Maria Gabriela Nielsen1, Chiara Congiu2, Marco Bortolomasi3, Cristian Bonvicini4, Stefano Bignotti5, Maria Abate3, Elena Milanesi6, Andreas Conca7, Nadia Cattane2, Elisabetta Tessari3, Massimo Gennarelli8, Alessandra Minelli9. 1. Psychiatric Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy; Genetic Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy. 2. Department of Molecular and Translational Medicine, University of Brescia, Biology and Genetic Division, Viale Europa, 11, 25123 Brescia, Italy. 3. Psychiatric Hospital "Villa Santa Chiara", Verona, Italy. 4. Genetic Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy. 5. Psychiatric Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy. 6. Genetic Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. 7. Department of Psychiatry, Central Hospital of Bolzano, Bolzano, Italy. 8. Genetic Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy; Department of Molecular and Translational Medicine, University of Brescia, Biology and Genetic Division, Viale Europa, 11, 25123 Brescia, Italy. 9. Department of Molecular and Translational Medicine, University of Brescia, Biology and Genetic Division, Viale Europa, 11, 25123 Brescia, Italy. Electronic address: alessandra.minelli@unibs.it.
Abstract
BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) genetic variations have been widely studied in major depressive disorder (MDD) and antidepressants outcome. An interaction with catechol-O-methyltransferase (COMT) has also been proved affecting depression. The aim of this study was to clarify the role of the most commonly studied single nucleotide polymorphisms (SNPs) of MTHFR gene in MDD and in treatment response mechanisms, along with the impact of the interaction with COMT. METHODS: A total of 613 MDD patients, of whom 389 were classified as having treatment resistant depression (TRD), and 463 controls were enrolled. The A1298C, C677T and COMT Val158Met were genotyped. Genetic data were integrated with a transcriptional level analysis in peripheral blood cells (PBCs) and fibroblasts. RESULTS: The A1298C CC homozygotes were more frequent in MDD patients compared to controls in women, increasing twice the genetic risk to develop depression. Moreover this genotype resulted in epistasis with COMT Met carriers in association with MDD. No significant effects were obtained concerning response to treatment. Transcriptional analyses highlighted a strong correlation between the mRNA levels of MTHFR in fibroblasts and COMT genotypes whereas no significant association with MDD was found. PBCs results revealed relevant influences of environmental factors. LIMITATION: We did not measure folate and homocisteine levels. CONCLUSION: This study showed the involvement of A1298C, Val158Met and their interaction in MDD. The transcriptional analyses supported the participation of COMT in the folate pathway, which partakes in the complex network of gene×gene and gene×environment interactions of MDD etiopathogenesis.
BACKGROUND:Methylenetetrahydrofolate reductase (MTHFR) genetic variations have been widely studied in major depressive disorder (MDD) and antidepressants outcome. An interaction with catechol-O-methyltransferase (COMT) has also been proved affecting depression. The aim of this study was to clarify the role of the most commonly studied single nucleotide polymorphisms (SNPs) of MTHFR gene in MDD and in treatment response mechanisms, along with the impact of the interaction with COMT. METHODS: A total of 613 MDDpatients, of whom 389 were classified as having treatment resistant depression (TRD), and 463 controls were enrolled. The A1298C, C677T and COMT Val158Met were genotyped. Genetic data were integrated with a transcriptional level analysis in peripheral blood cells (PBCs) and fibroblasts. RESULTS: The A1298C CC homozygotes were more frequent in MDDpatients compared to controls in women, increasing twice the genetic risk to develop depression. Moreover this genotype resulted in epistasis with COMT Met carriers in association with MDD. No significant effects were obtained concerning response to treatment. Transcriptional analyses highlighted a strong correlation between the mRNA levels of MTHFR in fibroblasts and COMT genotypes whereas no significant association with MDD was found. PBCs results revealed relevant influences of environmental factors. LIMITATION: We did not measure folate and homocisteine levels. CONCLUSION: This study showed the involvement of A1298C, Val158Met and their interaction in MDD. The transcriptional analyses supported the participation of COMT in the folate pathway, which partakes in the complex network of gene×gene and gene×environment interactions of MDD etiopathogenesis.
Authors: A Minelli; C Magri; A Barbon; C Bonvicini; M Segala; C Congiu; S Bignotti; E Milanesi; L Trabucchi; N Cattane; M Bortolomasi; M Gennarelli Journal: Transl Psychiatry Date: 2015-12-01 Impact factor: 6.222