The effect of the DISC1 Ser704Cys polymorphism on striatal dopamine synthesis capacity : an [F-18]-DOPA PET study

Show simple item record Dahoun, Tarik Pardinas, Antonio F. Veronese, Mattia Bloomfield, Michael A. P. Jauhar, Sameer Bonoldi, Ilaria Froudist-Walsh, Sean Nosarti, Chiara Korth, Carsten Hennah, William Walters, James Prata, Diana Howes, Oliver D. 2019-01-04T13:37:01Z 2019-01-04T13:37:01Z 2018-10-15
dc.identifier.citation Dahoun , T , Pardinas , A F , Veronese , M , Bloomfield , M A P , Jauhar , S , Bonoldi , I , Froudist-Walsh , S , Nosarti , C , Korth , C , Hennah , W , Walters , J , Prata , D & Howes , O D 2018 , ' The effect of the DISC1 Ser704Cys polymorphism on striatal dopamine synthesis capacity : an [F-18]-DOPA PET study ' , Human Molecular Genetics , vol. 27 , no. 20 , pp. 3498-3506 .
dc.identifier.other PURE: 120726968
dc.identifier.other PURE UUID: bd3c9c0f-e485-4768-b337-25d6049603c3
dc.identifier.other WOS: 000452533900003
dc.identifier.other Scopus: 85054364723
dc.description.abstract Whilst the role of the Disrupted-in-Schizophrenia 1 (DISC1) gene in the aetiology of major mental illnesses is debated, the characterization of its function lends it credibility as a candidate. A key aspect of this functional characterization is the determination of the role of common non-synonymous polymorphisms on normal variation within these functions. The common allele (A) of the DISCI single-nucleotide polymorphism (SNP) rs821616 encodes a serine (ser) at the Ser704Cys polymorphism, and has been shown to increase the phosphorylation of extracellular signal-regulated protein Kinases 1 and 2 (ERK1/2) that stimulate the phosphorylation of tyrosine hydroxylase, the rate-limiting enzyme for dopamine biosynthesis. We therefore set out to test the hypothesis that human ser (A) homozygotes would show elevated dopamine synthesis capacity compared with cysteine (cys) homozygotes and heterozygotes (TT and AT) for rs821616. [F-18]-DOPA positron emission tomography (PET) was used to index striatal dopamine synthesis capacity as the influx rate constant K-i(cer) in healthy volunteers DISC1 rs821616 ser homozygotes (N = 46) and healthy volunteers DISC1. rs821616 cys homozygotes and heterozygotes (N = 56), matched for age, gender, ethnicity and using three scanners. We found DISC1 rs821616 ser homozygotes exhibited a significantly higher striatal K-i(cer) compared with cys homozygotes and heterozygotes (P = 0.012) explaining 6.4% of the variance (partial eta(2) = 0.064). Our finding is consistent with its previous association with heightened activation of ERK1/2, which stimulates tyrosine hydroxylase activity for dopamine synthesis. This could be a potential mechanism mediating risk for psychosis, lending further credibility to the fact that DISC1. is of functional interest in the aetiology of major mental illness. en
dc.format.extent 9
dc.language.iso eng
dc.relation.ispartof Human Molecular Genetics
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject BASAL GANGLIA
dc.subject PART II
dc.subject ASSOCIATION
dc.subject 3111 Biomedicine
dc.subject 1182 Biochemistry, cell and molecular biology
dc.subject 1184 Genetics, developmental biology, physiology
dc.title The effect of the DISC1 Ser704Cys polymorphism on striatal dopamine synthesis capacity : an [F-18]-DOPA PET study en
dc.type Article
dc.contributor.organization Institute for Molecular Medicine Finland
dc.contributor.organization Medicum
dc.contributor.organization University of Helsinki
dc.description.reviewstatus Peer reviewed
dc.relation.issn 0964-6906
dc.rights.accesslevel openAccess
dc.type.version acceptedVersion
dc.type.version publishedVersion

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