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Suicide is a leading cause of death in young people worldwide. Risk factors for suicidal behaviors and endophenotypes are partly heritable, and include variants in genes that drive stress diathesis in addition to, or by interaction with, certain adverse environments. Hypothalamic-Pituitary-Adrenal (HPA) axis genes are candidates for association with the dysregulated cortisol response to psychosocial stress that is observed in suicidal individuals. The role of HPA axis genetic variation will be explored in the context of varying “susceptibility” to suicidality after exposure to certain stressful life events.
A family-based association test was used on a case offspring-parent “trio” sample of 672 suicide attempt cases and their parents. Single nucleotide polymorphisms (SNP's) and/or haplotypes in CRHR1 were studied for interaction with age of exposure to physical and/or sexual assault, gender, and/or lifetime exposure to other types of stressful events.
Preliminary findings show interactions of certain CRHR1 SNP's with sexual and/or physical assault that are associated with suicide attempt, possibly using a violent method. Possible associations with candidate endophenotypes such as Cluster B personalities and early-onset major depression are under investigation.
Interactions of HPA axis genetic variants and stressful life events are consistent with a stress diathesis model of suicidal behavior, and may additionally influence the method and medical damage outcomes of suicide attempts, which may explain part of the diversity within this phenotype.
While suicidal behavior is frequently accompanied by serotonergic system alterations, specific associations with variants of the serotonin 2A receptor gene (HTR2A) have been inconsistent.
To confirm and extend previous associations of HTR2A with suicidal behavior.
To study genetic effects, as well as gene-environment interaction (GxE) and parent-of-origin effects (POE) that may further contribute to association.
Using a family-based study design of 660 offspring who have made a suicide attempt (SA) and both parents, we conducted an association and linkage analysis of single nucleotide polymorphisms (SNPs) with extensive gene coverage. We included the study of GxE with physical and sexual assault (with a cutoff age of 18 years), as well as cumulative types of stressful life events (lifetime SLEs). We also studied POE at SNP rs6313.
The main finding was a GxE between rs6313 and exposure to lifetime SLEs in the total sample, driven by overtransmission of CT and undertransmission of TT. Further exploratory analysis revealed a significant POE in this GxE in females which followed a polar overdominant imprinting pattern. In addition, several nominally significant findings were observed with other SNPs, many of which had previously reported and/or hypothesized functional effects.
This study found multiple associations of HTR2A with SA, and strongest statistical evidence for a GxE involving rs6313. It further suggested the importance of taking into account different genetic models of inheritance and GxEs with regard to HTR2A.
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