title: 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.
authors.affiliation: Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA. maenoch@niaaa.nih.gov
authors.forename: Mary-Anne
authors.initials: MA
authors.lastname: Enoch
authors.forename: Colin A
authors.initials: CA
authors.lastname: Hodgkinson
authors.forename: Elena
authors.initials: E
authors.lastname: Gorodetsky
authors.forename: David
authors.initials: D
authors.lastname: Goldman
authors.forename: Alec
authors.initials: A
authors.lastname: Roy
mesh_terms: D000328:Adult; D001741:Black or African American; D016009:Chi-Square Distribution; D002648:Child; D002649:Child Abuse / Q000523:psychology*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D019966:Substance-Related Disorders / Q000235:genetics*; D013406:Suicide, Attempted / Q000523:psychology*; D011795:Surveys and Questionnaires
chemical_list: D050486:Serotonin Plasma Membrane Transport Proteins
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