TY - JOUR
T1 - MTHFR
T2 - Genetic variants, expression analysis and COMT interaction in major depressive disorder
AU - Nielsen, Maria Gabriela
AU - Congiu, Chiara
AU - Bortolomasi, Marco
AU - Bonvicini, Cristian
AU - Bignotti, Stefano
AU - Abate, Maria
AU - Milanesi, Elena
AU - Conca, Andreas
AU - Cattane, Nadia
AU - Tessari, Elisabetta
AU - Gennarelli, Massimo
AU - Minelli, Alessandra
PY - 2015/9/1
Y1 - 2015/9/1
N2 - 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.
AB - 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.
KW - Catechol-O-methyltransferase
KW - Fibroblasts
KW - Major depressive disorder
KW - Methylenetetrahydrofolate reductase
KW - Transcriptional analyses
KW - Treatment resistant depression
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U2 - 10.1016/j.jad.2015.05.003
DO - 10.1016/j.jad.2015.05.003
M3 - Article
C2 - 26021967
AN - SCOPUS:84930506129
VL - 183
SP - 179
EP - 186
JO - Journal of Affective Disorders
JF - Journal of Affective Disorders
SN - 0165-0327
M1 - 7439
ER -