Table 3.
Epigenetic alterations in schizophrenia reported in studies using human samples
| Sample tissue | Approach | Number of samples | Main findings | Implicated genes | Reference |
|---|---|---|---|---|---|
| Postmortem occipital cortex and prefrontal cortex | Bisulfite sequencing* | 15 Sz, 15 CT | Hypermethylation of RELN in Sz | RELN encodes a protein related to cell positioning and neuronal migration during brain development | [46] |
| Postmortem prefrontal cortex | Bisulfite sequencing* | 11 Sz, 12 CT | Hypermethylation of SOX10 in Sz; downregulation of SOX10 transcription in Sz | SOX10 encodes an oligodendrocyte-specific transcription factor | [53] |
| Postmortem frontal cortex | Bisulfite sequencing*; methylation-specific PCR | 35 Sz, 35 CT | Hypomethylation of MB-COMT promoter in Sz | MB-COMT encodes the membrane-bound form of catechol-O-methyltransferase, which is involved in dopamine metabolism | [51] |
| Postmortem cerebellum | Pyrosequencing after bisulfite-PCR* | 15 Sz, 15 CT | No significant difference in COMT methylation | [52] | |
| Postmortem frontal cortex | CpG island microarray; pyrosequencing after bisulfite-PCR* | 35 Sz, 35 CT | Methylation changes in genes related to glutamatergic/GABAergic neurotransmission, brain development, mitochondrial function and stress response in Sz | Examples include: NR3B and GRIA2, both of which are involved in glutamatergic neurotransmission, and implicated in the etiology of schizophrenia | [49] |
| Postmortem prefrontal cortex | Pyrosequencing after bisulfite-PCR* | 15 Sz, 15 CT | No significant difference in RELN methylation | [50] | |
| Postmortem parahippocampus gyrus | Bisulfite sequencing* | 6 right and 7 left hemisphere of Sz; 5 right and 6 left hemisphere of CT | Hypermethylation of FOXP2 in left parahippocampus gyrus in Sz | FOXP2 encodes a transcriptional factor required for the development of language | [56] |
| Postmortem frontal lobe | Bisulfite sequencing*Methylation specific PCR | 35 Sz, 35 CT | Hypermethylation at and around -1438A/G SNP, hypomethylation at and around T102C SNP of HTR2A promoter in Sz | HTR2A encodes serotonin receptor 2A, one of the main target molecules of antipsychotic drugs | [57] |
| Peripheral blood | Bisulfite sequencing* | 1 MZ pair concordant for Sz; 1 MZ pair discordant for Sz | SZ twin in a pair discordant for SZ had more similar DRD2 methylation profiles to the affected concordant twin pair than to its unaffected cotwin | DRD2 encodes the D2 subtype of the dopamine receptor | [74] |
| Peripheral blood | High-performance liquid chromatography | 210 Sz (124 male, 86 female); 237 CT (108 male, 129 female) | Global hypomethylation in male Sz | [66] | |
| Peripheral blood | Radiolabeled [3H]dCTP-extension assay | 28 Sz, 26 CT | No difference in global DNA methylation | [68] | |
| Peripheral blood | Bisulfite sequencing* | 30 Sz, 30 CT | Hypermethylation in the neighborhood of disease-associated SNP rs1816071; hypomethylation at three CpG sites; hypermethylation at four CpG sites, in GABRB2 in Sz | GABRB2 encodes beta 2 subunit of GABA(A) receptor | [71] |
| Peripheral blood | High-resolution melt assay* | 40 Sz, 67 CT | Hypermethylation 5HTR1A promoter in Sz | 5HTR1A encodes serotonin receptor 1A | [70] |
| Saliva | Bisulfite sequencing*; methylation specific PCR | 63 Sz, 76 CT | Hypomethylation of T102C SNP in 5HTR2A in Sz | 5HTR2A encodes serotonin receptor 2A | [72] |
| Saliva | Bisulfite sequencing*; methylation specific PCR | 63 Sz, 76 CT | Hypomethylation of MB-COMT promoter in Sz | MB-COMT encodes membrane-bound form of catechol-O-methyltransferase, which is involved in dopamine metabolism | [73] |
| Peripheral blood | Bead array (Illumina Infinium Human-Methylation27)* | 11 MZ pairs discordant for Sz | Hypomethylation of ST6GALNAC1 promoter in psychosis; PUS3 is a top-ranked differentially methylated gene in Sz; differential methylation in psychological-disorder-related genes such as ADAMTS3 and SLC6A3 in Sz | ST6GALNAC1 encodes an enzyme that transfers sialic acid to O-linked N-acetylgalactosamine residues, and PUS3 encodes pseudouridylate synthase 3, both of which require further investigation | [62] |
| Peripheral blood | Global assay (restriction enzyme and pyrosequencing); pyrosequencing after bisulfite-PCR* | 177 Sz, 171 CT; (S-COMT: 47 Sz, 47 CT; SLC6A4: 67 Sz, 81 CT) | Global hypomethylation in SzEarly-onset-associated lower global methylation; haloperidol-associated higher global methylation; hypermethylation of S-COMT in Sz; no significant difference in SLC6A4 methylation | S-COMT encodes the soluble form of catechol-O-methyltransferase, which is involved in dopamine metabolism; SLC6A4 encodes a serotonin transporter | [67] |
*The limitation of bisulfite treatment (this approach does not allow precise discrimination between various forms of cytosine modifications).
CT, normal controls; DZ, dizygotic twin; GABA, γ-aminobutyric acid, MZ, monozygotic twin; SNP, single nucleotide polymorphism, Sz, schizophrenia (patients).