Table 2 Summary of studies reporting DNA methylation in bipolar disorder

Bromberg et al., 2009 [42]

49

27

39 (13)

42 (10)

41

37

Radiolabeled [3H] cytosine-extension assay ^{a, c, d}

Medication (valproate) ^h, sex ^h, smoking ^h, duration of illness ^h, family history of BD ^h

No global methylation differences ^h

Carlberg et al., 2014 [43]

60

278

42 (15)

32 (4)

45

62

MethyLight ^{b, c, d}

Age ^g, gender ^h, clinical variables, genotype ^h

No difference in methylation of BDNF (exon I promoter) ^h

D’Addario et al., 2012 [44]

94

52

52 (12)

-

60

-

Fluorescence-based real-time PCR ^{b, c, d}

Medication ^e, BD-I compared to BD-II ^h, mood state ^h

Hypermethylation of BDNF (exon I promoter) ^e only in BD-II;

Higher methylation associated with mood stabiliser and antidepressants, but lower for lithium and valproate

Dell’Osso et al., 2014 [45]

111

44

-

-

-

-

Fluorescence-based real-time PCR ^{b, c, d}

Age ^h, sex ^h, mood state ^e, medication, BD-I compared to BD-II

Hypermethylation of BDNF (exon I promoter) ^e in BD-II compared to BD-I;

Higher methylation in depressed compared to manic/mixed states; Higher methylation in BD-II males with increasing age

Kaminsky et al., 2012 [46]

370

382

43 (11)

42 (6)

58

55

Pyrosequencing ^{b, c, d}

Age ^e, sex, genotype ^f, medication (mood stabiliser) ^e

HCG9 (first exon extending into the first intron) ^f in BD (when controlling for age and genotype);

Higher methylation in BD/HC with increasing age;

Lower methylation in GG allele compared to GA allele carriers;

Higher mood stabiliser dose increases methylation towards HC levels

Kuratomi et al., 2008 [47]

23

18

57 (11)

46 (12)

52

33

Pyrosequencing ^{b, c, d}

Age ^h, sex ^e, medication (valproate) ^h, BD-I compared to BD-II ^f

Differential methylation of SMS (5'region) ^g, higher methylation for females in BD-I/II group compared to HC;

Hypomethylation of PPIEL (promoter and 5'region) ^f for BD-II compared to BD-I;

No difference in methylation of PIP5KL1 ^h, ARMC3 ^h

Sugawara et al., 2011 [48]

20

20

39 (13)

39 (9)

60

20

Pyrosequencing ^{b, c, d}

-

Differential methylation of SLC6A4 (promoter) ^g, higher methylation in CpG 3 and 4 for BD compared to HC