Table 3 Epigenetic alterations in schizophrenia reported in studies using human samples

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]