGA1, RELN, ITGA3, and ENAH were nominally significant. Further studies in independent samples are needed, including upcoming genome wide association study results, but our data suggest that MDGA1 is a new SZ susceptibility gene, and that altered neuronal migration is involved in SZ pathology.
ESTHER : Kahler_2008_Am.J.Med.Genet.B.Neuropsychiatr.Genet_147B_1089
PubMedSearch : Kahler_2008_Am.J.Med.Genet.B.Neuropsychiatr.Genet_147B_1089
PubMedID: 18384059

Title : The acetylcholinesterase inhibitor galantamine inhibits d-amphetamine-induced psychotic-like behavior in Cebus monkeys - Andersen_2007_J.Pharmacol.Exp.Ther_321_1179
Author(s) : Andersen MB , Werge T , Fink-Jensen A
Ref : Journal of Pharmacology & Experimental Therapeutics , 321 :1179 , 2007
Abstract : Cholinergic receptors (AChR) are reported altered in brains from schizophrenic patients, and a growing body of evidence suggests that muscarinic receptor agonists exhibit antipsychotic potential. Centrally acting selective muscarinic receptor agonists are currently not available for clinical use, but acetylcholinesterase (AChE) inhibitors, which indirectly stimulate AChR by blocking the breakdown of acetylcholine by AChE, are widely used in the clinic against Alzheimer's disease. AChE inhibitors have been reported to exhibit antipsychotic efficacy in Alzheimer's disease patients, and these compounds have also been investigated as adjunctive treatment to antipsychotic medication in schizophrenic patients with varying results. However, monotherapy with AChE inhibitors in schizophrenic patients has not been evaluated. We wanted to investigate the antipsychotic potential of the AChE inhibitor galantamine, which also allosterically potentiates nicotinic receptor stimulation. To this end, we investigated its ability to antagonize d-amphetamine-induced psychotic-like behavior in extrapyramidal side effects (EPS)-primed Cebus monkeys. Galantamine inhibited d-amphetamine-induced unrest, arousal, and stereotypy. Side effects such as emesis, sedation, and EPS were minor or not existing. The results indicate that AChE inhibitors have antipsychotic potentials and suggest that clinical trials investigating antipsychotic effects of AChE inhibitors as monotherapy would be of interest.
ESTHER : Andersen_2007_J.Pharmacol.Exp.Ther_321_1179
PubMedSearch : Andersen_2007_J.Pharmacol.Exp.Ther_321_1179
PubMedID: 17374745