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Table 1 Studies investigating the association between DNA methylation (DNAm) of the oxytocin receptor (OXTR) gene and human behaviour (by year of publication)

From: The role of oxytocin receptor gene (OXTR) DNA methylation (DNAm) in human social and emotional functioning: a systematic narrative review

Study

Characteristics

Main Measure

Tissue

OXTR region & measurement

Methylation Association

Adjustment

Gregory et al. (2009) [46]

(i). 119 Autistic Spectrum Disorder (ASD) probands (78% male) & families.

(ii). 20 ASD (50% male) & 20 controls. (iii). 16 brain samples in 8 ASD (75% male) & 8 controls (Caucasian US)

ASD (DSM-IV criteria) & ADI-R

PMCS & brain tissue (temporal cortex)

2 regions:

(i) exons 1, 2 & 3 incl. MT2 a

(ii). 3rd intron

No SNPs

DNAm Specific sequencing

i) ASD Family study: ↑ DNAm 5/22 CpG sites (− 860, − 901, − 924, − 934 & -959) in region (i) with significant associations at − 860 & - 934 in males & -959 in females

ii) ASD vs controls: ↑DNAm 3 CpG sites (− 860, − 934, − 959). iii) Brain samples: ↑ DNAm 4 CpG sites (− 860, − 901, − 924, − 934)

iv) ↓ Gene expression: PCR ↓mRNA in ASD male brains

Matched: age & gender.

Jack et al. (2012) [42]

42 healthy adults (55% male) 18–30 yrs. Inclusion: normal vision & no previous psychiatry (67%Caucasian US)

fMRI brain scan of during visual perception animation tasks.

PMCS

- 934 single site

No SNPs

Pyrosequencing

↑ DNAm site −934 associated with ↑fMRI activity in temporo-parietal junction incl. dACC during tasks.

No racial or gender differences

Unternaehr-er et al. (2012) [48]

76 adults (43% male) 61–67 yrs. (Caucasian Germany).

TSST

3× whole venous blood:

before TSST, 10 & 90 mins

2 regions in exon 3: OXTR1 & OXTR2

No SNPs

Sequenom EpiTYPER

↑DNAm 7/8 CpG sites OXTR1: pre to 10 mins post-test & ↓DNAm from 10 mins to 90 mins post-test.

↓DNAm trend 2/27 CPG sites OXTR2: 10 to 90 mins. Post-test.

Blood cell counts & batch effects. No sex differences.

Multilevel models

Cecil et al. (2014) [53]

84 youth with conduct disorderb (no gender ratio), (UK).

High Callous Unemotional (CU) traits maternal assessed at 13 yrs

PMCS in cord blood, 7 & 9 years

12 probes across gene.

SNPs:4 CU focus

Illumina array 450 Kc

↑DNAm 3/12 probes on exon 2 in cord blood with ↑ CU in low internalising problems group & with ↑parental risk exposures (prenatal & late-childhood. SNPs rs2301261, rs237915, rs4564970, rs4686302

NSd with DNAm, CU or internalising groups.

Gender stratified analysis (internalising problems)

Dadds et al. (2014) [49]

98 male; 4–16 yrs.: conduct disorder or Oppositional Defiant Disorder (ODD)

Exclusion: ASD, neurological /physical illness, ↓IQ.

(Australia).

i).ODD /Conduct Disorder assessmente

ii). CU traitsf

Blood

11 probes: exon 1 - intron 1.

No SNPs

Sequenom MassARRAY

Children 9-16 yrs., ↑ DNAm associated with ↑ CU traits. Examining the 6 individual CpG sites, these findings were predominantly with CpG 5

Subset 37 youth ↑DNAm associated with ↓ circulating OXT protein levels, in older children only.

Covariates tested.

Kim et al. (2014) [39]

51 females, 18 + yrs. (15 Anorexia Nervosa (AN); 36 healthy controls (South Korea) Exclusion: ASD, psychosis & substance use disorder.

SCID (DSM-IV) & EDE-Q, BMI, AQ (ASD traits), DBI & STAI.

Buccal

48 probes: exon 1-intron 1.

No SNPs

DNAm specific sequencing

↑DNAm 5/48 CpG sites & averaged across region associated with AN.

↓BMI correlated ↑DNAm at 5/48 CpG sites

ASD traits did not associate with DNAm

Age, BMI & clinical variables (ASD, anxiety & depression)

Bell et al. (2015) [34]

269 female postnatal depression (131 antenatal depression); 276 matched controls (135 antenatal depression). 2/3 s: 25–34 yrs. (Caucasian UK)

EDPS: antenatal & postnatal

Whole antenatal blood

- 934 single site

SNPs rs53576 & rs2254298

Pyrosequencing

↑DNAm for females with postnatal depression only in rs53576 GG

Matched: age, parity, depress-ion. Adjusted Models: psychosocial covariates.

Chagnon et al. (2015) [33]

43 females > 65 yrs. (18 prev. Anxiety & MDD, 1 with MDD; 24 controls. Excluded: psychosis, schizophrenia or MMSE score < 22. (Canada).

Anxiety & MDD (DSM-IVR)g

Saliva

9 probes in 2 regions: exon 3.

SNPs: rs53576

Pyrosequencing

No difference between groups overall.

↑DNAm (× 2) for females with anxiety/depression who were rs53576 AA when averaged across region 1 (4 probes) and for 1/5 CpG sites of region 2.

Matched: no details

Puglia et al. (2015) [47]

98 healthy adults, (43% male) 18–30 yrs.: normal vision. (Caucasian, US)

fMRI brain scan during emotional face matching task

PMCS

- 934 single site

No SNPs

Pyrosequencing

↑ DNAm associated with fMRI responses: ↑ face & emotion processing areas (amygdala, fusiform & insula) & ↓ connectivity between social perception systems & ↓ coupling amygdala & emotional regulation regions.

Gender stratified analysis. Age: NS

Reiner et al. (2015) [35]

85 premenopausal female adults (43 depressed & 42 controls), aged 19–52 yrs. Excluded: psychosis, medical, personality, eating & substance use disorders. (Caucasian Germany).

MDD (SCID-DSMIV)

PMCS

Mean DNAm: exon 1(36 sites); exon 2(6 sites)

SNP: rs53576

DNAm Specific sequencing (ESME software)

↓DNAm in exon I (not exon 2) in depressed females.

↓DNAm in depressed females rs53576 GG > AG/AA but in healthy controls ↑DNAm in GG > AG/AA.

↓DNAm in exon 2 associated with rs53576 GG & not depression

Matched: age and education. Mixed models: age, alcohol, smoking, BMI antidepressant use.

Unternaehr-er et al. (2015) [52]

85 university students with maternal care: low (45) and high (40) (79% female) aged 19–66 (median 24). (Caucasian, Switzerland)

PBI (maternal care) when < 16 years: retrospective assessment

Whole blood

2 regions in exon 3 (OXTR TS1 & OXTR TS2 ). (35 CpG units) No SNPs

Sequenom EpiTYPER

↑ DNAm in low versus high maternal care in OXTR TS2

↓DNAm in males compared to females independent of maternal care in OXTR TS2 .

Adjusted: age, gender, batch effects. Mixed model analysis: cell count, BMI & depression considered.

Ziegler et al. (2015) [51]

220 adults: 110 un-medicated social anxiety (76 female & 34 male); 110 controls (77 female & 33 male) Excluded: medical, psychosis & substance use disorders. (Caucasian Germany)

Psychological: SIAS, SPS; cortisol response to TSST, fMRI of amygdala during social anxiety word task.

Whole blood

Region in exon 3 with 12 CpG sites.

SNP: rs53576

DNAm Specific sequencing (ESME software)

↓DNAm at 1/12 CpG site with psychological measures, cortisol response & fMRI.

↓average DNAm across all 12 CpG sites in social anxiety patients compared to controls.

↓average DNAm & at 7/12 CPG sites for rs53576 AA/AG > GG.

Matched: age and sex

Cappi et al. (2016) [40]

73 adults: 42 OCD (9 CBT or fluoxetine /33 treatment naïve); 31 controls: 18–65 yrs. Excluded: psychosis, suicide risk, prev. Head injury, medical & substance use disorders (Brazil)

OCD(DSMIV): Y-BOCS score ≥ 16 (obsessions & compulsions) or ≥ 10 (obsessions or compulsions), BDI, BAI, YGTTS.

Peripheral blood leucocyte ≤2 weeks treatment

2 regions exon 3:OXTR 1 (4 CpG sites) & OXTR 2 (5 CpG sites).

No SNPs

Pyrosequencing

↑DNAm at 2/9 CpG sites in OCD > controls.

↑DNAm correlated with ↑OCD severity

↑DNAm at 8/9 CpG sites with ↓BDI score.

No difference DNAm between 33 treatment naïve or 9 fluoxetine/CBT.

No DNAm correlation between OCD & tics.

Examined age, sex, education, BDI score, BAI score, tics, YBOCS score

Elagoz Yuksel et al. (2016) [41]

66 children: 27 ASD (23 male & 4 female); 39 controls (6 female & 33 male), 22–94 months. Excluded: medication, ↓development, neuro-degenerative, medical & psychiatric disorders(Turkey)

ASD (DSMIV-TR) CARS (≥30 for ASD).

Peripheral blood

4 regions: exon 1 – exon 3 (MT 1–4).

No SNPs

DNAm Specific sequencing

↓DNAm in 2/4 regions: MT1 & MT3 in ASD > controls.

MT1 site (exon 1) DNAm %: 44.4% ASD & 71.8% healthy controls

MT3 site (intron 1, exon 2, intron 2) DNAm %: 29.6% ASD & 61.5% healthy controls.

Matched: age & gender.

Kimmel et al. (2016) [43]

51 females postnatal depression: average 30.6 yrs. (70% Caucasian). Previous mood disorder (66% MDD, 33% Bipolar Disorder) (US)

MDD (DSMIV) ≤ 1st month >birth.

Whole blood T3h

18 CpGs sites

SNP: rs53576

Illumina array 450 K (Brain Cloud tool)

DNAm 1/18 CpG site in female postnatal depression.

rs53576 NS

Adjusted cell proportions.

Rubin et al. (2016) [50]

242 adults: 167 with psychosis (affective/bipolar disorder & non-affective/schizophrenia (92 female & 75 male); 75 healthy controls (38 female & 37 male). Excluded: previous head injury, ↓ reading, medical & substance use disorders (US)

Psychosis (DSMIV); Penn Emotional Recognition Task; fMRI during facial recognition task (79% sample)

Whole blood

A single CpG site (−934)

No SNPs

Pyrosequencing

↑DNAm schizophrenia > bipolar disorder

↑DNAm psychotic females >males

↑DNAm with ↓emotional recognition in females & controls > males.

↑DNAm with ↓ brain volumes: temporal-limbic and prefrontal regions (social cognition) in healthy controls & schizophrenia females.

Plasma OXT levels and DNAm NS in psychotic/ controls Gender differences in plasma OXT & DNAm: (−) males & (+) for females.

Age, race, intracranial brain volume

Sex stratified.

Smearman et al. (2016) [36]

393 adults (70.7% female) 18–77 yrs.: childhood abuse & current anxiety/depression (African American, US).

CTQ, HAMA, BDI

Traumatic Events Inventory

Whole blood

18 CpG sites (before exon 1-intron 3)

SNPs 44

Illumina array 450 K

↑ DNAm associated childhood abuse at 2/18 CpG sites but NS. DNAm not a mediator of psychiatric symptoms. 44 proximal SNPs: 68% associated DNAm of nearby CPG sites.

Age, sex & cell type

Unternaehr-er et al. (2016) [44]

39 infants with mothers mean age 31.9 yrs. (no sex ratio)(Switzerland)

Pregnant mother: EDPS, TICS-K, ILE, saliva cortisol in T2i, T3h.

Cord blood

13 CpG sites (exon 3)

No SNPs Sequenom EpiTYPER

↓ DNAm associated with ILE, EDPS, T2 maternal cortisol (AUCg).

Batch effects, demographics, pregnancy & births.

Rijlaarsdam et al. (2017) [45]

743 children (51% male) ≤6 years yrs. (Netherlands)

ASD 6 yrs. with parental ratings: SRS. Maternal prenatal stress

Cord blood

3 CpG sites across gene.

SNP: rs53576

Illumina array 450 K

DNAm & prenatal maternal stress or ASD: NS

↑DNAm associated ↓social communication: rs53576 GG

Child sex, age, cell type, maternal smoking & technical array.

  1. a. MT2 segment is a genomic region on OXTR identified by Kusui, 2001; b. Diagnostic Interview Schedule for Children, Adolescents & Parents; c. 450 K: Illumina Human Methylation 450 Bead Chip array (Illumina, USA); d. Not Significant; e. Antisocial Process Screening Device/ASPD & pro-social subscale of Strengths & Difficulties/ PSSSDQ; f. Youth with early onset & persistent conduct problems assessed by Strengths & Difficulties Questionnaire ‘Conduct problem’ subscale; g. Diagnostic Interview Schedule and Composite International Diagnostic Interview for anxiety and depressive disorders; h. pregnancy second Trimester; i. pregnancy third Trimester