Accumulating evidence suggests that certain abnormal
Accumulating evidence suggests that certain abnormal emotional traits, such as impulsive aggression and cluster B personality, are associated with suicidal behaviors (Currier and Mann, 2008, Mann et al., 2009, Rujescu et al., 2007, Turecki, 2005). Impulsive aggression appeared to be associated with familial loading of suicidal behaviors and increased risk of suicide among patients of the same psychiatric disorder (Dumais et al., 2005, Ernst et al., 2009, McGirr et al., 2009). Familial aggregation of suicidal behaviors seems to be partly explained by the transmission of impulsive aggressive behaviors and cluster B personality traits (Ernst et al., 2009, McGirr et al., 2009). Thus, genetic factors affecting such emotional traits could possibly be involved in suicidal behaviors as well.
Prostaglandin E2 (PGE2) receptor 1 (EP1, also called PTGER1) was recently shown to control impulsive and aggressive behaviors in mice under both social and environmental stresses (Matsuoka et al., 2005). Stresses can cause various characteristic responses including activation of the neuroendocrine and sympathetic nervous systems, and emotional responses, such as fear and aggression. The impulsive aggression seen in EP1-deficient mice was mainly due to overstimulated dopaminergic activity in the prefrontal RN 1734 and striatum (Furuyashiki and Narumiya, 2009, Matsuoka et al., 2005). This is consistent with previous observations that PGE2 receptor pathway might directly affect the activity of the dopaminergic system (Carasco et al., 2007, Kitaoka et al., 2007). The dopaminergic system has been associated with various psychiatric disorders including suicide and various endophenotypes related to suicide (Carballo et al., 2008; Suda et al., 2009). Taken together, these findings raise the possibility that EP1 receptor signaling is involved in the pathogenesis of suicide through abnormal impulsive and aggressive behavioral responses to various harmful stresses.
Materials and methods
Results No significant difference in either genotypic distribution or allelic frequency between the control and completed suicide groups were observed for any of the SNPs tested. Gender based analysis revealed that both genotypic distribution and allelic frequency of rs3810255 (p=0.025 and 0.035, respectively), rs3810254 (p=0.028 and 0.034, respectively), rs3810253 (p=0.037 and 0.031, respectively), and rs10416814 (p=0.031 and 0.026, respectively) were significantly different between the female control and female suicide completers. These differences did not withstand correction for multiple comparisons (Table 1). The distribution of all five SNPs examined was in HWE for both the control and suicide groups. Four SNPs (rs3810255, rs3810254, rs3810253 and rs10416814) were in tight LD with each other (D′>0.98, data not shown). Haplotype analyses revealed no significant differences between the control and completed suicide groups (data not shown). Frequencies of AAGT haplotype of the four SNPs were also nominally significantly different between the female controls (0.679) and female suicide completers (0.578) (p=0.019 and corrected p=0.083). Analyses of the subgroup that used violent suicide methods revealed similar results (data not shown).
Discussion The genetic predisposition to suicide has been extensively studied. Because central serotonergic disruption is consistently found in suicide completers, some genetic studies have linked genetic variants in the serotonergic system to suicide (Bondy et al., 2006, Currier and Mann, 2008). However, these reports are inconsistent with our previous studies which did not find a clear association of the serotonergic system with suicide in the Japanese population (Mouri et al., 2009, Nishiguchi et al., 2001, Nishiguchi et al., 2002, Okamura et al., 2005, Ono et al., 2000, Ono et al., 2001). On the other hand, we were recently able to show that genetic variants in multiple non-serotonergic pathways are associated with suicide, including RGS2 (Cui et al., 2008) and NOS1 (Cui et al., 2010), which have previously been reported to be associated with aggressive behaviors and anxiety in mice (Chiavegatto et al., 2001, Demas et al., 1999, Nelson et al., 1995, Oliveira-Dos-Santos et al., 2000, Tanda et al., 2009).