Turecki G, Briere R, Dewar K, Antonetti T, Lesage AD, Seguin M et al. Prediction of level of serotonin 2A receptor binding by serotonin receptor 2A genetic variation in postmortem brain samples from subjects who did or did not commit suicide. Am J Psychiatry 156: 1456-1458
Postmortem studies have indicated that suicide victims have greater serotonin receptor 2A (5-HTR2A) binding in prefrontal brain regions. However, there remains some controversy regarding the biological specificity of these findings. The authors hypothesized that the variance observed in brain 5-HTR2A binding is genetically mediated, at least in part.
Postmortem data from 56 subjects who had committed suicide and 126 normal comparison subjects were studied; brain tissue was available from 11 subjects who committed suicide and 11 comparison subjects. Homogenate binding assays were carried out with [3H]ketanserin. Variation at the 5-HTR2A gene (HTR2A) was investigated by means of two polymorphisms: T102C and A-1438G.
5-HTR2A binding was greater in the prefrontal cortex of the subjects who committed suicide. In addition, the findings suggest that HTR2A variation significantly affects 5-HTR2A binding. However, no interaction between suicidal behavior and this locus was observed.
These results confirm previous reports of greater 5-HTR2A binding in subjects who committed suicide; they also provide preliminary evidence suggesting that the number of 5-HTR2A receptors is genetically mediated.
"c o m / l o c a t e / p a i d functional polymorphisms in the HTR1A and HTR2A receptor genes are widely studied with respect to their association with affective responses. The C/C genotype of 102T>C (rs6313) in the HTR2A gene has been shown to be related to reduced post-synaptic serotonin receptor expression (Myers, Airey, Manier, Shelton, & Sanders- Bush, 2007; Turecki et al., 1999), increased levels of impulsivity (Bjork et al., 2002; Jakubczyk et al., 2012) and aggression (Hwu & Chen, 2000), and more frequent suicidal ideation (Du, Bakish, Lapierre , Ravindran, & Hrdina, 2000). In the HTR1A gene, the G allele of the functional SNP 1019C>G (rs6295) is associated with higher expression of pre-synaptic receptors, suicide (Lemonde et al., 2003), neuroticism (Strobel et al., 2003), susceptibility to depression (Parsey et al., 2006; Yu, Tsai, Liou, Hong, & Chen, 2006), responses to threatening stimuli (Mekli et al., 2011), and increased levels of impulsivity (Benko et al., 2010). "
[Show abstract][Hide abstract] ABSTRACT: Individual differences in the evaluation of affective stimuli, such as the positivity offset and negativity bias may have a biological basis. We tested whether two SNPs (HTR2A; 102T>C and HTR1A; 1019C>G) related to serotonin receptor function, a biological pathway associated with affective regulation, were differentially related to positivity offset and negativity bias for males and females. Participants were 109 cigarette smokers who rated a series of affective stimuli to assess reactions to positive and negative pictures. Gender × genotype interactions were found for both SNPs. Males with the 102T allele showed a greater positivity offset than males with the 102C allele. For females, in contrast, the 1019C allele was associated with a greater positivity offset than the 1019G allele, whereas the 102T allele was associated with a greater negativity bias than the 102C allele. Identifying how gender differences may moderate the effect of serotonin receptor genes on affective information processing may provide insight into their role in guiding behavior and regulating affect.
"It should be mentioned, however, that other studies have failed to identify associations between genetic variants of 5-HT 2A and aggression in suicide victims (Videtic et al., 2006) and alcoholic patients (Preuss et al., 2000). Furthermore, most of the studies failed to find a significant association between T102C or His452Tyr and suicidal ideation (Bondy et al., 2000; Preuss et al., 2000; Fanous et al., 2009) suicide attempts (Preuss et al., 2000; Arias et al., 2001; Tan et al., 2002; Oswald et al., 2003; Etain et al., 2004; Khait et al., 2005; Zalsman et al., 2005; Giegling et al., 2006; Correa et al., 2007; Saiz et al., 2008; Zhang et al., 2008), severity of suicidal behaviour (De Luca et al., 2008a), suicide (Bondy et al., 2000; Crawford et al., 2000; Faludi et al., 2000; Ono et al., 2001), suicidal behaviour (Ertugrul et al., 2004; Murphy et al., 2011) or completed suicide (Turecki et al., 1999). Few studies found significant association between the "
[Show abstract][Hide abstract] ABSTRACT: Alterations in serotonin (5-HT) neurochemistry have been implicated in the aetiology of all major neuropsychiatric disorders, ranging from schizophrenia to mood and anxiety-spectrum disorders. This review will focus on the mulifaceted implications of 5-HT-ergic dysfunctions in the pathophysiology of aggressive and suicidal behaviours. After a brief overview of the anatomical distribution of the 5-HT-ergic system in the key brain areas that govern aggression and suicidal behaviours, the implication of 5-HT markers (5-HT receptors, transporter as well as synthetic and metabolic enzymes) in these conditions is discussed. In this regard, particular emphasis is placed on the integration of pharmacological and genetic evidence from animal studies with the findings of human experimental and genetic association studies.
Traditional views postulated an inverse relationship between 5-HT and aggression and suicidal behaviours; however, ample evidence has shown that this perspective may be overly simplistic, and that such pathological manifestations may reflect alterations in 5-HT homeostasis due to the interaction of genetic, environmental and gender-related factors, particularly during early critical developmental stages. The development of animal models that may capture the complexity of such interactions promises to afford a powerful tool to elucidate the pathophysiology of impulsive aggression and suicidability, and find new effective therapies for these conditions.
"Sample Size n (Cases-Controls) Location Diagnosis Number of C alleles Gender (males/females) Mean age (years) Cases Controls Cases Controls Tan (2002) 47/94 Singapore SA with schizophrenia 32 47 94 Pooley (2003) 129/329 United Kingdom Caucasians SA 154 52/77 138/191 38 38 Chen (2001) 471/523 Hong Kong SA with schizophrenia 193 314 308/215 Saiz (2008) 193/420 Asturias in Northern Spain SA 196 70/123 216/204 35 40 Du (2000) 42/131 Ottowa SA with major depression 99 48/30 61/70 40 36 Wrsozek (2011) 38/118 Polish Caucasians SA with alcohol-dependent 33 26/12 81/29 >18 >18 Khait (2005) 52/63 European Caucasians SA with depression 54 30/24 12/51 37 40 Correa (2007) 42/85 Brazilian SA with schizophrenia 83 23/19 45/40 Vaquero-Lorenzo (2008) 441/410 Spanish Caucasians SA 472 161/280 237-173 38 36 Du (1999) 24/31 Budapest, Hungary SC with depression 32 24 31 45 50 Bondy (2000) 131/125 Caucasians Germany SA with major depression 142 91/40 60/75 46 47 Zhang (2008) 297/303 Shangai SA with schizophrenia, anxiety and organic mental disorder 229 171/126 217/112 46 43 Preuss (2000) 45/117 Caucasians Germany SA with alcohol-dependence 52 45 56/61 47 Preuss (2000) 62/117 Caucasians Germany SI with alcohol-dependence 66 62 56/61 47 Ertugrul (2004) 71/26 Caucacians and African-americans SA with schizophrenia 49 26/12 81/29 Crawford (2000) 78/131 Caucasians Australian SC 73 68 95 Crawford (2000) 68/95 Caucasians Australian SI 99 78 131 Turecki (1999) 56/126 Montreal SC 68 56 126 36 33 Ono (2001) 151/163 Japanese SC 157 106/45 108/55 47 47 Zhang (1997) 15/150 Japanese SA with mood disorders 21 15 65/85 33 37 Tsai (1999) 61/96 Taipei SA with mood disorders 49 61 96 71 Arias (2001) 33/164 Spanish SA 42 33 83/71 55 41 Tovilla (2012) 161/244 Mexican SA 220 61/100 82/162 25 33 "
[Show abstract][Hide abstract] ABSTRACT: Background
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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