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. 2012 Dec 13;4(12):96. doi: 10.1186/gm397

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).

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