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Article: Epistasis between the DAT 3′ UTR VNTR and the COMT Val158Met SNP on cortical function in healthy subjects and patients with schizophrenia

TitleEpistasis between the DAT 3′ UTR VNTR and the COMT Val158Met SNP on cortical function in healthy subjects and patients with schizophrenia
Authors
KeywordsChemicals And Cas Registry Numbers
Issue Date2009
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
Citation
Proceedings Of The National Academy Of Sciences Of The United States Of America, 2009, v. 106 n. 32, p. 13600-13605 How to Cite?
AbstractDopamine has a crucial role in the modulation of neurocognitive function, and synaptic dopamine activity is normally regulated by the dopamine transporter (DAT) and catechol-O-methyltransferase (COMT). Perturbed dopamine function is a key pathophysiological feature of schizophrenia. Our objectives were (i) to examine epistasis between the DAT 3′ UTR variable number of tandem repeats (VNTR) and COMT Val158Met polymorphisms on brain activation during executive function, and (ii) to then determine the extent to which such interaction is altered in schizophrenia. Regional brain response was measured by using blood-oxygen-level-dependent fMRI during an overt verbal fluency task in 85 subjects (44 healthy volunteers and 41 patients with DSM-IV schizophrenia), and inferences were estimated by using an ANOVA in SPM5. There was a significant COMT × DAT nonadditive interaction effect on activation in the left supramarginal gyrus, irrespective of diagnostic group (Z-score=4.3; familywise error (FWE) p=0.03), and in healthy volunteers alone (Z-score= 4.7; FWEp = 0.006). In this region, relatively increased activation was detected only when COMT Met-158/Met-158 subjects also carried the 9-repeat DAT allele, or when, reversely, Val-158/Val-158 subjects carried the 10/10-repeat genotype. Also, there was a significant diagnosis × COMT × DAT nonadditive interaction in the right orbital gyrus (Z-score = 4.3; FWEp = 0.04), where, only within patients, greater activation was only associated with a 9-repeat allele and Val-158 conjunction, and with a 10-repeat and Met-158 conjunction (Z-score=4.3; FWE p=0.04). These data demonstrate that COMT and DAT genes interact nonadditively to modulate cortical function during executive processing, and also, that this effect is significantly altered in schizophrenia, which may reflect abnormal dopamine function in the disorder.
Persistent Identifierhttp://hdl.handle.net/10722/141835
ISSN
2014 Impact Factor: 9.674
2014 SCImago Journal Rankings: 5.781
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
Portuguese Fundacao para a Ciencia e Tecnologia
Wellcome Trust Training Fellowship
Funding Information:

D. P. P. was funded by the Portuguese Fundacao para a Ciencia e Tecnologia. C. H. F. was funded by a Wellcome Traveling Fellowship. M. P. was funded by a Wellcome Trust Training Fellowship.

References

 

DC FieldValueLanguage
dc.contributor.authorPrata, DPen_HK
dc.contributor.authorMechelli, Aen_HK
dc.contributor.authorFu, CHYen_HK
dc.contributor.authorPicchioni, Men_HK
dc.contributor.authorToulopoulou, Ten_HK
dc.contributor.authorBramon, Een_HK
dc.contributor.authorWalshe, Men_HK
dc.contributor.authorMurray, RMen_HK
dc.contributor.authorCollier, DAen_HK
dc.contributor.authorMcGuire, Pen_HK
dc.date.accessioned2011-09-27T03:02:53Z-
dc.date.available2011-09-27T03:02:53Z-
dc.date.issued2009en_HK
dc.identifier.citationProceedings Of The National Academy Of Sciences Of The United States Of America, 2009, v. 106 n. 32, p. 13600-13605en_HK
dc.identifier.issn0027-8424en_HK
dc.identifier.urihttp://hdl.handle.net/10722/141835-
dc.description.abstractDopamine has a crucial role in the modulation of neurocognitive function, and synaptic dopamine activity is normally regulated by the dopamine transporter (DAT) and catechol-O-methyltransferase (COMT). Perturbed dopamine function is a key pathophysiological feature of schizophrenia. Our objectives were (i) to examine epistasis between the DAT 3′ UTR variable number of tandem repeats (VNTR) and COMT Val158Met polymorphisms on brain activation during executive function, and (ii) to then determine the extent to which such interaction is altered in schizophrenia. Regional brain response was measured by using blood-oxygen-level-dependent fMRI during an overt verbal fluency task in 85 subjects (44 healthy volunteers and 41 patients with DSM-IV schizophrenia), and inferences were estimated by using an ANOVA in SPM5. There was a significant COMT × DAT nonadditive interaction effect on activation in the left supramarginal gyrus, irrespective of diagnostic group (Z-score=4.3; familywise error (FWE) p=0.03), and in healthy volunteers alone (Z-score= 4.7; FWEp = 0.006). In this region, relatively increased activation was detected only when COMT Met-158/Met-158 subjects also carried the 9-repeat DAT allele, or when, reversely, Val-158/Val-158 subjects carried the 10/10-repeat genotype. Also, there was a significant diagnosis × COMT × DAT nonadditive interaction in the right orbital gyrus (Z-score = 4.3; FWEp = 0.04), where, only within patients, greater activation was only associated with a 9-repeat allele and Val-158 conjunction, and with a 10-repeat and Met-158 conjunction (Z-score=4.3; FWE p=0.04). These data demonstrate that COMT and DAT genes interact nonadditively to modulate cortical function during executive processing, and also, that this effect is significantly altered in schizophrenia, which may reflect abnormal dopamine function in the disorder.en_HK
dc.languageengen_US
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.orgen_HK
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of Americaen_HK
dc.subjectChemicals And Cas Registry Numbersen_US
dc.titleEpistasis between the DAT 3′ UTR VNTR and the COMT Val158Met SNP on cortical function in healthy subjects and patients with schizophreniaen_HK
dc.typeArticleen_HK
dc.identifier.emailToulopoulou, T:timothea@hku.hken_HK
dc.identifier.authorityToulopoulou, T=rp01542en_HK
dc.description.naturelink_to_OA_fulltexten_US
dc.identifier.doi10.1073/pnas.0903007106en_HK
dc.identifier.pmid19666577en_HK
dc.identifier.pmcidPMC2726372-
dc.identifier.scopuseid_2-s2.0-69449095609en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-69449095609&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume106en_HK
dc.identifier.issue32en_HK
dc.identifier.spage13600en_HK
dc.identifier.epage13605en_HK
dc.identifier.eissn1091-6490-
dc.identifier.isiWOS:000268877300081-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridPrata, DP=14632352500en_HK
dc.identifier.scopusauthoridMechelli, A=6603693131en_HK
dc.identifier.scopusauthoridFu, CHY=8502155300en_HK
dc.identifier.scopusauthoridPicchioni, M=6507443795en_HK
dc.identifier.scopusauthoridToulopoulou, T=8855468700en_HK
dc.identifier.scopusauthoridBramon, E=8089378900en_HK
dc.identifier.scopusauthoridWalshe, M=8855469300en_HK
dc.identifier.scopusauthoridMurray, RM=35406239400en_HK
dc.identifier.scopusauthoridCollier, DA=26642980600en_HK
dc.identifier.scopusauthoridMcGuire, P=7101880438en_HK

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