Oxytocin receptor (OXTR) does not play a major role in the aetiology of autism: Genetic and molecular studies

doi:10.1016/j.neulet.2010.03.035

Neuroscience Letters

Volume 474, Issue 3, 3 May 2010, Pages 163-167

https://doi.org/10.1016/j.neulet.2010.03.035 Get rights and content

Abstract

Oxytocin (OXT) has been hypothesized to play a role in aetiology of autism based on a demonstrated involvement in the regulation of social behaviours. It is postulated that OXT reduces activation of the amygdala, inhibiting social anxiety, indicating a neural mechanism for the effects of OXT in social cognition. Genetic variation at the oxytocin receptor gene (OXTR) has been reported to be associated with autism. We examined 18 SNPs at the OXTR gene for association in three independent autism samples from Ireland, Portugal and the United Kingdom. We investigated cis-acting genetic effects on OXTR expression in lymphocytes and amygdala region of the brain using an allelic expression imbalance (AEI) assay and by investigating the correlation between RNA levels and genotype in the amygdala region. No marker survived multiple correction for association with autism in any sample or in a combined sample (n = 436). Results from the AEI assay performed in the lymphoblast cell lines highlighted two SNPs associated with relative allelic abundance in OXTR (rs237897 and rs237895). Two SNPs were found to be effecting cis-acting variation through AEI in the amygdala. One was weakly correlated with total gene expression (rs13316193) and the other was highlighted in the lymphoblast cell lines (rs237895). Data presented here does not support the role of common genetic variation in OXTR in the aetiology of autism spectrum disorders in Caucasian samples.

Section snippets

Conflict of interest

The authors report no conflicts of interests.

Acknowledgements

We thank the families who took part in this study for their support and cooperation. Family collection in Ireland and data analysis was supported by grants from the Health Research Board, Ireland, The Wellcome Trust, UK, and the National Alliance for Autism Research, USA. We would like to thank Dr. Robert Walker from the Edinburgh MRC Sudden Death Tissue and Brain Bank for providing the brain samples.

References (37)

S. Baron-Cohen et al.
The amygdala theory of autism
Neurosci. Biobehav. Rev.
(2000)
C.S. Carter
Developmental consequences of oxytocin
Physiol. Behav.
(2003)
C.S. Carter
Sex differences in oxytocin and vasopressin: implications for autism spectrum disorders?
Behav. Brain Res.
(2007)
G. Domes et al.
Oxytocin attenuates amygdala responses to emotional faces regardless of valence
Biol. Psychiatry
(2007)
D.H. Geschwind
Autism: many genes, common pathways?
Cell
(2008)
L Green et al.
Oxytocin and autistic disorder: alterations in peptide forms
Biol. Psychiatry
(2001)
E. Hollander et al.
Oxytocin increases retention of social cognition in autism
Biol. Psychiatry
(2007)
S. Jacob et al.
Association of the oxytocin receptor gene (OXTR) in Caucasian children and adolescents with autism
Neurosci. Lett.
(2007)
R. Landgraf et al.
Vasopressin and oxytocin release within the brain: a dynamic concept of multiple and variable modes of neuropeptide communication
Front. Neuroendocrinol.
(2004)
M.M. Lim et al.
Neuropeptidergic regulation of affiliative behavior and social bonding in animals
Horm. Behav.
(2006)

J.L. McCauley et al.

Genome-wide and Ordered-Subset linkage analyses provide support for autism loci on 17q and 19p with evidence of phenotypic and interlocus genetic correlates

BMC Med. Genet.

(2005)

Y. Mizumoto et al.

A genomic element within the third intron of the human oxytocin receptor gene may be involved in transcriptional suppression

Mol. Cell. Endocrinol.

(1997)

C. Modahl et al.

Plasma oxytocin levels in autistic children

Biol. Psychiatry

(1998)

S. Purcell et al.

PLINK: a tool set for whole-genome association and population-based linkage analyses

Am. J. Hum. Genet.

(2007)

D.H. Skuse et al.

Dopaminergic–neuropeptide interactions in the social brain

Trends Cogn. Sci.

(2009)

S. Wu et al.

Positive association of the oxytocin receptor gene (OXTR) with autism in the Chinese Han population

Biol. Psychiatry

(2005)

C.M. Yrigollen et al.

Genes controlling affiliative behavior as candidate genes for autism

Biol. Psychiatry

(2008)

B.S. Abrahams et al.

Advances in autism genetics: on the threshold of a new neurobiology

Nat. Rev. Genet.

(2008)

Cited by (91)

Understanding altruistic behavior: The joint role of prefrontal damage and OXTR genotype
2023, Neuropsychologia
Altruism is a type of prosocial behavior that is carried out in the absence of personal benefit or even at an expense to self. Trait altruism varies greatly across individuals, and the reasons for this variability are still not fully understood. Growing evidence suggests that altruism may be partly determined by the oxytocin receptor (OXTR) gene, which regulates the emotions underlying altruistic attitudes, such as empathy and trust. Neuroimaging and lesion studies have also implied several higher-order brain regions, including the prefrontal cortex, in altruistic behaviors. Yet the existing reports are contradictory and suggest that the top-down control exercised by the prefrontal cortex may promote both altruistic and self-interested behaviors and, thus, could obscure one's natural proclivity towards altruism encoded by OXTR.
Here, we hypothesized that extensive prefrontal damage would result in an increased influence of the OXTR genotype on one's altruistic attitudes and actions. To test this hypothesis, we recruited 115 male combat veterans with penetrating traumatic brain injury to the prefrontal cortex and other brain regions, as well as 35 demographically matched control subjects without brain injury. Participants completed a self-report altruism questionnaire and were genotyped for four OXTR single nucleotide polymorphisms implicated in prosocial behavior, including rs53576, rs1042778, rs2254298 and rs7632287.
Consistent with the previous studies, we found that individuals homozygotic for the G allele of rs53576 and rs7632287 were significantly more altruistic than carriers of at least one “vulnerable” A allele. Remarkably, in patients with prefrontal cortex damage, greater lesion extent was associated with significantly lower altruism scores in carriers of the A allele of rs7632287, but not in G-homozygotes, suggesting that significant disruption of the prefrontal cortex increased the influence of genetic polymorphisms on prosocial behavior. This study presents the first account of an interaction effect between the OXTR genotype and the location and extent of brain damage.
Neuroimaging genetics of oxytocin: A transcriptomics-informed systematic review
2022, Neuroscience and Biobehavioral Reviews
The last couple of decades have witnessed a rapid accumulation of studies implicating oxytocin (OT) in several neurobiological underpinnings of human behaviour and their impairment in psychiatric illness. Specifically, a neuroimaging genetics approach is helping elucidate the impact of variations in OT pathway genes on the human brain. In this review, we provide the first systematic account and discussion of all previous findings arising from human neuroimaging (epi)genetic studies of OT-related genes. To improve our mechanistic interpretation of such findings, we used data from the Genotype-Tissue Expression project to explore the functional impact the genetic variations may have on the human transcriptome. As a result, we provide an up-to-date summary of brain circuits found to be impacted by OT-relevant (epi)genetic variability, map brain pathways linking OT genes to disease, and highlight several (epi)genetic factors that modulate brain responses to intranasal OT. Finally, we provide some suggestions we believe might improve future research in the field.
Rationale, design, and methods of the Autism Centers of Excellence (ACE) network Study of Oxytocin in Autism to improve Reciprocal Social Behaviors (SOARS-B)
2020, Contemporary Clinical Trials
Citation Excerpt :
The role of the oxytocin system in social function across species has led multiple groups to investigate whether it may contribute to ASD risk, with suggestive but inconclusive results. Multiple genetic variants in the oxytocin signaling system have been associated with ASD relative to typically developing controls, while others have been associated with cognition or functioning within ASD; although none of these findings have reached genome-wide significance [30,33–43]. Modestly greater (~20–40%) OXTR methylation relative to controls has been reported in two small, independent ASD samples [44].
To describe the rationale, design, and methods of the Autism Centers of Excellence (ACE) network Study of Oxytocin in Autism to improve Reciprocal Social Behaviors (SOARS-B).
This phase 2 clinical trial was designed to evaluate the use of intranasal oxytocin treatment to improve social difficulties in individuals with autism spectrum disorder (ASD). In total, 290 participants ages 3 to 17 years with a DSM-5 diagnosis of ASD were enrolled to receive 24 weeks of treatment with either oxytocin or a matched placebo at one of seven collaborating sites. Participants were subsequently treated with open-label oxytocin for 24 additional weeks. Post-treatment assessments were done approximately 4 weeks after treatment discontinuation. Plasma oxytocin and oxytocin receptor gene (OXTR) methylation level were measured at baseline, and week 8, 24 and 36 to explore potential relationships between these biomarkers and treatment response.
This report describes the rationale, design, and methods of the SOARS-B clinical trial.
There is a tremendous unmet need for safe and effective pharmacological treatment options that target the core symptoms of ASD. Several studies support the hypothesis that intranasal oxytocin could improve social orienting and the salience of social rewards in ASD, thereby enhancing reciprocal social behaviors. However, due to conflicting results from a number of pilot studies on the prosocial effects of exogenous oxytocin, this hypothesis remains controversial and inconclusive. SOARS-B is the best powered study to date to address this hypothesis and promises to improve our understanding of the safety and efficacy of intranasal oxytocin in the treatment of social deficits in children with ASD.
Epigenetic variability in the human oxytocin receptor (OXTR) gene: A possible pathway from early life experiences to psychopathologies
2019, Neuroscience and Biobehavioral Reviews
The human oxytocin (OXT) system is implicated in the regulation of complex social behaviors, as well as in psychopathologies characterized by social deficits. Emerging evidence suggests that variation in epigenetic regulation of the oxytocin receptor gene (OXTR) provides the oxytocin system with flexibility in response to environmental events, especially those occurring during early childhood. Changes in DNA methylation patterns of OXTR associated with these events may reflect biological alterations of social sensitivity. This is often related to an increased risk of developing mental disorders later in life. Here, we systematically reviewed all human studies (n = 30) discussing OXTR methylation in relation to socio-behavioral phenotypes. As such, we provide a complete and up-to-date overview of the literature that will aid future research in the interdisciplinary field of epigenetics and socio-behavioral sciences.
The oxytocin receptor gene polymorphism -rs237902- is associated with the severity of autism spectrum disorder: A pilot study
2018, Asian Journal of Psychiatry
Citation Excerpt :
Preliminary studies have investigated the relationship between the diagnosis of ASD and variations of OXTR SNPs. ( Francis et al., 2016; Jacob et al., 2007; Lerer et al., 2008; Liu et al., 2010; Tansey et al., 2010; Wermter et al., 2010; Wu et al., 2005). Despite the common findings of these studies, many have produced quite different data in different societies.
Previous studies showed the association of Autism Spectrum Disorder (ASD) and oxytocin receptor (OXTR) gene. We aimed to explore the OXTR gene single nucleotide polymorphisms (SNPs) across the ASD severity categories based on DSM-5.
The whole encoding regions of the human OXTR gene were sequenced to identify the SNPs in 100 Turkish children with ASD. Genotypes of detected SNPs were also compared with the Childhood Autism Rating Scale (CARS) scores.
Disease severity of the patients carrying GA and AA genotypes (GA/AA) of rs237902 were found more severe compared to those carrying GG genotype (χ² = 6.456, df = 2, p = .040). This finding was more powerful in boys (χ² = 9.288, df = 2, p = .010). Similarly, GA/AA genotypes of rs237902 were found associated with higher CARS scores in boys (U = 650.5, r = 0.24, p = .021).
Significant relationship between the ASD severity categories of DSM-5 and rs237902 was shown for the first time.
Oxytocin receptor and G-protein polymorphisms in patients with depression and separation anxiety
2017, Journal of Affective Disorders
Citation Excerpt :
Whether the in silico observed difference in p53 binding could account for patterns of altered OXTR expression in specific neuron populations represents a promising area for future research. Consistent with our hypothesis, additional SNPs located in intron 3 have been found to influence OXTR expression (Tansey et al., 2010; Dixon et al., 2007). Although the functionality of rs53576 remains unknown, there is evidence for its potential involvement in structural neural alterations in key oxytocinergic regions.
The impact of combined variants of Oxytocin Receptor (OXTR) and G protein β3 subunit genes was investigated in relation to retrospective reports of childhood as well as contemporary adult separation anxiety (SA), based on evidence of a β/γ dimer-mediated signaling for OXTR.
A case-control association study (225 healthy adults and 188 outpatients with depression) was performed to establish Risk-Combined Genotype (RCG) of the studied variants (OXTR rs53576 and the functional Gβ3 subunit rs5443). Current SA was evaluated by the ASA-27 and retrospective childhood symptoms by the SASI. GG genotype of OXTR rs53576 combined with T-carrier genotype of Gβ3 rs5443 represented the RCG.
Compared to non-RCG, those with RCG had significantly higher levels of childhood and adult SA. The RCG was significantly associated with childhood SA threshold score (OR=2.85, 90%CI: 1.08–7.50). Childhood SA was, in turn, strongly associated with a threshold SA score in adulthood (OR=15.58; 95% CI: 4.62–52.59).
Although the overall sample size is sizable, comparisons among subgroups with specific combination of alleles are based on relatively small numbers.
Our study indicates that variations in OXTR and Gβ3 genes are specifically associated with presence and severity of SA in childhood and adulthood, but not with depression or anxiety in general. Because there is increasing interest in oxytocin in social behavior, the gene-SA associations identified have potential translational and clinical relevance.

View all citing articles on Scopus

View full text

Oxytocin receptor (OXTR) does not play a major role in the aetiology of autism: Genetic and molecular studies

Abstract

Section snippets

Conflict of interest

Acknowledgements

Neurosci. Biobehav. Rev.

Physiol. Behav.

Behav. Brain Res.

Biol. Psychiatry

Cell

Biol. Psychiatry

Biol. Psychiatry

Neurosci. Lett.

Front. Neuroendocrinol.

Horm. Behav.

BMC Med. Genet.

Mol. Cell. Endocrinol.

Biol. Psychiatry

Am. J. Hum. Genet.

Trends Cogn. Sci.

Biol. Psychiatry

Biol. Psychiatry

Advances in autism genetics: on the threshold of a new neurobiology

Nat. Rev. Genet.