Relationship of a common OXTR gene variant to brain structure and default mode network function in healthy humans

Abstract

A large body of research suggests that oxytocin receptor (OXTR) gene polymorphisms may influence both social behaviors and psychiatric conditions related to social deficits, such as autism spectrum disorders (ASDs), schizophrenia, and mood and anxiety disorders. However, the neural mechanism underlying these associations is still unclear. Relative to controls, patients with these psychiatric conditions show differences in brain structure, and in resting state fMRI (rs-fMRI) signal synchronicity among default mode network (DMN) regions (also known as functional connectivity). We used a stepwise imaging genetics approach in 328 healthy young adults to test the hypothesis that 10 SNPs in OXTR are associated with differences in DMN synchronicity and structure of some of the associated brain regions. As OXTR effects may be sex-dependent, we also tested whether our findings were modulated by sex. OXTR rs2254298 A allele carriers had significantly lower rsFC with PCC in a cluster extending from the right fronto-insular cortex to the putamen and globus pallidus, and in bilateral dorsal anterior cingulate cortex (dACC) compared to individuals with the GG genotype; all observed effects were found only in males. Moreover, compared to the male individuals with GG genotype ofrs2254298, the male A allele carriers demonstrated significantly thinner cortical gray matter in the bilateral dACC. Our findings suggest that there may be sexually dimorphic mechanisms by which a naturally occurring variation of the OXTR gene may influence brain structure and function in DMN-related regions implicated in neuropsychiatric disorders.

Musculoskeletal Pain and Brain Morphology: Oxytocin’s Potential as a Treatment for Chronic Pain in Aging

“…Additionally, the OXTR rs2254298 A-allele genotype was positively associated with amygdala volume in Japanese adults (Inoue et al, 2010). Adult GG homozygote men, compared to A-allele carriers, showed thinner cortical gray matter in the dorsal anterior cingulate (Wang et al, 2017). However, there is evidence that adolescent girls with homozygous G alleles had greater overall gray matter and dorsomedial anterior cingulate volume but smaller amygdala and brainstem volumes than A-allele carriers (Furman et al, 2011).…”

Genetics and epigenetics of autism: A Review

“…The participants were imaged with fMRI, which showed differences in their default mode network synchronicity and structure of some of the associated brain regions that are implicated in the neuropsychiatric disorder of autism and ASD. 95 • OXTR risk-allele association evidence: Similarly, results of 41 children with ASD and 41 control children were studied and a OXTR risk-allele dosage association with symptom severity was found, which is also related to the corresponding connectivity of the nucleus accumbens (a hub of the reward network in the brain) with the frontal brain regions involved in mentalizing (an observation that is related to scores on a standardized measure of social function). 96 • Evidence combining machine-learning/OXTR SNP/oxytocin intervention: Using a machinelearning algorithm designed to evaluate collective effects of multiple SNP and automatically identify most informative SNP, 27 representative OXTR SNP and six types of behavioral/neural responses to oxytocin in ASD individuals were found after extracting results from a previous placebocontrolled clinical trial of intranasal oxytocin to 38 high-function adult Japanese men with ASD.…”

“…The involvement of the OXTR gene in human autism has also been demonstrated in several studies: Brain imaging evidence for OXTR: A neuroimaging/genetics study involved 327 healthy young adults with differences in 10 SNP of the OXTR. The participants were imaged with fMRI, which showed differences in their default mode network synchronicity and structure of some of the associated brain regions that are implicated in the neuropsychiatric disorder of autism and ASD OXTR risk‐allele association evidence: Similarly, results of 41 children with ASD and 41 control children were studied and a OXTR risk‐allele dosage association with symptom severity was found, which is also related to the corresponding connectivity of the nucleus accumbens (a hub of the reward network in the brain) with the frontal brain regions involved in mentalizing (an observation that is related to scores on a standardized measure of social function) …”

The Social (Neural) Network: Towards a Unifying Endophenotype Between Genes and Behavior

“…Consequently, a critical mediator of oxytocinergic action in the brain is the oxytocin receptor gene (OXTR; hg38, chr3: 8,750,409-8,769,614). Broadlyspeaking, genetic variants in OXTR (single nucleotide polymorphisms, SNPs; and copy number variants, CNVs) have been linked to differences in brain structure [55][56][57] , function 50,[57][58][59][60][61] , and may also provide an etiological basis for autism spectrum disorders (ASD) [62][63][64][65][66][67] . Frustrated efforts to replicate these associations [68][69][70] …”

“…More specifically, we sought to identify potential molecular mechanisms that might guide or support differences in network function, ultimately translating into variation in behavior. While there is rising interest in the genetic and epigenetic bases of network connectivity 61,100,[138][139][140][141][142] , these factors remain poorly understood-especially given that many studies still turn to genetic polymorphisms that are merely associative, lacking clearly-defined functions. A major strength of our approach was our focus on epigenetic modifications to the oxytocin receptor gene-a molecular variable with known functional consequences, both in terms of gene transcription 72 (thereby regulating endogenous access to oxytocin) and social behavioral phenotypes 63 .…”