Depression in suicidal males: Genetic risk variants in the CRHR1 gene

Department of Public Health Sciences, The National Prevention of Suicide and Mental Ill-Health (NASP), Karolinska Institute, Stockholm, Sweden.
Genes Brain and Behavior (Impact Factor: 3.66). 03/2009; 8(1):72-9. DOI: 10.1111/j.1601-183X.2008.00446.x
Source: PubMed


Dysregulation in the stress response of the hypothalamic-pituitary-adrenal axis, involving the corticotrophin-releasing hormone and its main receptor (CRHR1), is considered to play a major role in depression and suicidal behavior. To comprehensively map the genetic variation in CRHR1 in relation to suicidality and depression, as a follow-up to our initial report on SNP rs4792887, we analyzed six new single nucleotide polymorphisms (SNPs), in an extended sample of family trios (n = 672) with suicide attempter offspring, by using family-based association tests. The minor T-allele of exonic SNP rs12936511, not previously studied in the context of psychiatric disorders and suicidal behaviors, was significantly transmitted to suicidal males with increased Beck Depression Inventory (BDI) scores (n = 347; P = 0.0028). We found additional evidence of association and linkage with increased BDI scores among suicidal males with an additional SNP, located proximally to the index SNP rs4792887, as well as with two distal SNPs, which were correlated with index SNP rs4792887. Analysis of haplotypes showed that each of the risk alleles segregated onto three separate haplotypes, whereas a fourth 'nonrisk' haplotype ('CGC') contained none of the risk alleles and was preferentially transmitted to suicidal males with lowered BDI scores (P = 0.0007). The BDI scores among all suicidal males, who carried a homozygous combination of any of the three risk haplotypes (non-CGC/non-CGC; n = 160), were significantly increased (P = 0.000089) compared with suicidal male CGC carriers (n = 181). Thus, while the characteristics of the suicide female attempters remained undetermined, the male suicidal offspring had increased depression intensity related to main genetic effects by exonic SNP rs12936511 and homozygous non-CGC haplotypes.

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Available from: Vsevolod Rozanov
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    • "In this study, we did not find association between polymorphisms of CRHR1 gene and suicidal patients although Wasserman et al. identified a CRHR1 SNP that showed an association in the suicide attempters exposed to low-medium stress and a relationship between neurotic personality traits and suicidality. The genetic variation in the TBX19 gene (a regulator of the HPA axis) was observed by Wasserman et al. [24, 25]. In suicidal males, they found an association between the T and A alleles of SNPs rs4792287 and rs110402 and the T allele of rs12936511 of the CRHR1 gene. "
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    ABSTRACT: Family twin and adoption studies have noted the heritability of specific biological factors that influence suicidal behaviour. Exposure to stress is one of the factors that strongly contribute to suicide attempts. The biological response to stress involves the hypothalamic-pituitary-adrenal axis (HPA). Therefore, we found it interesting to study polymorphisms of genes involved in the HPA axis (CRHR1, NR3C1, and AVPBR1). The study was performed on 597 patients, 225 of whom had a history of suicide attempts. We did not observe any significant differences in the studied polymorphisms between the group of patients with a history of suicide attempts and the control subjects. Our haplotype analysis of the AVPR1b gene revealed an association between the GCA haplotype and suicide attempts; however, this association was not significant after correcting for multiple testing. We did not observe any other association in haplotype and MDR analysis. We report here a comprehensive analysis of the HPA axis genes and a lack of association for genetic variations regarding the risk of suicide attempts in affective disorder patients. Nonetheless, the inconsistencies with the previously published results indicate the importance of the further investigation of these polymorphisms with respect to the risk of suicide attempts.
    Full-text · Article · Nov 2013 · The Scientific World Journal
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    • "Tagging SNPs for the CRHR1 gene, rs1876831 and rs242938, were selected from the literature, based on detailed linkage disequilibrium information of CRHR1 SNPs from several publications (e.g. Treutlein et al. 2006 ; Wassermann et al. 2009 ; "
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    ABSTRACT: BACKGROUND: Enhanced acquisition and delayed extinction of fear conditioning are viewed as major determinants of anxiety disorders, which are often characterized by a dysfunctional hypothalamic-pituitary-adrenal (HPA) axis.Method In this study we employed cued fear conditioning in two independent samples of healthy subjects (sample 1: n=60, sample 2: n=52). Two graphical shapes served as conditioned stimuli and painful electrical stimulation as the unconditioned stimulus. In addition, guided by findings from published animal studies on HPA axis-related genes in fear conditioning, we examined variants of the glucocorticoid receptor and corticotropin-releasing hormone receptor 1 genes. RESULTS: Variation in these genes showed enhanced amygdala activation during the acquisition and reduced prefrontal activation during the extinction of fear as well as altered amygdala-prefrontal connectivity. CONCLUSIONS: This is the first demonstration of the involvement of genes related to the HPA axis in human fear conditioning.
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    • "This study expanded on our previous studies that described one G×E among depressed SA males (confirmed here as G×E #2; Wasserman et al. 2008, 2009), now further identifying two novel G×Es (#1 and #3) between two distinct SNPs and PA with different life timing in females and males, respectively (Fig. 2 and Figs S1 and S3). These two novel G×Es shared the characteristic of aggression, but showed differences on other aspects of SA heterogeneity (Figs S2 and S3). "
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    ABSTRACT: Risk factors for suicidal behaviors are partly heritable, including genetic variants that drive diathesis-stress in addition to, or by interaction with, exposure to certain stressful life events (SLEs). Hypothalamic-pituitary-adrenal (HPA) axis regulatory genes are candidates for association with suicide as well as its endophenotypes. Using a family-based design of offspring who attempted suicide (SA) and both parents, we investigated gene-environment interactions (G×Es) of SLE exposures with single nucleotide polymorphisms (SNPs) in corticotropin-releasing hormone receptor-1 (CRHR1), a major HPA axis regulatory gene. We observed a novel G×E among predominantly female SA between 5'-SNP rs7209436 and childhood/adolescence physical assault or attack (PA), as well as a second novel and male-specific G×E between 3'-SNP rs16940665 and adulthood PA exposure. A third male-specific G×E previously reported by us among depressed SA, between SNP rs4792887 and cumulative SLEs, was also further confirmed. The two novel G×Es presented here shared the SA characteristic of aggression, while showing differences on other aspects of SA heterogeneity. We conclude that different SA subjects were observed to differentially associate with two novel G×Es involving exposures to PA with different life timing and SNPs located in opposite ends of CRHR1. Concerning sex differences, we observed three subsets of distinct male SA that associated with each of the three observed G×Es, whereas female SAs were affected by only one of the G×Es. These results are consistent with a diathesis-stress model of suicidal behavior and may help to explain SA heterogeneity.
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