Elsevier

Psychoneuroendocrinology

Volume 34, Issue 10, November 2009, Pages 1506-1514
Psychoneuroendocrinology

Oxytocin receptor polymorphisms and adult attachment style in patients with depression

https://doi.org/10.1016/j.psyneuen.2009.05.006Get rights and content

Summary

Much evidence of an association between specific attachment styles and depression prompted us to investigate, in depressive disorders, the potential role of polymorphisms within the gene encoding the receptor of the main neurohormone involved in attachment processes, oxytocin. For this purpose, two single nucleotide polymorphisms (SNPs), 6930G>A (rs53576) and 9073G>A (rs2254298), within the oxytocin receptor gene (OXTR), were studied in a cohort of 185 patients with major depression (50.3%) or bipolar I or II disorders (49.7%) and 192 matched healthy controls. A positive association between the GG genotype of OXTR SNPs (6930G>A or 9073G>A) and unipolar depression was demonstrated. In this group, GG individuals showed high scores on Attachment Style Questionnaire factors that have been previously associated with depression. Moreover, the GG genotype was also associated with high levels of adult separation anxiety. These findings support the involvement of the oxytocinergic system in the mechanisms that underlie depression and specific adult attachment styles.

Introduction

Depressive episodes are thought to result from the interplay of multiple genes interacting with environmental factors (Swaab et al., 2005, Grippo et al., 2007).

Several authors have suggested the involvement of the neuropeptide oxytocin (OXT) in depression based on evaluation of its levels in plasmatic/cerebrospinal fluid and of OXT transcripts in post mortem tissues (Zetzsche et al., 1996, Purba et al., 1996, Van Londen et al., 1997, Bell et al., 2006, Scantamburlo et al., 2007, Cyranowski et al., 2008, Wang et al., 2008). The traditional view of OXT as an endocrine hormone acting on peripheral organs (i.e., to induce labor and milk ejection) has been revised such that this neuropeptide is now considered to be a neurotransmitter or neuromodulator with central actions in the limbic system, the forebrain and the autonomic centers of the brainstem. Oxytocin plays a role in a variety of central functions, such as sexual behavior, maternal behavior, affiliation, social memory, satiety and stress responsiveness. In particular, there is strong evidence concerning the involvement of OXT in attachment processes in animals (Insel, 1997, Insel, 1992) and, despite a limited amount of detailed experimental data, some evidence to support similar behavioral effects in humans as well (Carter, 1998, Uvnäs-Moberg, 1998, Donaldson and Young, 2008). In a number of clinical studies, an association between specific adult attachment styles and depression has been found (Carnelley et al., 1994, Murphy and Bates, 1997, Mickelson et al., 1997, Bifulco et al., 2002, Shaver et al., 2005). Specifically, attachment anxiety, which concerns apprehension over rejection and abandonment, has been associated with depression (Carnelley et al., 1994, Murphy and Bates, 1997, Mickelson et al., 1997, Bifulco et al., 2002, Shaver et al., 2005). Attachment anxiety represents one of the two primary dimensions involved in self-report measures of adult attachment style (Bartholomew and Horowitz, 1991, Brennan et al., 1998). The second dimension, attachment avoidance, concerns the degree to which a person feels uncomfortable depending on and being emotionally close to others. Hypothesized explanations for the association between attachment anxiety and depression include anxious peoples’ negative models of self (e.g., believing they are unlovable; Bartholomew and Horowitz, 1991), low self-esteem (Griffin and Bartholomew, 1994), self-criticism (Murphy and Bates, 1997) and dysfunctional attributions to partners’ behavior that increase the likelihood of separation anxiety (Collins, 1996). In contrast, people high in avoidance generally invest less in relationships, are less upset when they end and are relatively low in commitment and relationship satisfaction (Mikulincer and Shaver, 2007).

Genetic factors have been reported to play a role in the development of depression (aan het Rot et al., 2009, Martinowich et al., 2009) without any reference to attachment styles. Genetic studies on attachment styles have also been performed (Carlson, 1998, Donnellan et al., 2008). These data, despite providing information about the possible contribution of genes to adult attachment style, rarely reveal which genes are involved. To the best of our knowledge, only polymorphisms of the D2 and D4 dopamine receptor genes and the 5HT2A serotonin receptor gene have been associated with specific attachment styles (Van Ijzendoorn and Bakermans-Kranenburg, 2006, Gillath et al., 2008).

All these data together prompted us to focus in the present report on the OXT receptor (OXTR) gene as a possible candidate for genetic vulnerability to depression. For this aim, a comparison of genotype distributions of the two OXTR single nucleotide polymorphisms (SNPs), 6930G>A (rs53576) and 9073G>A (rs2254298), among patient groups with depression and healthy control group was performed. Moreover, associations between certain genotype groups and specific adult attachment styles were also investigated. To this end, we compared the scores on the five subscales of the Attachment Style Questionnaire among genotype groups.

Section snippets

Subjects and psychometric evaluation

For the study, 185 patients referred to the clinics of the Department of Psychiatry at the University of Pisa for treatment of a depressive episode were recruited. All subjects were assessed with the SCID-I (First et al., 2002) to establish a DSM-IV Axis-I diagnosis and psychiatric comorbidity. The Hamilton Depression Rating Scale (Hamilton, 1960) and the Young Mania Rating Scale (Young et al., 1978) were used to assess the severity of depression and mania, respectively. Anxiety was assessed by

Case–control associations

The demographic and clinical characteristics of the study sample are reported in Table 2.

The SNP identification numbers, the mapping positions, the region where the SNPs map and the observed allele frequencies are all shown in Table 3.

Genotype distributions and statistical analyses for the two studied SNPs within the OXTR gene are summarized in Table 4. All the statistical analyses were carried out using the dominant model. As shown in Table 4, the low number of rare homozygotes did not allow

Discussion

In this study, we examined OXT Receptor (OXTR) gene polymorphisms as possible candidates in genetic vulnerability to depression. The potential role of OXT in depression has been suggested by several studies. Zetzsche et al. (1996) have shown a significant reduction of plasma OXT in depressed patients compared to controls. In contrast, no significant difference has been found between mean plasma levels of OXT in depressed patients and controls by Van Londen et al. (1997); however, other authors (

Role of funding source

Funding for this study was provided by the Italian Ministry of University and Scientific Research (PRIN 2005: prot. 2005069159) and Fondazione IDEA (Institute for Research and Prevention of Depression and Anxiety). None of the organizations funding the research had any further role in study design, in data collection, in analysis or interpretation of the data, in writing of the report, or in the decision to submit the paper for publication.

Conflict of interest

All authors declare that they have no conflicts of interest and the manuscript has not been published elsewhere.

Acknowledgments

This work was supported by grants from the Italian Ministry of University and Scientific Research (PRIN 2005: prot. 2005069159) and Fondazione IDEA (Institute for Research and Prevention of Depression and Anxiety). A special acknowledgement is due to both patients and healthy individuals for donating their blood for the present study. We gratefully acknowledge Giulia Gray for her kind revision of English language.

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      With regards to OXTR/rs2254298, the debate on the role of vulnerability genes is still open. In fact, if on one side G/G genotype has been observed to be highly associated with separation anxiety and depression [56], on the other, females G/G homozygotes showed less attachment anxiety than A-carriers, while male G/G homozygotes exhibited less autism-associated traits than A-carriers [57]. The majority of studies consider A/A genotype as the one conferring the vulnerability to the environment when adopting the Differential Susceptibility Model [58, 59].

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    1

    B.C. and S.P. contributed equally as first authors to this manuscript.

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