Bojorquez 1

Jesus Bojorquez
Independent Research
ID
In the article published on Scientific Reports of www.nature.com “A new stress sensor and risk
factor for suicide: the T allele of the functional genetic variant in the GABRA6 gene” the
correlation amongst low gamma-aminobutyric acid (GABA) transmission levels in suicide and
the GABRA6 rs3219151 T allele which codes the protein Gamma-aminobutyric acid receptor
subunit alpha-6. GABRA6 rs3219151 T allele has been related to great physiological and
endocrine stress response. The aspects of rs3219151 T allele that were studied are the effect of
the GABRA6 gene interacting with negative life events, depression, anxiety and suicide. Every
aspect that was considered must have happened recently or have been currently happening in
order to analyze the correlation with the rs3219151 allele. Post hoc analysis measures for
phenotypes related to suicide were tested, too, in interaction with environmental stress and the
rs3219151. The sample used was that of 2283 subjects of European descent.
The study points out that there is no correlation amongst the transmission of suicidal behavior
and the diagnosis of Axis I and Axis II disorders. Axis I disorders are all psychological
diagnostic categories except mental retardation and personality disorder; however, Axis II
encloses both mental retardation and personality disorder.
The major purpose of the study was to assess the role of GABRA6 rs3219151 T allele as a risk
factor for suicide and stress sensor. The study focused on GABA which is the major inhibitory
neurotransmitter in the central nervous system, and plays a paramount role in the downregulation
of the HPA-axis (hypothalamic–pituitary–adrenal axis) when exposed to acute stress. One clear
example of this interaction of GABA and the HPA-axis in the inhibitory effect that alprazolam,
commonly known as Xanax, has on the HPA-axis. Although, no main effect of the allele was
detected, in the subjects exposed to negative life eventers the GABTA6 rs3219151 increased
current anxiety and depression, likewise death-related thoughts, feeling of hopelessness. In the
study it is mentioned that GABTA6 rs3219151 appears to possess a modulatory effect on the
HPA-axis activity because of an association between the T allele and higher levels of plasma
cortisol. The GABA system can affected by stress in a long-term basis or a short-term basis;
stress alters the composition and sensitivity of GABA-A receptors. The data of the study
illustrates that stress-associated suicide risk is higher in carriers of the GABRA6 rs3219151 T
allele with many other markers and predictors of suicidal behaviors contributing to the increased
risk.
It is important to mention that the sample was divided in two cohorts of different geographic
locations. One of the cohorts was integrated by subjects from Budapest, and the other one of
people from Manchester. There was not a correlation amongst genotype and demographic or
lifestyle measures identified, however, both cohorts were significantly different in demographics.
Manchester cohort reported higher levels of RLE (Recent negative life events), BSI-DEP
(current depression), BSI-ANX (current anxiety), DEP (self-reported lifetime depression), as
well as SUIC (self-reported lifetime suicide attempt or deliberate self-harm).
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The study divided the results in several categories that include Depression, Anxiety and suicide
attempt, a Sensitivity analysis, Post hoc analysis of BSI systems, Post hoc analysis of additional
risk factors for suicide and In silico functional analysis. The GABRA6 rs3219151 showed no
significant main effect on DEP, SUIC, or BSI-DEP, and BSI-ANX. However, a significant
association was found with BSI-DEP and BSI-ANX scores when combined with RLE score.
Another aspect that was observed was the scores of the two homozygotes CC and TT. It was
found that the CC homozygote groupe had lower mean symptom scores than he other two
genotype groups. When high and mild RLE groups were compared average of 27% increase in
BSI-DEP and BSI-ANX was found in subjects with the CC genotype, in contrast the TT
genotype showed an average of 114%. Thus, the effect of high RLE score on either BSI-DEP or
BSI-ANX was four times higher in average in TT compared to CC genotype individuals.
Also, the rs321915xRLE interaction had a nominally significant effect on DEP and
showed a trend in SUIC, however, none of them survived correction for multiple testing. Both
cohorts were analyzed separately. The rs3219151xRLE interaction effects were significant in
both cohorts, and showed similar patterns of change in mean BSI-DEP and BSI-ANX scores
with increasing RLE. Individuals carrying the minor CC genotype showed a slower increase in
mean BSI-DEP and BSI-ANX than those carrying the TT genotype. However, the effect of the
interaction was nominally significant on DEP and on SUIC in the Manchester cohort and that
was not the case for the Budapest cohort probably because there was not a high prevalence of
DEP and SUIC.
In reference to the sensitivity analysis, after excluding subjects who reported history of manic or
hypomanic episodes, psychotic symptoms or obsessive –compulsive disorder, the findings are
that the genotype x RLE interactions remained statistically significant. Therefore, suggesting that
the interactions are not explained by major effects in less common disorders associated with
abnormal mood.
In the Post hoc analysis of additional risk factors for suicide they tested personality factors such
as neuroticism and impulsiveness to determine if the T allele had a main effect or gene x
environmental effect on those traits that might be related to suicide risk. No significant direct
association with the T allele was found, but in interaction with RLE a strong association was
found when the STOP task SSRT (stop signal reaction time) was performed, TT genotype
carriers showed increase stop signal reaction time if RLE was present (whether it was moderate
or high). Hopelessness was also tested in the Budapest cohort because in the past it has been
proved that it reliably can predict suicide risk. No main effect was found, but interaction of
rs3219151 x RLE was significant.
Finally, in the silico analysis it was showed that rs3219151 is located between 2 regions of high
conservation and can be used to impute de genotype for 5 additional SNPs (single nucleotide
polymorphisms) with a high level of accuracy in the Caucasian HapMap CEU population. All
analyses were done using UCSC Genome Browser on Human Dec. 2013 (GRCh38/hg38) with
standard setting on all selected options.
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In the discussion of the results the researches talked about previous literature done in some of the
aspects of the study, in some of these aspects the literature showed contradictory results.
However, the results reported in this study are close, and are in agreement with previous
literature. As shown above, they identified a complex interaction between GABRA6 rs3219151
T allele and recent life stress in multiple phenotypes associated with suicidal behavior
converging to a significant suicide risk. no main effects of rs3219151on any investigated
phenotypes were revealed in mediating the effects of recent stress in the emergence of suicidal
behavior. also found a strong association between cognitive impulsivity as measured by the
STOP task and the T allele in interaction with stress exposure, but neuroticism and
impulsiveness showed no association. Thus, the data suggest a possible role of the T allele in
stress-related suicide risk as a result of the cooperation of several independent suicide-related
phenotypes.
At the beginning of the study the researches were hoping to find a correlation of gene-
environment on the effects of stress in suicide risk, however, the study’s results showed no such
relationship on the investigated variables. Although, the study did find a strong increase in
depression and anxiety scores observable with increasing recent life stress in subjects carrying
the TT genotype.
The possible pathway that related the results could be traced back to the fact that no main action
of the rs3219151 was found. However, when analyzed with the recent negative life events
variable and the response of the TT carriers when facing stress, the rs3219151 showed an
important role in depression like behavior and the probability of the subjects of having
depression or suicidal thoughts this supports and extend findings that this genetic variant may
have a role in mediating the effects of stress.
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Bibliography
Gonda, Xenia. www.nature.com “A new stress sensor and risk factor for suicide: the T allele of the
functional genetic variant in the GABRA6 gene”. 10 October 2017. electronic .