Genetic association of the oxytocin receptor genes with panic, major depressive disorder, and social anxiety disorder.

Oxytocin (OXT) is secreted into the brain through the pituitary gland. It stimulates neurons expressing oxytocin receptors (OXTR) and controls multiple physiologic and reproductive functions. OXT plays a role in the modification of stress response and stress-related behaviors (Arletti and Bertolini, 1987). OXT also plays an important role in anxiety and social interaction. Serum OXT level is related to parent–child bonding behavior, romantic feelings, and trust (Feldman et al., 2007). The individuals with the A allele (AG/AA) showed lower empathy and higher stress reactivity compared with the individuals who were homozygous for the G allele (GG) in humans (Rodrigues et al., 2009). The girls who both were heterozygous for the OXTR rs2254298 polymorphism and had high early adversity reported the highest levels of symptoms of depression, physical anxiety, and social anxiety (Thompson et al., 2011). The objective of this study was to investigate the relationship between polymorphisms of OXTR rs2254298 and rs53576 and panic disorder, social anxiety disorder, and major depressive disorder risk through a case–control study of 1257 Japanese participants. The patient and the control group comprised 643 controls and 210 panic disorder, 117 social anxiety disorder, 287 major depressive disorder patients diagnosed according to the criteria of Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text revision (DSM-IV-TR) (the MiniInternational Neuropsychiatric Interview). This study was approved by the Ethics Committee for Genome Research of the Oita University Faculty of Medicine. All participants provided written informed consent. The proportion of AA, AG, and GG of rs2254298 in panic disorder, social anxiety disorder, and major depressive disorder healthy individuals was 8.7, 30.1, 61.2%; 14.5, 38.5, 47.0%; 15.4, 39.0, 45.6%; and 11.3, 39.8, 48.9%, respectively. The proportion of AA, AG, and GG of rs53576 was 41.3, 44.6, 14.1%; 43.6, 42.7, 13.7%; 42.0, 51.4, 6.6%; and 43.5, 48.0, 8.5%, respectively. The frequencies of the genotypes did not fit the Hardy– Weinberg equilibrium. The presence of the AA+AG genotype of rs2254298 in panic disorder had a protective effect compared with the GG genotype [odds ratio (OR)=1.6 (1.2–2.3), P=0.002]. The presence of the AA+AG genotype of rs53576 in panic disorder had a protective effect compared with the GG genotype [OR=1.8 (1.1–2.8), P=0.02]. The presence of the AA+AG genotype of rs53576 was associated with increased major depressive disorder risk compared with the GG genotype [OR=0.3 (0.2–0.4), P<0.0001]. However, there was no association between rs2254298 and major depressive disorder [OR=0.9 (0.7–1.2), P=0.36]. There was no association between OXTR rs2254298 and rs53576, and social anxiety disorder [OR=0.9 (0.6–1.4), P=0.71; OR=0.8 (0.4–1.3), P=0.34]. Some reports showed that there was a positive association between the GG genotype of OXTR rs53576 and major depressive disorder (Costa et al., 2009). However, there are no reports on the association between OXTR genotype and social anxiety disorder. Some reports showed that there was a significant relationship between OXTR and panic disorder (Johnson et al., 2010). Our data suggest that G carriers of the OXTR thus might have been more vulnerable to panic and major depressive disorder.