Variant in oxytocin receptor gene is associated with amygdala volume

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Summary

The oxytocin system plays a significant role in modulating stress responses in animals and humans; perturbations in this system may contribute to the pathogenesis of psychiatric disorder. Attempts to identify clinically relevant genetic variants in the oxytocin system have yielded associations between polymorphisms of the oxytocin receptor (OXTR) gene and both autism and major depression. To date, however, little is known about how such variants affect brain structures implicated in these disorders. Applying a manual tracing procedure to high-resolution structural magnetic resonance images, amygdala volumes were measured in 51 girls genotyped on OXTR rs2254298(G>A), a single nucleotide polymorphism associated with psychopathology. Results of this study indicate that despite having greater gray matter volume, participants homozygous for the G allele were characterized by smaller volumes of both left and right amygdala than were carriers of the A allele. A subsequent whole-brain voxel-based morphometry analysis revealed additional genotype-mediated volumetric group differences in the posterior brain stem and dorsomedial anterior cingulate cortex. These findings highlight one neurobiological pathway by which oxytocin gene variants may increase risk for psychopathology. Further research is needed to characterize the mechanism by which this polymorphism contributes to anatomical variability and to identify functional correlates of these alterations in regional brain volume.

Introduction

The neuropeptide oxytocin has received considerable attention for its role in modulating stress reactivity and emotionality. The oxytocin system regulates hypothalamic–pituitary–adrenal (HPA) axis functioning. Research with rodents, for example, indicates that oxytocin buffers both the behavioral and corticosteroid responses to acute stress (e.g., Windle et al., 1997). In humans, oxytocin is posited to blunt stress reactivity by decreasing the amount of adrenocorticotrophin (ACTH) released in response to corticotrophin releasing hormone (CRH; Page et al., 1990), thereby diminishing cortisol secretion. In addition, brain oxytocin may directly modulate neural dynamics within the amygdala, a site of high oxytocin receptor concentration (Veinante and Freund-Mercier, 1997). Ebner et al. (2004) demonstrated that levels of oxytocin are increased in the rat amygdala under conditions of emotional and physical stress. Upon release, oxytocin is posited to bind to functional receptors within the central nucleus, enhancing GABAergic transmission and leading to the inhibition of amygdalar output to the hypothalamus and brainstem (Huber et al., 2005), regions critical to the generation of stress and fear responses. Indeed, several functional neuroimaging studies with humans have now demonstrated modulation of amygdala reactivity in vivo. Specifically, intranasal administration of oxytocin has been shown to attenuate ordinarily robust amygdala responses to emotional faces and threatening scenes (e.g., Kirsch et al., 2005). Moreover, consistent with the formulation that oxytocin mediates decreases in amygdalar output to brainstem regions, Kirsch et al. (2005) demonstrated that the observed reduction in amygdala reactivity was accompanied by a corresponding decrease in the functional coupling of the amygdala and the brainstem.

Considered collectively, these findings raise the possibility that variations or perturbations within the oxytocin system are involved in the pathogenesis of psychopathology. In fact, there is increasing interest in identifying variants in the genes that code for oxytocin and its receptor, particularly in the context of elucidating heritable risk factors for psychiatric disorders. Among the single nucleotide polymorphisms (SNPs) that have been associated with autism, the G-allele of the rs2254298 polymorphism of the oxytocin receptor [OXTR] gene (located on chromosome 3p25.3) appears to be overtransmitted in certain autistic populations (Jacob et al., 2007) and central to several haplotypes associated with risk for autism (Lerer et al., 2007). Moreover, Costa et al. (2009) have documented an increased frequency of the G allele in individuals diagnosed with unipolar depression.

Given the neuromodulatory functions of oxytocin in the amygdala and the associations between SNPs of the OXTR gene and autism and depression, it is noteworthy that abnormal amygdala structure has been implicated in the pathophysiology of both of these disorders. For example, in a recent meta-analysis, Hamilton et al. (2008) concluded that unmedicated major depression is consistently associated with decreased amygdala volume; several investigators have also reported decreased amygdala volume in adolescents and adults with autism (e.g., Nacewicz et al., 2006). Nacewicz et al. (2006) further describe an association between smaller amygdala volume and social impairment in autistic individuals, supporting the hypothesis that variation in amygdala volume has significant behavioral correlates, if not consequences.

Although researchers are beginning to elucidate the nature of the interaction of oxytocin and amygdala function, we know little about how genetic variation in the oxytocin system may affect amygdala structure. Given the role of oxytocin in diminishing levels of corticosteroids, which with chronic exposure may lead to atrophy of amygdala dendrites (Mitra and Sapolsky, 2008), oxytocin receptor gene polymorphisms may affect amygdala volume beginning at a relatively young age. The present study was designed to explore this formulation. We recruited a healthy adolescent sample, one likely to exhibit the structural brain phenotypes consistent with risk for psychopathology without having yet experienced the onset of a disorder. Because amygdala volume has been shown to increase throughout adolescence in males but to remain stable in females (Giedd et al., 1996), we restricted our sample to young females. Using a manual tracing procedure, we examined the influence of the (G>A) polymorphism on amygdala volume in this sample. Given that the OXTR rs2254298 G allele has been associated with disorders characterized by decreased amygdala volumes, and that diminished oxytocin system activity may adversely affect amygdala neurons by altering levels of circulating corticosteroids, we hypothesized that participants who carry two copies of the G allele would have smaller amygdalae than would A-allele carriers. In addition, we conducted voxel-based morphometry (VBM) to explore whether the OXTR rs2254298 genotype affects the volume of other regions of the brain that have been found to be associated with stress, fear, and anxiety.

Section snippets

Sample

Participants were 51 girls between the ages of 10 and 15, recruited with their mothers through advertisements in the local community as part of a larger study on the intergenerational transmission of psychopathology. Given potential interactions between gonadal steroid hormones and oxytocin actions, we obtained self-reports of menarcheal status from the girls. All participants gave informed assent in accordance with the Stanford University Institutional Review Board.

Assessment of psychopathology

Initial telephone interviews

Participant characteristics

Participant characteristics are presented in Table 1. The sample did not contain any participants with the A/A genotype. Genotype frequencies were in Hardy–Weinberg equilibrium, χ2(2) = 1.76, p > 0.05. There were no differences between the two genotype groups in either age (t[49] = .165) or CDI-S scores (t[49] = .972), both ps > 0.05. Seven participants did not provide data on menarcheal status; the data for the remaining participants yielded no significant group difference (χ2[1] = .39).

White and gray matter volume

The two groups did

Discussion

This study provides the first evidence of a neuroanatomical correlate of an oxytocin receptor polymorphism. Using a manual tracing technique, we documented a reduction in total amygdala volume, despite greater overall gray matter volume, in healthy female OXTR rs2254298 G-allele homozygotes relative to G/A heterozygotes. Notably, decreased amygdala volume has also been found to be associated with both unipolar (e.g., Hamilton et al., 2008) and bipolar (e.g., Kalmar et al., 2009) depression, as

Role of funding source

This research was supported by grants from the National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD) and the National Institute of Mental Health (MH74849) to IHG; funding sources had no further role in the design of the study or in the collection, analysis or interpretation of data.

Contributors

DJF and IHG designed the study, and DJF and MCC conducted the statistical analyses. DJF wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript.

Conflict of interest

The authors report no conflicts of interest.

Acknowledgments

The authors thank Yamanda Wright, Caity Monroe, and Rebecca Johnson for their help in interviewing and scanning participants and preparing data for analysis, and Joachim Hallmayer for processing the genetic data.

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