Independent effects of 5' and 3' functional variants in the serotonin transporter gene on suicidal behavior in the context of childhood trauma

Abstract

The serotonin transporter, encoded by the SLC6A4 gene, influences the synaptic actions of serotonin and is responsive to stress hormones. We hypothesized that 5-HTTLPR, a functional SLC6A4 promoter polymorphism, and two tightly-linked, putatively functional 3' UTR SNPs (rs3813034, rs1042173) might have independent effects on suicidal behavior in the context of childhood trauma (CT). DNA and Childhood Trauma Questionnaire scores were available for a total of 474 African Americans, including 112 suicide attempters and 362 non-suicide attempters. Genotyping was performed for the triallelic 5-HTTLPR polymorphism, 14 SLC6A4 haplotype-tagging SNPs, and 186 ancestry informative markers. There were independent G × E interactive effects of 5-HTTLPR (p = 0.017) and the rs3813034-rs1042173 diplotype (p = 0.011) on suicidal behavior. In individuals exposed to high CT the risk of suicide attempt was 0.52 in carriers of the low activity 5-HTTLPR variant and 0.32 in medium/high activity variant carriers. Likewise, CT exposed carriers of the major rs3813034-rs1042173 ATAT diplotype had an increased risk of suicidal behavior relative to the ATCG/CGCG diplotype carriers (0.40 vs 0.31). Neither the 5' nor the 3' functional variants had an effect in individuals without CT: suicide attempt risk = 0.12-0.22. In individuals exposed to high CT the prevalence of suicide attempt was 0.56 in carriers of both 5' and 3' risk variants, 0.39 in carriers of one risk variant and 0.25 in individuals without either risk variant. Our findings suggest that the 5' and 3'SLC6A4 functional variants have independent effects on the risk for suicidal behavior in CT exposed individuals.

FIGURE 1

SLC6A4 haplotype block structure in African Americans The numbers in the squares refer to pairwise linkage disequilibrium measured as D'. Haplotype blocks were defined using a setting of average pairwise D' within-block of ≥ 0.80. The direction of gene transcription is from right to left. The position of the biallelic 5-HTTLPR polymorphism is indicated by an arrow at the proximal (5') end of the gene. The other arrow indicates rs25531 that is part of the triallelic polymorphism. The two putative functional SNPs at the distal (3') end of the gene are indicated by rectangles.

FIGURE 2

Independent effects of 5-HTTLPR and rs3813034-rs1042173 diplotypes on suicide risk after exposure to high childhood trauma

FIGURE 3

Cumulative effects of SLC6A4 risk variants on suicidal behavior in the context of childhood trauma Risk variants: 5-HTTLPR low activity; rs3813034-rs1042173 major ATAT diplotype