Article: Epistasis between the DAT 3′ UTR VNTR and the COMT Val158Met SNP on cortical function in healthy subjects and patients with schizophrenia
| Title | Epistasis between the DAT 3′ UTR VNTR and the COMT Val158Met SNP on cortical function in healthy subjects and patients with schizophrenia |
|---|---|
| Authors | Prata, DP1 Mechelli, A1 Fu, CHY1 Picchioni, M1 Toulopoulou, T1 Bramon, E1 Walshe, M1 Murray, RM1 Collier, DA1 McGuire, P1 |
| Keywords | Chemicals And Cas Registry Numbers |
| Issue Date | 2009 |
| Publisher | National 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?] DOI: http://dx.doi.org/10.1073/pnas.0903007106 |
| Abstract | Dopamine 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. |
| ISSN | 0027-8424 2011 Impact Factor: 9.681 2011 SCImago Journal Rankings: 1.754 |
| DOI | http://dx.doi.org/10.1073/pnas.0903007106 |
| PubMed Central ID | PMC2726372 |
| References | References in Scopus |
| dc.contributor.author | Prata, DP | ||||||
|---|---|---|---|---|---|---|---|
| dc.contributor.author | Mechelli, A | ||||||
| dc.contributor.author | Fu, CHY | ||||||
| dc.contributor.author | Picchioni, M | ||||||
| dc.contributor.author | Toulopoulou, T | ||||||
| dc.contributor.author | Bramon, E | ||||||
| dc.contributor.author | Walshe, M | ||||||
| dc.contributor.author | Murray, RM | ||||||
| dc.contributor.author | Collier, DA | ||||||
| dc.contributor.author | McGuire, P | ||||||
| dc.date.accessioned | 2011-09-27T03:02:53Z | ||||||
| dc.date.available | 2011-09-27T03:02:53Z | ||||||
| dc.date.issued | 2009 | ||||||
| dc.description.abstract | Dopamine 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.nature | link_to_subscribed_fulltext | ||||||
| dc.identifier.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?] DOI: http://dx.doi.org/10.1073/pnas.0903007106 | ||||||
| dc.identifier.doi | http://dx.doi.org/10.1073/pnas.0903007106 | ||||||
| dc.identifier.eissn | 1091-6490 | ||||||
| dc.identifier.epage | 13605 | ||||||
| dc.identifier.isi | WOS:000268877300081
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.issn | 0027-8424 2011 Impact Factor: 9.681 2011 SCImago Journal Rankings: 1.754 | ||||||
| dc.identifier.issue | 32 | ||||||
| dc.identifier.pmcid | PMC2726372 | ||||||
| dc.identifier.pmid | 19666577 | ||||||
| dc.identifier.scopus | eid_2-s2.0-69449095609 | ||||||
| dc.identifier.spage | 13600 | ||||||
| dc.identifier.uri | http://hdl.handle.net/10722/141835 | ||||||
| dc.identifier.volume | 106 | ||||||
| dc.language | eng | ||||||
| dc.publisher | National Academy of Sciences. The Journal's web site is located at http://www.pnas.org | ||||||
| dc.publisher.place | United States | ||||||
| dc.relation.ispartof | Proceedings of the National Academy of Sciences of the United States of America | ||||||
| dc.relation.references | References in Scopus | ||||||
| dc.subject | Chemicals And Cas Registry Numbers | ||||||
| dc.title | Epistasis between the DAT 3′ UTR VNTR and the COMT Val158Met SNP on cortical function in healthy subjects and patients with schizophrenia | ||||||
| dc.type | Article |
Author Affiliations
- King's College London