Lack of association between the serotonin transporter and tryptophan hydroxylase gene polymorphisms and completed suicide

Abstract

Neurobiological studies have shown that serotonergic dysfunction and disturbances in serotonin transmission are most frequently reported neurobiological substrates of suicidal behavior (Kamali et al., 2001;Hranilovic et al., 2003). The tryptophan hydroxylase (TPH) and the serotonin transporter (5-HTT) genes play a vital role in serotonin metabolism by coding the rate-limiting enzyme in serotonin biosynthesis and in serotonin neurotransmission by reclaiming synaptic serotonin, respectively. In previous studies, variations in these genes have been regarded as prime candidates in the susceptibility to suicidal behavior (Arango et al., 2003). In this study, we investigated both 5-HTTLPR (a 44-base pair insertion/ deletion functional polymorphism) and TPH (A218C) polymorphisms with suicidal behavior by comparing the allele and genotype distribution between suicide victims and normal controls. Liver tissue samples were obtained from 58 suicide victims (43 men, 15 women; average age 30.17 ± 13.07 years) at the Department of Forensic Medicine, Faculty of Medicine, Gazi University. Methods of suicide included hanging (n = 33), firearms (n = 18), fall from heights (n = 4), and drug overdose (n = 3). The medical records for each patient were subjected to retrospective and detailed review to extract demographic data and suicidal history. The control group consisted of 100 blood donors from a local hospital blood bank (52 men, 48 women; average age 35.0 ± 3.9 years) without any history of neuropsychiatric disorders (in their firstdegree and second-degree relatives). The study population consisted entirely of a Turkish population. Genotypes were determined for 58 completed suicide victims and 100 controls by using the polymerase chain reaction and restriction-fragment length polymorphism techni-ques. Statistical significance of differences between case and control group distributions for alleles and genotypes was determined using w 2 Fisher's exact tests. Statistical analyses were carried out using the SPSS package (SPSS standard version, release 10.0; SPSS Inc., Chicago, Illinois, USA). At the 5-HTTLPR locus, there were 49 long alleles (42.3%) and 67 (57.7%) short alleles in the suicide victim sample and 70 short alleles (35%) and 130 long alleles (65%) in the normal controls. The frequency of the A allele of the A218C polymorphism in TPH was 48 out of 116 (41.3%) in suicide cases and 90 out of 200 controls. The C allele frequency was 68 out of the total of 116 alleles in the suicide cases (58.7%) and 110 alleles out of the total 200 control alleles (55%). No association was found between the A218C polymorphism of the TPH gene (w 2 = 1.00; P = 0.60) and a 44-base pair insertion/ deletion functional polymorphism in the 5-HTTLPR (w 2 = 4.54; P = 0.10) and suicide. No significant genotypic or allelic association of the 5-HTTLPR and TPH polymorphisms with history of completed suicide was found. Gender-related analyses for these polymorphisms demonstrated no differences in allele frequencies and distributions between men and women...

Tryptophan hydroxylase 2 (TPH2) haplotypes predict levels of TPH2 mRNA expression in human pons

“…23 Since the discovery of the TPH2 gene in 2003, 4 14 published studies have examined possible associations between TPH2 SNPs and various mental disorders including major depression, 17,24,25 bipolar disorder, 26 anxiety disorders, 27,28 attention-deficit/ hyperactivity disorder (ADHD), 29,30 autism 31 or suicidal behavior. 17,[32][33][34][35][36] The results of these studies have been mixed, with nine studies showing weak, but statistically significant associations between one or more TPH2 SNP and a specific mental disorder, 17,[24][25][26][27][29][30][31][32] and five showing no significant associations. 28,[33][34][35][36] Most of the studies reporting negative results failed to detect statistically significant associations for SNPs in the putative promoter region or intronic SNPs in the 5 0 -end of the gene.…”

“…17,[32][33][34][35][36] The results of these studies have been mixed, with nine studies showing weak, but statistically significant associations between one or more TPH2 SNP and a specific mental disorder, 17,[24][25][26][27][29][30][31][32] and five showing no significant associations. 28,[33][34][35][36] Most of the studies reporting negative results failed to detect statistically significant associations for SNPs in the putative promoter region or intronic SNPs in the 5 0 -end of the gene. These regions are also not associated with allelic mRNA expression observed in our study.…”

The role of the serotonergic system in suicidal behavior

“… 71 Individuals who reattempted suicide have been shown to have significantly higher frequencies of the homozygous (ss) genotype. 66 However, one should not that other studies have failed to replicate these findings, 63 , 123 , 127 thus highlighting the importance of further research into this area.…”

Suicidal behaviour: genes, environmental stress and temperamental traits

“…Many studies reported positive association with suicidal behaviour and two meta-analyses of the literature confirmed a positive association between the S-allele in 5-HTTLPR and suicidal behaviour, in particular violent suicide attempt (Anguelova et al, 2003;Lin & Tsai, 2004). However, many negative studies have also been published (Akar et al, 2010;Baca-Garcia et al, 2010;Chen et al, 2007;Chong et al, 2000;Contreras et al, 2010;Courtet et al, 2003;De Luca et al, 2008;De Luca, Tharmalingam, King et al, 2005;Geijer et al, 2000;Gerra et al, 2004;Helbecque et al, 2006;Mann et al, 2000;Maurex et al, 2010;Mergen et al, 2006;Pungercic et al, 2006;Roy et al, 2001;Rujescu et al, 2001;Saiz et al, 2008a;J. Segal et al, 2009;Wang et al, 2009;Zalsman, Anderson et al, 2005;Zalsman et al, 2001;J.…”