Epigenetics in psychiatry: Beyond DNA methylation

Table 1 Detailed data on DNA hydroxymethylation studies and psychiatric disorders

Ref.	Studied disorder	Subjects	Tissue	Method	Main results
Gross et al[35], 2017	Suicidal behavior/major depressive disorder	Subjects with major depressive disorder; n = 19 and psychiatrically healthy controls; n = 19	Prefrontal cortex	AbaSI sequencing	No differences in 5hmC density across the genome. Site-specific differential hydroxymethylation in the depressed brain
Lutz et al[36], 2018	Suicidal behavior	Suicide completers (severe child abuse history); n = 30, suicide completers (no child abuse history); n = 30 and control group; n = 34	Anterior insula	Targeted oxidative bisulfite sequencing	Childhood abuse in the past is associated with decreased hydroxymethylation of Kappa Intron 2
Jiang et al[41], 2017	Schizophrenia	Schizophrenic subjects; n = 264 and controls; n = 221	Peripheral blood	Dot blot-based measurement	5hmC levels increased in male SZ patients but decreased levels in female SZ patients
Zong et al[42], 2017	Schizophrenia	Schizophrenic subjects; n = 279 and controls; n = 256	Peripheral white blood cells	HpaII/MspI restriction-based EpiMark 5hmC/5mC Analysis Kit followed by qPCR	5hmC increased in the promoter of the GABRB2 gene; correlation between heterozygous genotype rs72815526 (C/A) and 5hmC levels increased
Gavin et al[44], 2012	Schizophrenia and bipolar disorder	Schizophrenic subjects; n = 15, subjects with bipolar disorder; n = 11, and controls; n = 15	Parietal cortex (Brodmann area 39-40)	hMeDIP	5hmC increased at the promoter IXabcd of the BDNF gene
Dong et al[45], 2012	Schizophrenia and bipolar disorder	Schizophrenic subjects; n = 10, subjects with bipolar disorder; n = 9, and controls; n = 11	Inferior parietal lobule	Immuno-dot-blot analysis	5hmC increased at the GAD67 gene at -537 to -415, and -145 to +21; 5hmC increased at the BDNF IXabcd gene at -60 to +50 not within BDNF exon IXd at +1185 to +1305
D'Addario et al[57], 2019	Obsessive compulsive disorder	Obsessive compulsive disorder; n = 35, and controls; n = 32	Peripheral blood mononuclear cells	Bisulfite conversion or oxidative bisulfite conversion, followed by pyrosequencing	BDNF hydroxymethlation decreased at promoter exon I; no changes in promoter exon IV and IX
Clark et al[60], 2022	Substance use disorder	Alcohol use disorder; n = 25, and controls; n = 25	Prefrontal cortex (Brodmann area 10)	Selective chemical labelling and enrichment of hmC (hMe-Seal)	BAIAP2 hydroxymethylation increased

5hmC: 5-hydroxymethycytosine; SZ: Schizophrenia; 5mc: 5-methylcytosine; qPCR: Quantitative real-time polymerase chain reaction; BDNF: Brain-derived neurotrophic factor.