Table 3.
Potential DNA methylation markers in neuropsychiatric diseases.
| Cell/Tissue Type | Main Findings | Ref. | |
|---|---|---|---|
| Neuropsychiatric Diseases | |||
| SZ | Human Brain tissue from SZ patients and HCs | Increased DNMT1 expression and subsequently elevated DNA methylation levels were detected in SZ patients compared to HCs. | [83] |
| Brain tissue and PBL from SZ patients and HCs | The mRNA expression of DNMT1 and DNMT3A was increased in both brain tissue and PBL of SZ patients compared to HCs. | [84] | |
| PBL from SZ patients and HCs | The mRNA expression of DNMT1, TET1, GCortR, and BDNF was increased in PBL of SZ patients compared to HCs. | [98] | |
| Human fetal and adult brain tissue | >16,000 fetal brain mQTLs were identified. Fetal brain-specific mQTLs were enriched among SZ-associated SNPs identified in a recent study. | [90] | |
| Blood and brain tissue from SZ-discordant MZ twins, SZ patients, HCs | 25 DMPs associated with SZ (p-value < 10−7). The seven meQTLs were enriched for schizophrenia risk variants in both brain and blood samples. | [99] | |
| Genome-wide DNA methylation data from WB samples and postmortem DLPFC samples from SZ patients and HCs | Blood PMS signature can distinguish SZ patients from HCs and several other major neuropsychiatric disorders, enriched for methylation differences detected in DLPFC postmortem samples and was correlated with altered functional DLPFC-HC coupling during working memory and biological pathways with synaptic function. | [100] | |
| Postmortem PFC brain tissue from SZ patients and HCs (the results from three independent studies) | The seven DMRs identified in near CERS3, DPPA5, PRDM9, DDX43, REC8, LY6G5C genes, and a region on chromosome 10 across all three PFC brain data sets may play an important role in the pathogenesis and progression of SZ patients. | [101] | |
| Genome-wide DNA methylation data of WB samples from SZ patients and HCs | Accelerations in 3 mortality clocks in SZ may result from smoking and 6 age-associated proteins. 2 mitotic clocks were decelerated in SZ related to NK and CD8+ T cells and may be a biological basis for reduced cancer risk. Chronological age clocks were decelerated in patients treated with clozapine. | [102] | |
| Postmortem brain tissue of SZ patients and HCs | The methylation levels of two CpG sites within the 5′ UTR of GAD1 were significantly associated with SZ-risk SNP rs3749034 and GAD25 expression in DLPFC. The expression of full-length GAD1 transcript encoding GAD67 was significantly higher in DLPFC of SZ patients who died through suicide. | [86] | |
| TLE | Brain tissue of TLE patients and HCs | The expression of DNMT1 and DNMT3A was increased in TLE patients relative to HCs, especially in NeuN+ neurons, but not GFAP+ astrocytes. | [92] |
| Postmortem brain tissue of TLE patients with and without FS and HCs | The levels of DNMT3A1 and DNMT3A2 isoforms were decreased in the hippocampus of TLE patients with FS relative to HCs and other TLE groups. Increased levels of DNMT1, DNMT3A1, and global DNA methylation were found in the neocortex of all TLE patients compared to HCs. | [103] | |
| Postmortem hippocampus from TLE patients and HCs | 81.5% of 146 differentially methylated protein-coding gene promoters were hypermethylated in TLE patients relative to HCs, and these genes are related to development, neuron remodeling, and neuron maturation. Four differentially methylated lncRNAs and 13 methylation-sensitive miRNAs were identified. miR-876-3p was associated with WG1 hippocampal sclerosis. | [95] | |
| Postmortem hippocampus from TLE patients with and without GCD, and HCs | RELN promoter methylation was higher in TLE patients than in HCs. Increased methylation of the RELN promoter was associated with GCD among TLE patients. | [94] | |
| PB DNAs of TLE patients and HCs | 85% and 87% of differentially methylated miRNA and lncRNA promoters were hypermethylated in TLE patients compared to HCs. The aberrantly methylated miRNAs and lncRNAs were correlated to drug metabolism, ion channel activity, MAPK- and neurotrophin signaling pathways. | [97] | |
| WB of MLTE patients and HCs | 216 DAGs, with 52 sites involved in hypo- and 164 sites hypermethylation, related to pathways involved in drug metabolism, anion binding, growth regulation, oxidoreductase activity, and skeletal development, with the most distinct ones including CYP3A43, CYP3A4, CYP2C9, CLCA4, CLCN6, and SLC34A2. | [104] | |
BDNF: brain-derived neurotrophic factor; CERS3: ceramide synthase 3; CYP3A: cytochrome P450 family 3 subfamily A member; CYP2C9: cytochrome P450 family 2 subfamily C member 9; CLCA4: chloride channel accessory 4; CLCN6: chloride voltage-gated channel 6; DL-PFC: dorsolateral prefrontal cortex; DMRs: differentially methylated regions; DAGs: DMR-associated genes; DNMT: DNA (cytosine-5)-methyltransferase; DMPs: differentially methylated positions; DLPFC-HC: dorsolateral prefrontal cortex hippocampal; DPPA5: developmental pluripotency-associated 5; DDX43: DEAD-box helicase 43; FS: febrile seizures; GAD1: glutamate decarboxylase 1; GAD67: glutamate decarboxylase 67; GCortR: glucocorticoid receptor; GFAP: glial fibrillary acidic protein; GCD: granule cell dispersion; HCs: healthy controls; LY6G5C: lymphocyte antigen 6 family member G5C; lncRNA: long non-coding RNA; MZ: monozygotic; MTLE: mesial temporal lobe epilepsy; meQTLs: methylation quantitative trait loci; MAPK: mitogen-activated protein kinase; NK: natural killer cell; NeuN: neuronal nuclei; PFC: prefrontal cortex; PB: peripheral blood; PBL: peripheral blood lymphocytes; PMS: polymethylation score; RELN: Reelin; PRDM9: PR/SET domain 9; REC8: meiotic recombination protein; SZ: schizophrenia; SLC34A2: solute carrier family 34 member 2; TLE: temporal lobe epilepsy; TET1: Tet methylcytosine dioxygenase 1; WB: whole blood; WG1: Watson Grade1.