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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
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TitleEpistasis between the DAT 3′ UTR VNTR and the COMT Val158Met SNP on cortical function in healthy subjects and patients with schizophrenia
 
AuthorsPrata, DP1 1
Mechelli, A1 1
Fu, CHY1
Picchioni, M1 1
Toulopoulou, T1
Bramon, E1
Walshe, M1
Murray, RM1
Collier, DA1 1
McGuire, P1
 
KeywordsChemicals And Cas Registry Numbers
 
Issue Date2009
 
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
 
CitationProceedings Of The National Academy Of Sciences Of The United States Of America, 2009, v. 106 n. 32, p. 13600-13605 [How to Cite?]
DOI: http://dx.doi.org/10.1073/pnas.0903007106
 
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.
 
ISSN0027-8424
2012 Impact Factor: 9.737
2012 SCImago Journal Rankings: 5.473
 
DOIhttp://dx.doi.org/10.1073/pnas.0903007106
 
PubMed Central IDPMC2726372
 
ISI Accession Number IDWOS:000268877300081
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.

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorPrata, DP
 
dc.contributor.authorMechelli, A
 
dc.contributor.authorFu, CHY
 
dc.contributor.authorPicchioni, M
 
dc.contributor.authorToulopoulou, T
 
dc.contributor.authorBramon, E
 
dc.contributor.authorWalshe, M
 
dc.contributor.authorMurray, RM
 
dc.contributor.authorCollier, DA
 
dc.contributor.authorMcGuire, P
 
dc.date.accessioned2011-09-27T03:02:53Z
 
dc.date.available2011-09-27T03:02:53Z
 
dc.date.issued2009
 
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.
 
dc.description.naturelink_to_subscribed_fulltext
 
dc.identifier.citationProceedings Of The National Academy Of Sciences Of The United States Of America, 2009, v. 106 n. 32, p. 13600-13605 [How to Cite?]
DOI: http://dx.doi.org/10.1073/pnas.0903007106
 
dc.identifier.doihttp://dx.doi.org/10.1073/pnas.0903007106
 
dc.identifier.eissn1091-6490
 
dc.identifier.epage13605
 
dc.identifier.isiWOS:000268877300081
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.

 
dc.identifier.issn0027-8424
2012 Impact Factor: 9.737
2012 SCImago Journal Rankings: 5.473
 
dc.identifier.issue32
 
dc.identifier.pmcidPMC2726372
 
dc.identifier.pmid19666577
 
dc.identifier.scopuseid_2-s2.0-69449095609
 
dc.identifier.spage13600
 
dc.identifier.urihttp://hdl.handle.net/10722/141835
 
dc.identifier.volume106
 
dc.languageeng
 
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
 
dc.publisher.placeUnited States
 
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of America
 
dc.relation.referencesReferences in Scopus
 
dc.subjectChemicals And Cas Registry Numbers
 
dc.titleEpistasis between the DAT 3′ UTR VNTR and the COMT Val158Met SNP on cortical function in healthy subjects and patients with schizophrenia
 
dc.typeArticle
 
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Author Affiliations
  1. King's College London