Table 2.
Summary of the direction of the associations between DNAm, mental health disorders and clinical or biological outcomes presented in this review
| Gene (hyper ↑ or ↓ hypo DNAm) and citation | Candidate gene or EWAS | Tissue | Condition/sample | Clinical/biological outcome |
|---|---|---|---|---|
| Serotoninergic pathway | ||||
| SLC6A4 | ||||
| ↑Abdolmaleky et al. (2014) | Candidate gene | PMB/saliva | SCZ | |
| Kang et al. (2013) | Candidate gene | Blood | Depression | CA → ↑SLC6A4 → clinical severity |
| Olsson et al. (2010) | Candidate gene | Buccal | Depression | ↑SLC6A4 → ↑ Depressive symptoms |
| ↑Philibert et al. (2008) | Candidate gene | Blood | Depression | ↑SLC6A4 → ↑ history MDD |
| ↑Zhao et al. (2013) | Candidate gene | Blood | Twin male veterans | ↑SLC6A4 → ↑ Depressive symptoms |
| Perez-Cornago et al. (2014) | Candidate gene | Blood | General population | ↑SLC6A4 → decrease depressive symptoms from baseline to Follow-up |
| Boehm et al. (2019) | Candidate gene | Blood | Anorexia nervosa | ↑SLC6A4 → resting-state functional connectivity→ anorexia symptoms |
| Koenen et al. (2011) | Candidate gene | Blood | PTSD | CA + ↓SLC6A4 → PTSD |
| Peng et al. (2018) | Candidate gene | Blood | General population | CA → ↑SLC6A4 → depressive symptoms |
| Schiele et al. (2019) | Candidate gene | Blood | Panic disorder | ↑SLC6A4→ Comorbid depression |
| 5-HTR 1A | ||||
| ↑Carrard et al. (2011) | Candidate gene | Blood | SCZ/BD | |
| 5-HTR 2A | ||||
| ↑Cheah et al. (2017) | Candidate gene | PMB | SCZ | |
| ↑Abdolmaleky et al. (2011) | Candidate gene | PMB | SCZ/BD | |
| ↑Hranilovic et al. (2016) | Candidate gene | Blood | ASD | |
| 5-HT3A-R | ||||
| ↑Perroud et al. (2016) | Candidate gene | Blood | BD/Borderline PD | CA → ↑5-HT3A-R → clinical severity |
| A MAOA | ||||
| ↓ Ziegler et al. (2016) | Candidate gene | Blood | Panic disorder | ↑ → Better response to CBT in agoraphobic symptpms |
| ↓Schiele et al. (2018) | Candidate gene | Blood | Agoraphobia | |
| ↓Domschke et al. (2012) | Candidate gene | Blood | Panic disorder | CA → ↓A (MAOA) |
| Peng et al. (2018) | Candidate gene | Blood | General population | CA → ↓A (MAOA) → depressive symptoms |
| Dopaminergic pathway | ||||
| DRD2 | ||||
| ↑Kordi-Tamandani et al. (2013b) | Candidate gene | Blood | SCZ | |
| ↓Yoshino et al. (2016) | Candidate gene | Blood | SCZ | |
| ↑Frieling et al. (2010) | Candidate gene | Blood | Anorexia and bulimia nervosa | |
| DRD3 | ||||
| ↑Dai et al. (2014) | Candidate gene | Blood | SCZ | |
| DRD4 | ||||
| ↑Cheng et al. (2014) | Candidate gene | Blood | SCZ | |
| ↑Kordi-Tamandani et al. (2013b) | Candidate gene | Blood | SCZ | |
| DRD5 | ||||
| ↑Kordi-Tamandani et al. (2013b) | Candidate gene | Blood | SCZ | |
| MB-COMT | ||||
| ↓Abdolmaleky et al. (2006) | Candidate gene | PMB | SCZ/BD | |
| ↓Nohesara et al. (2011) | Candidate gene | Saliva | SCZ/BD | |
| Walton et al. (2014) | Candidate gene | Blood | SCZ | ↑ MB-COMT ->better neural activity in left DLPFC |
| ↓Nour El Huda et al. (2018) | Candidate gene | Blood | SCZ | ↑ MB-COMT-> ↓excited and depressed symptoms |
| S-COMT | ||||
| ↑Murphy et al. (2005) | Candidate gene | PMB | SCZ | |
| ↑Melas et al. (2012) | Candidate gene | Blood | SCZ | |
| COMTD1 | ||||
| ↓Nishioka et al. (2013) | EWAS | Blood | SCZ | |
| SLC6A3 | ||||
| ↓Nishioka et al. (2013) | EWAS | Blood | SCZ | |
| DAT1* | ||||
| ↑Frieling et al. (2010) | Candidate gene | Blood | Anorexia and bulimia nervosa | |
| FAM63B | ||||
| ↓Aberg et al. (2012) | EWAS | Blood | SCZ | |
| Glutamatergic/GABAergic pathway (Excitatory/inhibitory balance) | ||||
| PVALB | ||||
| ↑Fachim et al. (2018) | Candidate gene | PMB | SCZ | |
| GMR2, GMR5 | ||||
| ↓Kordi-Tamandani et al. (2013a) | Candidate gene | Blood | SCZ | |
| GRIA 3 | ||||
| ↑Kordi-Tamandani et al. (2013a) | Candidate gene | Blood | SCZ | |
| GRIA 2 | ||||
| ↓Mill et al. (2008) | EWAS | PMB | SCZ/BD | |
| ↓Aberg et al. (2012) | EWAS | Blood | SCZ | |
| GRIA 4 | ||||
| ↑Numata et al. (2014) | EWAS | PMB | SCZ | |
| GABBR1 | ||||
| ↑Hannon et al. (2021) | EWAS | Blood | Psychosis and SCZ | |
| GABBR2 | ||||
| ↑Pun et al. (2011) | Candidate gene | Blood | SCZ | |
| ↑Zong et al. (2017) | Candidate gene | Blood | SCZ | |
| GRIN 2B | ||||
| ↓Fachim et al. (2019) | Candidate gene | Blood | SCZ | CA → ↑GRIN2B |
| Engdahl et al. (2021) | Candidate gene | Saliva | General population | |
| GRIND1 | ||||
| Weder et al. (2014) | EWAS | Saliva | Trauma/non-trauma children | |
| GAD1 | ||||
| Ruzicka et al. (2015) | Candidate gene | PMB | SCZ/BD | |
| ↓Domschke et al. (2013) | Candidate gene | Blood | Panic disorder | Life events → ↓GAD1 DNAm |
| GRIN3B | ||||
| ↓Mill et al. (2008) | EWAS | PMB | SCZ/BD | |
| MARLIN-1 | ||||
| ↑Mill et al. (2008) | EWAS | PMB | SCZ/BD | |
| KCNJ6 | ||||
| ↑Mill et al. (2008) | EWAS | PMB | SCZ/BD | |
| HELT | ||||
| ↑Mill et al. (2008) | EWAS | PMB | SCZ/BD | |
| GRIK2 | ||||
| Nagy et al. (2015) | EWAS | PMB | Depression | |
| SLC6A12 | ||||
| ↑Hannon et al. (2021) | EWAS | Blood | Psychosis and SCZ | |
| Synaptic plasticity and neurogenesis | ||||
| RELN | ||||
| Tamura et al. (2007) | Candidate gene | PMB | SCZ/BD | ↓DNAm → poor cognition |
| Alfimova et al. (2018) | Candidate gene | Blood | SCZ | |
| Fikri et al. (2017) | Candidate gene | Blood | SCZ | |
| PI3K | ||||
| Wong et al. (2019) | EWAS | PMB | ASD | |
| BDNF | ||||
| ↑Ursini et al. (2016) | Candidate gene | Blood | SCZ | |
| ↑Duffy et al. (2019) | Candidate gene | Saliva | BD | |
| ↑Dell et al. (2014) | Candidate gene | Blood | Unipolar, BD and MDD | |
| ↑Kim et al. (2017) | Candidate gene | Blood | PTSD | |
| ↑Kang et al. (2015)* | Candidate gene | Blood | Depression | ↑BDNF->↑depressive symptoms |
| ↑Peng et al. (2018) | Candidate gene | Blood | Depression | CA -> ↑BDNF→ depressive symptoms |
| ↑Thomas et al. (2018) | Candidate gene | Saliva | Borderline PD | |
| D'Addario et al. (2019) | Candidate gene | Blood | OCD | |
| ↑Thaler et al. (2014) | Candidate gene | Blood | Bulimia nervosa | CA + Borderline PD →↑BDNF meth |
| Moser et al. (2015) | EWAS | Saliva | PTSD | CA → ↑BDNF meth / ↑BDNF meth-> maternal anxiety |
| Weder et al. (2014) | EWAS | Saliva/blood | Trauma/non-trauma children | Differently methylated between CA + and CA- |
| POU6F2 | ||||
| Comes et al. (2020) | EWAS | Blood | BD | ↑CA-> ↓POU6F2 |
| POU5F1 | ||||
| Arranz et al. (2021) | EWAS | Blood | Borderline PD | ↑CA-> ↓POU5F1 |
| POU3F1 | ||||
| Lutz et al. (2017) | EWAS | PMB | Depression | ↑CA-> ↓POU3F1 |
| CUX1* | ||||
| Osborne et al. (2020) | EWAS | Blood | General population | Differently methylated in CU (exploratory analyses) |
| CLMN*, SENP7* | ||||
| Clark et al. (2021) | EWAS | Blood | Adolescents | Differently methylated in CU users |
| Immune system and inflammation | ||||
| ZC3H12D | ||||
| ↓Montano et al. (2016) | EWAS | Blood | SCZ | |
| TCF3 | ||||
| ↑Montano et al. (2016) | EWAS | Blood | SCZ | |
| IKZF4 | ||||
| ↓Montano et al. (2016) | EWAS | Blood | SCZ | |
| YOD1 | ||||
| ↑Hüls et al. (2020) | EWAS | PMB | Depression | |
| IL17RA | ||||
| Prados et al. (2015) | EWAS | Blood | Borderline PD/depression | CA → ↑ IL17RA |
| TLR1 3 | ||||
| Uddin et al. (2010) | EWAS | Blood | PTSD | CA → ↓TLR1/3 |
| TNFRSF13C | ||||
| Arranz et al. (2021) | EWAS | Blood | Borderline PD | Differently methylated in CA exposed |
| FCGR2B, PIK3R3, INPP5D, INPP5D, IGHA1, FCAR | EWAS | Blood | SCZ | |
| Aberg et al. (2014) | ||||
| CD224, LAX1, TXK, PRF1, CD7, MPG, MPOG | EWAS | Blood | SCZ | |
| Liu et al. (2014) | ||||
| MARC2* | ||||
| Osborne et al. (2020) | EWAS | Blood | General population | Differently methylated in CU and tobacco users |
| CEMIP* | EWAS | Blood | General population | Differently methylated in CU |
| Markunas et al. (2020) | ||||
| Oxidative stress | ||||
| ↑GSTM5 | ||||
| Kebir et al. (2017) | EWAS | Blood | At the risk of psychosis | ↑GSTM5 in converters v. non-converters |
| GGT6 | ||||
| Arranz et al. (2021) | EWAS | Blood | Borderline PD | |
| Hypotalamus pituitary-adrenal axis pathway | ||||
| NR3C1 | ||||
| Bustamante et al. (2016) | Candidate gene | Blood | Depression | CA → ↓ NR3C1 DNAm |
| Farrell et al. (2018) | Candidate gene | Blood | Depression | CA → ↑ NR3C1 DNAm |
| Martin-Blanco et al. (2014) | Candidate gene | Blood | Borderline PD | CA → ↑ NR3C1 DNAm→ clinical severity |
| Perroud et al. (2011) | Candidate gene | Blood | Borderline PD /MDD | CA→ ↑ NR3C1 DNAm |
| Radtke et al. (2015) | Candidate gene | Blood | General population | CA + ↑ NR3C1 DNAm → Borderline PD symptoms |
| Labonte et al. (2014) | Candidate gene | Blood | PTSD | PTSD + → ↓ NR3C1 DNAm |
| Schechter et al. (2015) | Candidate gene | Saliva | PTSD | PTSD + → ↓ NR3C1 DNAm |
| Yehuda et al. (2015) | Candidate gene | Blood | PTSD | PTSD + → ↓ NR3C1 DNAm |
| ↑ Wang et al. (2017) | Candidate gene | Blood | GAD | CA → ↓ NR3C1 DNAm |
| Peng et al. (2018) | Candidate gene | Blood | General population | CA → ↑ NR3C1→ depressive symptoms |
| FKBP5 | ||||
| Tozzi et al. (2018) | Candidate gene | Blood | Depression | CA → ↓ FKBP5 DNAm |
| Misiak et al. (2020) | Candidate gene | Blood | SCZ | CA → ↓ FKBP5 DNAm |
| Klengel et al. (2013) | Candidate gene | Blood | PTSD | CA → ↓ FKBP5 DNAm |
| SKA2 | ||||
| Kaminsky et al. (2015) | Candidate gene | Blood/saliva | General population | CA ↑ x SKA2↑-> suicide attempt |
| ↑Sadeh et al. (2016a, 2016b) | Candidate gene | Blood | PTSD | CA↑-> SKA2↑-> cortical thickness |
*extensive reviews cover the role of BDNF Methylation in depression (Hing et al., 2018), Schizophrenia (Di Carlo et al., 2019), and eating disorders (Thaler and Steiger, 2017), therefore studies mentioned here are just examples of the literature in this particular domain. When various genes are reported in the same pathway and the same study, but no specific information on clinical/biological outcome or specific direction if the association is provided, these genes have been put in the same row (e.g Asberg et al., and Liu et al.,). When an arrow is next to the author's name it reflects the direction of the DNAm of the particular gene in in relation to the condition ↑ : increased ↓: decreased DNAm. When in column 1 there is no arrow is because information could not be obtained or was not clear, and the presence of that gene indicates the association of DNAm in that gene with the respective condition (differently methylated). When a three step sequence separated by an arrow is presented, this refers to mediation analyses (e.g peng et al.,: CA → ↑SLC6A4 → depressive symptoms: DNAm of SLC6A mediates the effect of CA on depressive symptoms). CA: childhood adversity; CU: cannabis use. Definition of each gene is presented in Table 1. DLPFC: Dorsolateral prefrontal cortex. ASD: autism spectrum disorder; SCZ: schizophrenia. PTSD: post-traumatic stress disorder; Borderline PD: Borderline personality disorder; MDD: major depression disorder; BD: bipolar disorder.