Abstract
Low GABA transmission has been reported in suicide, and GABRA6 rs3219151 T allele has been associated with greater physiological and endocrine stress response in previous studies. Although environmental stress also plays a role in suicide, the possible role of this allele has not been investigated in this respect. In our present study effect of rs3219151 of GABRA6 gene in interaction with recent negative life events on lifetime and current depression, current anxiety, as well as lifetime suicide were investigated using regression models in a white European general sample of 2283 subjects. Post hoc measures for phenotypes related to suicide risk were also tested for association with rs3219151 in interaction with environmental stress. No main effect of the GABRA6 rs3219151 was detected, but in those exposed to recent negative life events GABRA6 T allele increased current anxiety and depression as well as specific elements of suicide risk including suicidal and death-related thoughts, hopelessness, restlessness and agitation, insomnia and impulsiveness as measured by the STOP task. Our data indicate that stress-associated suicide risk is elevated in carriers of the GABRA6 rs3219151 T allele with several independent markers and predictors of suicidal behaviours converging to this increased risk.
Highlights
Every year suicide accounts for one million deaths worldwide, amounting to one every 40 seconds, a mortality rate of 16/100,0001
The Manchester cohort reported a higher level of recent negative life events (RLE)
An average of 27% increase in Brief Symptom Inventory (BSI)-DEP and BSI-ANX was found in individuals with CC genotype compared to an average 114% with TT genotype when high and mild (0–1) Recent negative life events (RLE) groups were compared (Figs 1 and 2). This means that the effect of high RLE score on either BSI-DEP or BSI-ANX was in average 4 times higher in TT compared to CC genotype individuals
Summary
Every year suicide accounts for one million deaths worldwide (nearly 2% of all deaths), amounting to one every 40 seconds, a mortality rate of 16/100,0001. As the major inhibitory neurotransmitter in humans, GABA plays an important role in downregulating HPA-axis in response to acute stress as demonstrated by the strong inhibitory effect of alprazolam on HPA-axis www.nature.com/scientificreports/. Rs3219151 in GABRA6 appears to have a modulatory effect on HPA-axis activity as demonstrated by an association between the T allele and higher plasma cortisol levels both at rest[13] and when stimulated during the Trier Social Stress Test[14] suggesting this allele may increase the stress response. Gene expression studies in post mortem brain strongly implicating abnormal GABA function[16,17] led us to explore phenotypes for suicide risk markers associated with this variant. In the present study we carried out exploratory analyses of association of GABRA6 rs3219151 with symptomatic and pathogenic risk factors of suicide in interaction with recent stressors in a large European nonpsychiatric population
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