title: Genetic and epigenetic associations of MAOA and NR3C1 with depression and childhood adversities.
abstract: Monoamine oxidase A (MAOA) harbours a polymorphic upstream variable-number tandem repeat (u-VNTR). The MAOA-L allele of the u-VNTR leads to decreased gene expression levels in vitro and has been found to increase the risk of conduct disorder in males with childhood adversities. Early-life adversities have been associated with hypermethylation of the glucocorticoid receptor (NR3C1). In this study, we first performed a genetic association analysis of the MAOA u-VNTR using individuals with depression (n = 392) and controls (n = 1276). Next, DNA methylation analyses of MAOA and NR3C1 were performed using saliva samples of depressed and control subgroups. Adult MAOA-L females with childhood adversities were found to have a higher risk of developing depression (p = 0.006) and overall MAOA methylation levels were decreased in depressed females compared to controls (mean depressed, 42% vs. mean controls, 44%; p = 0.04). One specific childhood adversity [early parental death (EPD)] was associated with hypermethylation of NR3C1 close to an NGFI-A binding site (mean EPD, 19% vs. mean non-EPD, 14%; p = 0.005). Regression analysis indicated that this association may be mediated by the MAOA-L allele (adjusted R² = 0.24, ANOVA: F = 23.48, p < 0.001). Conclusively: (1) depression in females may result from a gene × childhood-adversity interaction and/or a dysregulated epigenetic programming of MAOA; (2) childhood-adversity subtypes may differentially impact DNA methylation at NR3C1; (3) baseline MAOA-genotypic variations may affect the extent of NR3C1 methylation.
authors: Department of Molecular Medicine and Surgery, Neurogenetics Unit, Karolinska Institutet, Stockholm, Sweden.
authors: Philippe A
authors: PA
authors: Melas
authors: Yabin
authors: Y
authors: Wei
authors: Chloe C Y
authors: CC
authors: Wong
authors: Louise K
authors: LK
authors: Sjöholm
authors: Elin
authors: E
authors: Åberg
authors: Jonathan
authors: J
authors: Mill
authors: Martin
authors: M
authors: Schalling
authors: Yvonne
authors: Y
authors: Forsell
authors: Catharina
authors: C
authors: Lavebratt
mesh_terms: D000328:Adult; D000368:Aged; D016009:Chi-Square Distribution; D002648:Child; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D003863:Depression / Q000235:genetics*; D004777:Environment; D057890:Epigenomics; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008016:Life Change Events; D008297:Male; D008875:Middle Aged; D018598:Minisatellite Repeats / Q000235:genetics*; D008995:Monoamine Oxidase / Q000235:genetics*; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D012737:Sex Factors
chemical_list: C497713:NR3C1 protein, human; D011965:Receptors, Glucocorticoid; D008995:Monoamine Oxidase; C579458:monoamine oxidase A, human