Depressive disorder and antidepressants from an epigenetic point of view

Table 1 DNA methylation studies on depressed subjects, also associated with suicidality and life adversities

Gene (region)	Alteration	Subjects and collected tissue	Ref.
NR3C1 1-F and FKBP5 intron 7 promoter	↑ DNA methylation at NR3C1 1-F, without significant differences at any of the measured individual CpG site in depressed patients. Association in salivary cortisol level and DNA methylation. ↑ DNA methylation in NR3C1 1-F at CpG 38 site in depressed patients, with early life adversity. No differences in FKBP5 intron 7 promoter	33 depressed patients (24 females, 9 males), 34 controls (21 females, 13 males). Whole blood and saliva	Farrell et al[67], 2018
MAOA and NR3C1 exon 1-F	↓ DNA methylation at MAOA’s first exon/intron junction; significantly ↓ at CpG 8 site from the intron region. ↑ DNA methylation at NR3C1 1-F’s promoter and exon in individuals experienced early parental death; significant ↑ at CpG 35 and 10.11 (sites close to NGFI-A binding site)	82 (for MAOA gene) and 93 (for NR3C1 1-F gene) depressed females, victims of early-life adversity and 92 or 83 controls. Saliva	Melas et al[35], 2013
BDNF, NR3C1, and FKBP5	Significant alteration in DNA methylation at 9 sites in BDNF gene body, at 6 sites in NR3C1 promoter region, and at 4 sites in FKBP5 gene body, 3’UTR and promoter	94 maltreated and 96 non-traumatized children. Saliva	Weder et al[68], 2014
BDNF exon I	↓ DNA methylation; differences at loci 87, 88 and 92–94, located within the CpG island region on the promoter of the exon I	360 depressed patients (32 females, 328 males). Saliva	Song et al[69], 2014
BDNF promoter between –694 and –577 relative to the transcriptional start site (12 CpG sites). SLC6A4 promoter adjacent to exon 1a between –479 and –350 relative to the transcriptional start site (10 CpG sites)	Depressed mood in 2nd trimester associated with ↓ DNA methylation at maternal SLC6A4 promoter methylation status. ↓ DNA methylation at SLC6A4 promoter in infants, from mothers with higher depressed mood during 2nd trimester. No difference in BDNF gene	82 female and male infants exposed to prenatal maternal stress–33 mothers treated with SRI and 49 mothers not treated with SRI. Blood	Devlin et al[70], 2010
NR3C1 exon 1-F and BDNF promoter IV	↑ DNA methylation within NR3C1 1-F gene (male infants). ↓ DNA methylation within BDNF promoter IV region (female and male infants)	20 female and male infants exposed to prenatal maternal stress and 37 controls. Buccal tissue	Braithwaite et al[71], 2015
NR3C1 exon 1-F	Depressed mood in 2nd trimester associated with ↑ DNA methylation of CpG 2 site (relative to translational start site) at NR3C1 exon 1-F in infants. Depressed mood in 3d trimester associated with ↑ DNA methylation of CpG 2 and CpG 3 site (relative to translational start site) at NR3C1 exon 1-F in infants	46 depressed females (33 treated with SRI and 13 not medicated), 36 controls, and their infants. Blood	Oberlander et al[72], 2008
BDNF, NR3C1, CRHBP, CRHR1, FKBP5 promoter	Hypermethylated BDNF, NR3C1, CRHBP and FKBP5 promoter. mRNA down regulation of BDNF, NR3C1, FKBP5 and CRHBP in MDD-suicidal ideation group	15 females and 9 males with MDD (14 with and 10 without suicidal ideation) and 20 controls (14 females and 6 males). PBMC	Roy et al[73], 2017
BDNF exon I promoter	↑ percentage of methylated reference values	207 female and male MDD patients and 278 controls. PBMC	Carlberg et al[58], 2014
BDNF exon I promoter	↑ at CpG 1, CpG 3 and CpG 5 site, ↓ BDNF serum level	49 female and male MDD patients and 57 controls. Blood	Schröter et al[74], 2020
BDNF exon I and IV promoter	↑ methylation at CpG site 3 of promoter IV	251 female and male MDD patients aged 65 > and 773 controls. Buccal tissue	Januar et al[75], 2015
BDNF exon IX	Changes in DNA methylation; ↑ at CpG site 217, ↓ at CpG site 327, and 362. ↓ BDNF level and mRNA levels	51 MDD patients (35 females and 16 males) and 62 controls (39 females and 23 males). Venous blood	Hsieh et al[60], 2019
BDNF upstream of exon I and IV	Changes in DNA methylation within CpG exon I promoter	20 MDD patients (12 females and 8 males) and 18 controls (8 females and 10 males). Blood	Fuchikami et al[76], 2011
MYO16 and IDE	↑ 5hmc in one CpG position of MYO16 and two CpG positions of IDE in the PFC. ↑ gene expression of MYO16. ↓ gene expression of IDE	19 depressed male suicide victims and 19 controls. Brain tissue (PFC; inferior frontal gyrus)	Gross et al[77], 2017
GABAA receptor α1 subunit promoter	↑ DNA methylation of the CpG 2 and CpG 4 site (500 bp from transcriptional start site). ↑ DNMT-3B expression in FPC. ↓ expression of DNMT1 mRNA and ↑ expression of DNMT3b mRNA in FPC. ↓ expression of DNMT3b and DNMT1 mRNA in AMG	10 male suicide victims and 10 controls. Brain tissue (FPC, AMG)	Poulter et al[78], 2008
SLC6A4 promoter	↑ mean methylation level	28 MDD patients (20 females and 8 males) and 29 controls (21 females and 8 males). Blood	Iga et al[79], 2016
NR3C1 exon 1 promoter	↑ methylation at CpG 30 and 32 site. ↓ expression of total NR3C1 mRNA and NR3C1-1F mRNA in suicide victims without childhood abuse and control group	12 suicide victims with traumatic childhood experience, 12 suicide victims without traumatic childhood experience, and 12 controls. Brain tissue (HPC)	McGowan et al[80], 2009

↓: Decreased expression; ↑: Increased expression; AMG: Amygdala; BDNF: Brain derived neurotrophic factor; bp: Base pair; CpG: Cytosine-phosphate-guanine; CRHBP: Corticotropin releasing hormone binding protein; CRHR1: Corticotropin releasing hormone receptor 1; DNMT3B: DNA methyltransferase 3; FKBP5: FK506 binding protein 5; FPC: Frontopolar cortex; GABA_A: γ-aminobutyric acid; H3K14ac: Acetylation of lysine 14 on histone 3; HDAC2: Histone deacetylase 2; HPC: Hippocampus; IDE: Insulin-degrading enzyme; MDD: Major depressive disorder; MAOA: Monoamine oxidase A; mRNA: Messenger RNA; MYO16: Myoxin XVI; NGFI-A: Nerve growth factor-induced protein A; NR3C1: Nuclear receptor subfamily 3 group C member 1; PFC: Prefrontal cortex; PBMC: Peripheral blood mononuclear cells; SLC6A4: Solute carrier family 6 member 4; SRI: Serotonin reuptake inhibitor antidepressant; UTR: Untranslated region; 5hmc: 5-hydroxymethylcytosine.