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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
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