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