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Table 1 Summary of studies reporting DNA methylation in schizophrenia

From: DNA methylation in peripheral tissue of schizophrenia and bipolar disorder: a systematic review

Ref.

N

Mean age (SD)

Sex (F %)

Method

Subgroup analyses /covariates

RESULTS: methylation loci

 

SZ

HC

SZ

HC

SZ

HC

   

Aberg et al., 2014 [20]

759

738

53 (12)

55 (12)

45

46

MBD protein-enriched genome sequencing b, d, e

Age, sex, smoking m, alcohol use m, medication m, autoimmune disorders m

Differential methylation l of FAM63B, RELN (first intron), FCAR and 8 other genes linked to hypoxia & the immune system

Aberg et al., 2012 [21]

750

750

-

-

-

-

MBD protein-enriched genome sequencing b, d, i

Age, sex

Differential methylationl of GRIA2, HTRA3, CAMK2D, FNDC3B and DCTN

Bonsch et al., 2012 [22]

27

34

-

-

30

47

Modified non-radioactive elongation assay and MSRE-quantitative PCR a, c, d, e

Sex k, medication j, promoter methylation compared to global DNA methylation

Global methylation differences l;

Lower methylation of RELN and SOX10 promoters c, m in SZ;

SZ on medication had similar methylation levels to HC

Bromberg et al., [23]

28

26

39 (14)

42 (10)

64

62

Radiolabelled [3H] cytosine-extension assay a, d, e

Age m, sex, smoking l, illness duration m, medication m

No global methylation differences m;

Higher methylation in SZ non-smokers

Chen et al., 2012 [24]

371

288

-

-

46

57

Bisulfite sequencing c, d, e

Sex j

No differential methylation of MAOA (promoter) m

Greater methylation in SZ females compared to males

Ikegame et al., 2013 [25]

100

100

43 (13)

46 (12)

46

45

Pyrosequencing c, d, e

Age m, sex j

Hypermethylation of BDNF (promoter I) j for SZ CpG-72 compared HC, however methylation generally low in SZ/HC;

No diffferential methylation of BDNF (promoter IV) m between groups; higher methylation in SZ/HC females at all CpG sites

Kinoshita et al., 2014 [26]

63

42

49 (10)

47 (10)

22

40

450 K methylation array a, d, f

Age, sex, cell type heterogeneity l

Global methylation differences (485 764 CpG sites) l

Hypermethylation in SZ found in 1161 CpG sites when controlling for cellular heterogeniety

Kinoshita et al., 2013a [27]

42

42

52 (7)

52 (6)

0

0

450 K methylation array a, d, e

Age, medication

Global methylation differences (164 657 CpG sites) l including SLC18A2, GNAL, KCNH2 and NTNG2

Kinoshita et al., 2013b [28]

24

23

31 (11)

31 (10)

54

57

450 K methylation array a, d, e

Sex l

Global methylation differences in SZ (485 764 CpG sites) l including B3GAT2, HDAC4, DGKI, PCM1, INSIG2, GFRA2 and RAI1;

Did not replicate published methylation findings in SZ for COMT, HTA1A and MAOA

Kordi-Tamandani et al., 2013a [29]

81

71

48 (11)

47 (12)

25

20

Methylation specific PCR c, d, g

-

Hypermethylation of GMR2 j, GMR5 j, GRIA3 j, GMR8 j (all promoter regions)

Kordi-Tamandani et al., 2012 [30]

80

71

48 (11)

47 (12)

-

-

Methylation specific PCR c, d, g

-

Differential methylation of BDNF (promoter) l and DAT1 j

Kordi-Tamandani et al., 2013b [31]

94

99

48 (11)

47 (12)

29

27

Methylation specific PCR c, d, g

Genotype m

Hypermethylation of CTLA4 (promoter) j increased in SZ

Liao et al., 2014 [32]

2

1

25 (4)

31 (0)

100

100

MBD protein-enriched genome sequencing a, c, d, h

Paranoid j/undifferentiated illness type l

Global methylation differences l; GRB2 j, PRKCA j, DLG4 j, MAPT-S1 j, DISC1 j and 16 other genes;

Differential methylation mostly found in intergenic and intronic regions

Liu et al., 2013 [33]

98

108

34 (11)

-

25

36

27 K methylation assay a, d, f

Age, sex, ethnicity, alcohol/nicotine/cannabis use, SZ symptoms l, medication j, illness duration j, age of onset l

Global methylation differences (7562 CpG sites) in SZ l: MS4A1 j, MPG k, SLC25A10 j, CBFA2T3 k and 17 other genes l linked to inflammatory response, haematological development and cytotoxic reactions;

Hypermethylation of MS4A1 associated with chlorpromazine dosage;

Higher methylation of MPG and SLC25A10 associated with longer illness duration;

Hypomethylation of CBFA2T3 associated with age of SZ onset

Melas et al., 2012 [34]

177

171

52 (9)

-

51

-

Luminometric methylation assay and bisulfite sequencing a, c, d, e

Age m, sex m, smoking m, alcohol use m, medication (haloperidol) l, hospital admissions m, length of hospital stay m, familial absence of SZ m, age of onset k

Global methylation differences in SZ l ; No differential methylation of 5-HTT (8 CpG sites) m; hypermethylation of S-COMT (5 CpG sites) j

Murphy et al., 2008 [35]

18

31

-

-

-

-

Bisulfite sequencing c, d, e

-

No differential methylation of SYNIII m

Murphy et al., 2005 [36]

20

31

-

-

-

-

Bisulfite sequencing c, d, i

-

No differential methylation of S-COMT (promoter) m

Nishioka et al., 2013 [37]

17

15

23 (5)

23 (4)

59

33

27 K methylation assay a, d, f

Sex m, SZ symptoms, GAF score, duration of untreated psychosis, age at onset

Global methylation differences (603 CpG sites) in SZ l : COMTD1 (promoter) l, SLC6A3 k, HTR1E l and 7 other genes l related to the nuclear lumen, transcription factor binding and nucleotide binding

Ota et al., 2014 [38]

51

51

25 (8)

26 (8)

37

37

Bisulfite sequencing c, d, i

Age m, sex j

Hypermethylation of GCH1 j (CpG13, CpG15, CpG16 and CpG21 only) in first episode psychosis;

Only CpG21 j in SZ males

Pun et al., 2011 [39]

30

30

-

-

50

37

Bisulfite sequencing c, d, e

Single-nucleotide polymorphism

Hypermethylation of GABRB2 in SZ (CpG sites 1–26) j

Shimabukuro et al., 2007 [40]

210

237

-

-

41

54

HPLC a, d, f

Age l, sex k, subtypes of SZ m

Global hypomethylation in SZ k

In SZ males hypomethylation decreases with age

Van Eijk et al., 2014 [41]

264

252

-

-

-

-

27 K methylation assay a, d, f

Age, sex, gene expression associations l

Global methylation differences (11 320 CpG sites)in SZ l: including PRRT1, HLA-C, MRPL41, CALHM1;

Significant association between DNA methylation and gene expression

  1. SZ schizophrenia, HC healthy control, N sample number, F female, SD standard deviation, MBD methyl-CpG-binding domain, MSRE methylation specific restriction enzymes, HPLC high performance liquid chromatography, UTR untranslated regions, PCR polymerase chain reaction, GAF global assessment of functioning. Genes: FAM63B family with sequence similarity 63 member B, RELN reelin, FCAR Fc fragment of IgA receptor, GRIA2 glutamate receptor ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid 2, HTRA3 HtrA serine peptidase 3, CAMK2D calcium/calmodulin-dependent protein kinase 2 delta, FNDC3B fibronection type 3 domain containing 3B, DCTN dynactin, SOX10 sex determining region Y box 10, MAOA monoamine oxidase A, BDNF brain-derived neurotrophic factor, SLC18A2 vesicular monoamine transporter 2, GNAL guanine nucleotide binding protein G alpha activating polypeptide olfactory type, KCNH2 potassium voltage-gated channel subfamily H member 2, NTNG2 netrin G2, B3GAT2 beta-1 3-glucuronyltransferase 2, HDAC4 histone deacetylase 4, DGKI diacylglycerol kinase iota, PCM1 pericentriolar material 1, INSIG2 insulin induced gene 2, GFRA2 glial cell line-derived neurotrophic factor family receptor alpha 2, RAI1, retinoic acid induced 1, GMR2 glutamate metabotrophic receptor 2, GMR5 glutamate metabotrophic receptor 5, GRIA3 glutamate receptor ionotrophic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid 3, GMR8 glutamate metabotrophic receptor 8, DAT1 dopamine active transporter 1, CTLA4 cytotoxic T-lymphocyte-associated protein 4, GRB2 growth factor receptor-bound protein 2, PRKCA protein kinase C alpha, DLG4 discks large homolog 4, MAPT-S1 microtubule-associated protein tau, DISC1 disrupted in schizophrenia 1 protein, GCH1 guanosine triphosphate cyclohydrolase 1, PRRT1 proline-rich transmembrane protein 1, HLA-C human leukocyte antigen receptor C, MRPL41 mitochondrial ribosomal protein L41, MS4A1 membrane-spanning 4-domains subfamily A member 1, MPG N-methylpurine-DNA glycosylase, SLC25A10 solute carrier family 25 member 10, CBFA2T3 core-binding factor alpha subunit 2 translocated to 3, 5-HTT serotonin neurotransmitter transporter, SYNIII synapsin 3, S-COMT soluble catechol-O-methyltransferase, COMTD1 catechol-O-methyltransferase domain containing 1, SLC6A3 solute carrier family 6 transporter member 3, HTR1E 5-hydroxytryptamine serotonin receptor 1E G protein-coupled, GABRB2 gamma-aminobutyric acid A receptor beta 2
  2. Study type
  3. a global DNA methylation
  4. b methylome-wide association study
  5. c candidate gene study
  6. Tissue type
  7. d blood
  8. Measure of Methylation
  9. e percentage
  10. f beta-value
  11. g odds ratio
  12. h peak score
  13. i no reported
  14. Results
  15. j significant hypermethylation
  16. k significant hypomethylation
  17. l significant differentially methylated
  18. m no significant difference