A new stress sensor and risk factor for suicide: the T allele of the functional genetic variant in the GABRA6 gene

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.

Figure 1

Significant interaction between recent negative life events (RLE) and GABRA6 rs3219151 on current depression scores in the total population. Significant (p = 0.001) genetic interaction in mean BSI depression scores over RLE scores with standard error bars. Subjects carrying the T allele of GABRA6 rs3219151 showed higher increase in current depression scores when exposed to severe recent negative life events compared to those carrying the CC genotype. (Subject numbers in the RLE categories, respectively: CC genotype: RLE0: 288, RLE1: 92, RLE2: 69; TC genotype: RLE0: 728, RLE1: 196, RLE2: 154; TT genotype: RLE0: 506, RLE1: 131, RLE2: 110; ★ indicates p = 0.03 CC vs TT; ☆ indicates p = 0.08 CC vs TC, and p = 0.009 CC vs TT, pairwise comparisons for visualisation of results.) RLE0: 0–1 RLE; RLE1: 2 RLE; RLE2: 3 or more RLE (used only for display purposes). BSI: Brief Symptom Inventory; RLE: recent negative life events.

Figure 2

Significant interaction between recent negative life events (RLE) and GABRA6 rs3219151 on current anxiety scores in the total population. Significant (p = 0.003) genetic interaction in mean BSI anxiety scores over RLE scores with standard error bars. Subjects carrying the T allele of GABRA6 rs3219151 showed higher increase in current anxiety scores when exposed to severe recent negative life events compared to those carrying the CC genotype (Subject numbers in the RLE categories, respectively: CC genotype: RLE0: 288, RLE1: 92, RLE2: 69; TC genotype: RLE0: 728, RLE1: 196, RLE2: 154; TT genotype: RLE0: 506, RLE1: 131, RLE2: 110; ★ indicates p = 0.016 CC vs TT; pairwise comparisons for visualisation of results.). RLE0: 0–1 RLE; RLE1: 2 RLE; RLE2: 3 or more RLE (used only for display purposes). BSI: Brief Symptom Inventory; RLE: recent negative life events.

Figure 3

Significant interaction between recent negative life events (RLE) and GABRA6 rs3219151 on current stop task reaction time (SSRT) scores in the Manchester Level 2 population. Significant (p = 0.0009) genetic interaction in mean SSRT over RLE scores with standard error bars. Subjects carrying the TT genotype of GABRA6 rs3219151 showed higher increase in SSRT when exposed to recent negative life events compared to those carrying the C allele (subject numbers in the RLE categories, respectively: CC genotype: RLE0: 26, RLE1: 6, RLE2: 9; TC genotype: RLE0: 51, RLE1: 21, RLE2: 23; TT genotype: RLE0: 39, RLE1: 9, RLE2: 16; ★ indicates p = 0.037 TC vs TT; pairwise comparisons for visualisation of results). RLE0: 0–1 RLE; RLE1: 2 RLE; RLE2: 3 or more RLE (used only for display purposes). BSI: Brief Symptom Inventory; RLE: recent negative life events.

Figure 4

rs3219151 (*) located in the 3′UTR of GABRA6 imputes for 5 additional SNPs in the Caucasian HapMap CEU population. The imputed SNPs in order of appearance from left to right are rs1992646, rs3811995, rs3811992, rs13184586, rs13172914, with rs3219151 in the far right. Sequence conservation across species is shown as is the presence of DNase I hypersensitivity regions that are often associated with transcriptional regulation. Imputed SNP rs13172914 (•) is located just adjacent to a conserved region with potential transcriptional activity. Analyses were done using UCSC Genome browser on Human Dec. 2013 (GRCh38/hg38) with standard settings on all selected options.

Figure 5

rs3219151, which is located in the 3′UTR of GABRA6 imputes for a total of 9 SNPs and 2 indels (rs151249729 and rs35477281) were in linkage disequilibrium (r2 > 0.8) with rs3219151 in the 1000 genome projects British in England and Scotland (GBR) sample. Sequence conservation across species is shown, as are DNase I hypersensitivity regions and H3K27Ac histone marks which are often associated with transcriptional regulation. Analysis is shown using UCSC Genome Browser on Human Feb. 2009 (GRCh37/hg19).