Association of RGS2 Gene Polymorphisms with Suicide and Increased RGS2 Immunoreactivity in the Postmortem Brain of Suicide Victims

Abstract

Regulators of G-protein signaling are a family of proteins that negatively regulate the intracellular signaling of G protein-coupled receptors, such as the serotonin receptor. Recent studies have suggested that one of these proteins, the regulator of G-protein signaling 2 (RGS2), plays an important part in anxiety and/or aggressive behavior. To explore the involvement of the RGS2 gene in the vulnerability to suicide, we screened Japanese suicide victims for sequence variations in the RGS2 gene and carried out an association study of RGS2 gene polymorphisms with suicide victims. In the eight identified polymorphisms that were identified by mutation screening, we genotyped four common single-nucleotide polymorphisms (SNPs) in the RGS2 gene, and found significant differences in the distribution of the SNP3 (C + 2971G, rs4606) genotypes and alleles of the SNP2 (C-395G, rs2746072) and the SNP3 between completed suicides and the controls. The distribution of the haplotype was also significantly different between the two groups (global po0.0001). Furthermore, RGS2 immunoreactivity significantly increased in the amygdala and the prefrontal cortex (Brodmann area 9 (BA9)) of the postmortem brain of the suicide subjects. These findings suggest that RGS2 is genetically involved in the biological susceptibility to suicide in the Japanese population.

Relationship between Rgs2 gene expression level and anxiety and depression-like behaviour in a mutant mouse model: serotonergic involvement

“…The minor (G) allele of one of these SNPs, rs4606, has been also associated with reduced expression of the RGS2 gene in human fibroblasts (Semplicini et al 2006). Cui et al (2008) showed an association between several RGS2 SNPs (among them the G allele of rs4606) and increased probability to commit suicide. Several studies conducted by the Gelernter group on victims of the 2004 Florida hurricanes (Amstadter et al 2009a, b ;Koenen et al 2009) showed associations between the C allele of rs4606 and increased chances of developing posttraumatic stress disorder symptomatology, generalized anxiety disorder and suicidal ideation.…”

Structural Determinants of G-protein α Subunit Selectivity by Regulator of G-protein Signaling 2 (RGS2)

“…9 and 10). RGS2/G0S8, one of the first mammalian RGS proteins identified (11) and member of the R4-subfamily (10), has a critical role in the maintenance of normostatic blood pressure both in mouse models (12, 13) and in humans (14, 15); additionally, Rgs2-deficient mice exhibit impaired aggression and increased anxiety (16, 17), behavioral phenotypes with potential human clinical correlates (18,19).Although many RGS proteins are promiscuous and thus act on multiple G␣ substrates in vitro (e.g. Ref.…”

Recent molecular genetic studies and methodological issues in suicide research

“…In addition to the previously mentioned genetic studies, recent findings have associated several genes with SB, including the angiotensin-converting enzyme (ACE) (Hishimoto et al, 2006;Fudalej et al, 2009;Sparks et al, 2009), the regulator of G-protein signaling 2 (Cui et al, 2008), the corticotropin-releasing hormone receptor-1 (Wasserman et al, 2008), apolipoprotein E (apoE) (Hwang Lethality in suicide attempts 20 suicide attempters 66Met allele was associated with high lethality in SB et al, 2006b), the spermine/spermidine N(1)-acetyltransferase gene (Sequeira et al, 2006), 14-3-3 epsilon (Yanagi et al, 2005), neuronal nitric oxide synthase (Cui et al, 2010), and cholecystokinin (Shindo and Yoshioka, 2005). Although three studies have reported the association between ACE and SB, two studies in the Japanese population found that the "I" allele of the ACE insertion/deletion (I/D) polymorphism is the risk allele for completed suicide (Hishimoto et al, 2006;Fudalej et al, 2009) while a study of Caucasians found that the DD genotype increased suicide (Sparks et al, 2009).…”