The 5-HT(2A) receptor gene 102T/C polymorphism is associated with suicidal behavior in depressed patients.
Unitat d'Antropologia, Departament de Biologia Animal, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain. American Journal of Medical Genetics
(Impact Factor: 3.23).
Several lines of evidence suggest that genetic factors constitute an important determinant of suicidal behavior. A significant association between the 5-HT(2A)-C allele and suicidality has recently been reported. The aim of this study was to investigate whether the proposed association between 5-HT(2A)-102T/C polymorphism and suicidality could be replicated in a larger and independent sample of Spanish patients with major depression. The 102T/C polymorphism of the 5-HT(2A) receptor gene was analyzed in 159 patients with major depression (DSM-IV criteria) and 164 unrelated and healthy controls using a case control design. All individuals were subjects of Spanish origin. Significant differences in allele (chi-square = 4.13, df = 1, P = 0.04) and genotype (chi-square = 6.19, df = 2, P = 0.04) distributions were found between non-suicide attempters and suicide attempters. Moreover, those patients carrying 5-HT(2A)-C allele had more than five times the risk for attempting suicide than noncarriers (OR = 5.50, 95% CI = 1.18-35.20, P = 0.01). Our results replicate the proposed association between 5HT(2A)-C allele and suicidality in major depression. Moreover, no overall associations are detected when patients with major depression and controls are compared for 102T/C frequencies, suggesting that the increased risk for suicidality conferred by 5-HT(2A)-C allele is primarily associated with suicidal behavior and not with the diagnosis of major depression itself.
Available from: Jin-Yu Wang
- "1.20 (0.88–1.63) 1.50 (0.83–2.71) 1.44 (0.68–3.08) 1.47 (0.64–3.36) 0.95 (0.44–2.04) 1.34 (0.58–3.09) 0.93 (0.68–1.27) 2.06 (0.97–4.35) 1.12 (0.88–1.42) 1.13 (0.89–1.43) 1.27 (0.98–1.63) 1.15 (0.95–1.38) 2.07 (0.70–6.11) 0.81 (0.54–1.23) 2.37 Weight(%) (M–H) 7.34 1.86 24.62 36.21 5.28 4.33 6.58 4.54 4.51 63.79 100.00 38.55 Tsai et al. (1999) Chen et al. (2001) Tan et al. (2002) D+L subtotal Europeans/Americans Press et al. (2000) Arias et al. (2001) Correa et al. (2002) Correa et al. (2007) D+L subtotal D+L overall "
Available from: Gaël Quesseveur
- "Given the dysfunction of the serotonergic system in major depressive episodes (MDE) of MDD (Baldwin and Rudge, 1995), genetic association studies have focused on the genetic variants at the gene encoding for the 5-HT 2A R, HTR2A (see (Anguelova et al., 2003; Serretti et al., 2007) for review). The association between MDD and three single nucleotide polymorphisms (SNPs), G-to-A substitution at nucleotide − 1438 (rs6311, − 1438G/A), C-to-T substitution at nucleotide 102 (rs6313, 102C/T) and C-to-T substitution at nucleotide 1354 (rs6314, His452Tyr, 1354C/T) has been investigated, showing inconsistent results for the C allele of rs6313 (association: (Arias et al., 2001; Du et al., 2000; Zhang et al., 1997), no association: (Illi et al., 2009; Kishi et al., 2009; Minov et al., 2001; Tsai et al., 1999; Wang et al., 2009; Zhang et al., 2008)), for the A allele of rs6311 (association: (Christiansen et al., 2007; Enoch et al., 1999; Jansson et al., 2003; Kamata et al., 2011; Lee et al., 2006), opposite association: (Choi et al., 2004), no association: (Illi et al., 2009; Kishi et al., 2009; Ohara et al., 1998; Tencomnao et al., 2010)) and for rs6314 which has been poorly studied (no association: (Minov et al., 2001)). Moreover, the functional consequences of these SNPs on 5-HT 2A R function and/or HTR2A expression remain poorly studied (Serretti et al., 2007), especially for the C allele of rs6313, which could be submitted to methylation, a process known to prevent gene expression (Polesskaya et al., 2006) and for the T allele of rs6314 which could be associated with a decreased 5-HT 2A R-mediated intracellular signaling (Ozaki et al., 1997). "
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ABSTRACT: An association between serotonin 2A receptor (5-HT2AR), encoded by HTR2A gene, and major depressive disorder (MDD) has been suggested. Here, we combined preclinical and ecological clinical approaches to explore the impact of impaired 5-HT2AR-mediated transmission on MDD or anxio-depressive-like phenotype in mice.
Htr2a knock-out mice (Htr2a-/- ) and wild-type mice were compared for the ability of chronic corticosterone to elicit some anxio-depressive-like phenotype in three behavioral paradigms (elevated plus maze, tail suspension test and splash test). Accordingly, two single nucleotide polymorphisms of the HTR2A gene (rs6314 ie His452Tyr and rs6313 ie 102C/T), which specific allelic variants may decrease 5-HT2AR-mediated transmission (as in Htr2a-/-mice), were studied in a sample of 485 Caucasian patients with MDD.
In response to chronic corticosterone exposure, Htr2a-/- mice displayed more pronounced anxiodepressive-like phenotype than wild-type mice, as shown by a significant higher “emotionality score” (p < 0.01). In patients, the C allele of rs6313 was more frequent in depressed patients (p = 0.019) and was also associated with a more severe major depressive episode (p = 0.03).
This translational and ecological study involving constitutive Htr2a-/- knock-out mice and related SNPs in depressed patients suggests that a lower neurotransmission at the 5-HT2AR may favor the susceptibility and severity of MDE. It also suggests that specific allelic variants of the rs6313 and rs6314 may reduce 5-HT2AR-mediated transmission.
Available from: Humberto Nicolini
- "Since 2000, growing interest on this issue prompted a variety of studies in Caucasian and Asian populations dealing with 5HTR2A and suicidal behavior. Although many studies have reported this association [21,22,33,42], there are other reports that have not encountered an association of either the T or C allele in rs6313 of 5HTR2A [20,23,31,32,35,38,43] with suicidal behavior. The slight preponderance of the T allele is in agreement with other reports in the literature. "
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The polymorphism rs6313 (T102C) has been associated with suicidal behavior in case–control and meta-analysis studies, but results and conclusions remain controversial. The aim of the present study was to examine the association between T102C with suicidal behavior in a case–control study and, to assess the combined evidence – this case–control study and available data from other related studies – we carried out a meta-analysis.
We conducted a case–control study that included 161 patients with suicide attempts and 244 controls; we then performed a meta-analysis. The following models were evaluated in the meta-analysis: A) C allele vs T allele; B) T allele vs C allele; C) Caucasian population, D) Asian population, and E) suicide attempters with schizophrenia.
We found an association between attempted suicide and control participants for genotype (χ2=6.28, p=0.04, df=2) and allele (χ2=6.17, p=0.01, df=1, OR 1.48 95% IC: 1.08-2.03) frequencies in the case–control study. The meta-analysis, comprising 23 association studies (including the present one), showed that the rs6313 polymorphism is not associated with suicidal behavior for the following comparisons:T allele vs C allele (OR: 1.03; 95% CI 0.93-1.13; p(Z)=0.44); C allele vs T allele: (OR:0.99; 95% CI: 0.90-1.08; p(Z)=0.22); Caucasians (OR:1.09; 95% CI: 0.96-1.23), and Asians (OR:0.96; 95% CI: 0.84-1.09).
Our results showed association between the rs6313 (T102C) polymorphism and suicidal behavior in the case–control study. However, the meta-analysis showed no evidence of association. Therefore, more studies are necessary to determine conclusively an association between T102C and suicidal behavior.
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