title: MTHFR: Genetic variants, expression analysis and COMT interaction in major depressive disorder.
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.
  
  
  CONCLUSIONS
  We did not measure folate and homocisteine levels.
  
  
  CONCLUSIONS
  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.affiliation: Psychiatric Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy; Genetic Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Gabriela Nielsen
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, Biology and Genetic Division, Viale Europa, 11, 25123 Brescia, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Congiu
authors.affiliation: Psychiatric Hospital "Villa Santa Chiara", Verona, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Bortolomasi
authors.affiliation: Genetic Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
authors.forename: Cristian
authors.initials: C
authors.lastname: Bonvicini
authors.affiliation: Psychiatric Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Bignotti
authors.affiliation: Psychiatric Hospital "Villa Santa Chiara", Verona, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Abate
authors.affiliation: Genetic Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Elena
authors.initials: E
authors.lastname: Milanesi
authors.affiliation: Department of Psychiatry, Central Hospital of Bolzano, Bolzano, Italy.
authors.forename: Andreas
authors.initials: A
authors.lastname: Conca
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, Biology and Genetic Division, Viale Europa, 11, 25123 Brescia, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Cattane
authors.affiliation: Psychiatric Hospital "Villa Santa Chiara", Verona, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Tessari
authors.affiliation: 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.
authors.forename: Massimo
authors.initials: M
authors.lastname: Gennarelli
authors.affiliation: 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.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Minelli
mesh_terms: D000328:Adult; D000928:Antidepressive Agents / Q000627:therapeutic use; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors
chemical_list: D000928:Antidepressive Agents; D042965:Methylenetetrahydrofolate Reductase (NADPH2); C588010:COMT protein, human; D002394:Catechol O-Methyltransferase
keywords: Catechol-O-methyltransferase; Fibroblasts; Major depressive disorder; Methylenetetrahydrofolate reductase; Transcriptional analyses; Treatment resistant depression