Oxytocin receptor gene polymorphisms exert a modulating effect on the onset age in patients with obsessive-compulsive disorder

Highlights

• The oxytocin receptor (OXTR) plays an important role in human cognition and emotion.

• We investigated the association between common SNPs of the OXTR gene and OCD.

• Several SNPs of the OXTR gene were associated with late-onset OCD.

• The oxytocin system may be involved in the modulation of OCD onset.

Abstract

The oxytocin receptor (OXTR) is a potential candidate in the pathophysiology of obsessive-compulsive disorder (OCD). The present study investigated the association between common single-nucleotide polymorphism (SNPs) of the OXTR gene and the affected status of OCD or distinct clinical subtypes of OCD including the age at onset and symptom dimensions. Ten SNPs of OXTR were examined in 615 patients with OCD and 581 healthy controls. Single-marker and haplotype-based association analyses were conducted. While OXTR variants were not associated with the affected status of OCD or its clinical symptom dimensions, rs2268493 (p = 0.00185) and rs13316193 (p = 0.00461) of the OXTR gene were associated with the age at onset in patients with OCD. In addition, in haplotype-based association analyses, there was a significant association between the OXTR gene and the onset age in patients with OCD. In particular, the G-C-G haplotype of rs2268493-rs2254298-rs11316193 and the T-G-A haplotype of rs237887-rs2268490-rs4686301 were positively associated with late-onset OCD. Our results suggest that common variants of OXTR may exert a modulating effect on the onset age in OCD pathophysiology. The potential involvement of the oxytocin system in the development and expression of OCD warrants further longitudinal research.

Introduction

Obsessive-compulsive disorder (OCD) is a common and debilitating mental disorder characterised by maladaptive patterns of repetitive, inflexible thoughts and behaviours that cause severe distress and interfere with interpersonal functioning. Cognitive perspectives on OCD propose that the lack of cognitive flexibility is a key feature of OCD (Gruner and Pittenger, 2017). Psycho-dynamically, isolation of affect is a core defence of OCD, which allows patients to control intolerable emotions and aggression by disconnecting affective elements from thoughts or situations (Barth, 1990, Fenichel, 1945). However, the mechanisms underlying these cognitive and socio-emotional characteristics of OCD remain unclear.

It is well known that neurotransmitters such as serotonin and dopamine play major roles in the pathophysiology of OCD. However, beyond the serotonin and dopamine systems, increasing evidence suggests that the neuropeptides oxytocin and arginine vasopressin are also important in the pathophysiology of OCD (McDougle et al., 1999). Oxytocin and arginine vasopressin are known to have neuromodulatory effects on brain function and are thought to be involved in cognitive and socio-emotional development (Bachner-Melman and Ebstein, 2014, Carter, 2003, Neumann, 2008). In particular, the oxytocin system is also reported to interact anatomically and functionally with the serotonin and dopamine systems (Baskerville and Douglas, 2010, Dolen et al., 2013, Lefevre et al., 2017). Growing evidence shows that coordinated actions of oxytocin and serotonin in the nucleus accumbens affect social rewards (Dolen et al., 2013), and interactions of oxytocin and dopamine partially mediate social behaviors via their integrated brain circuits (Baskerville and Douglas, 2010). A recent study in non-human primates showed that oxytocin administration influences serotoninergic neurotransmission by provoking 5-HT release and availability of 5-HT_1AR receptors in limbic regions (Lefevre et al., 2017). In addition, there is supporting evidence implicating the involvement of oxytocin in OCD. In animal studies, oxytocin has been shown to exaggerate grooming behaviours, which is considered an experimental model of compulsion (Marroni et al., 2007, Van Wimersma Greidanus et al., 1990). Human studies also support that oxytocin may play a crucial role in OCD. For example, the cerebrospinal fluid oxytocin level was higher in adults with non-tic-related OCD and was correlated with symptom severity of OCD (Leckman et al., 1994). Similarly, another study showed that the plasma oxytocin level was higher in patients with OCD than it was in healthy controls (Marazziti et al., 2015). In addition, the baseline oxytocin level was reportedly negatively correlated with the age at onset in patients with OCD (Humble et al., 2013). Although the therapeutic effects of oxytocin on OC symptoms remain controversial (den Boer and Westenberg, 1992, Epperson et al., 1996), one study reported improvements in OC symptoms after treatment with intranasal oxytocin (Ansseau et al., 1987). Collectively, these findings suggest that the oxytocin system may be involved in the aetiology and expression of OCD.

Since the actions of oxytocin are transduced via oxytocin receptors (OXTR), OXTR is an attractive candidate gene for OCD. OXTRs are present in certain brain areas including the cortex, limbic system, basal ganglia, thalamus, and hypothalamus, which are all areas that have been implicated in the aetiology of OCD (Rasmussen et al., 2013). Additionally, a number of genetic studies on the OXTR gene have been conducted to determine its role on human sociality and various social psychopathologies (Feldman et al., 2016). In particular, several OXTR gene variants are considered to be associated with autism spectrum disorder (ASD) (LoParo and Waldman, 2015). Furthermore, clinical trials of ASD have shown that OXTR gene variants may contribute to the differential treatment responses that have been observed following oxytocin administration in patients with autism (Kosaka et al., 2016, Watanabe et al., 2017). However, few genetic studies have investigated the influence of OXTR on OCD. To the best of our knowledge, only one epigenetic study has reported an association between the OXTR gene and OCD (Cappi et al., 2016).

Therefore, the aim of the present study was to investigate the association between common SNPs of the OXTR gene and OCD. Because OCD is a heterogeneous condition (Miguel et al., 2005), we also stratified patients with OCD into more homogeneous subtypes according to the age at onset and OC symptom dimensions.