We have identified 4 SNPs (rs4755404, rs2269272, rs6296 and rs1659400) in genes SLC1A2, SLC1A3, 5-HTR1B and NTRK2, respectively, which showed evidence of association with SA compared to a non-attempter psychiatric control group. At present, there is no published data on 3/4 of the genetic variants (rs4755404, rs2269272 and rs1659400) reported here and their association with suicide or SA. In addition, we identified a 3-locus (rs6296 (C/G) × rs4755404 (C/G or G/G) × rs1659400 (C/C)) G×G interaction, which was a significant predictor of SA, suggesting that variation in SLC1A2, 5-HTR1B and NTRK2 genes may contribute to the risk of SA independently, and in an interactive manner. This paper provides evidence for the first time of a putative G×E interaction, where genetic variation at the rs1659400 locus may moderate the risk associated with history of childhood abuse and subsequent suicidal acts.
SLC1A2 and SLC1A3 are glial high-affinity transporter molecules that regulate glutamate concentrations at synapses . Aberrant expression of these key transporters could impair reuptake of glutamate, hence prolong synaptic activation and potentially lead to cytotoxic damage to neurons and glia . SLC1A2 and SLC1A3 are downregulated in the brains of MDD patients compared to controls . Moreover, decreased SLC1A3 expression has been observed in suicide brains .
In this study, the SLC1A2 gene variant, rs4755404, was associated with SA and schizophrenia and other psychotic disorders. Consistent with these findings, rs4755404 was previously associated with schizophrenia in a Japanese patient cohort . In contrast, the SLC1A3 gene variant, rs2269272, was significantly associated with male non-attempters, where a gene-sex interaction was observed. The T/T genotype is absent from the attempter group and over-represented in the male non-attempter group, suggesting a T/T genotype may confer a protective effect on risk of SA, particularly in males with underlying psychiatric disorders. HWE analysis revealed that the control group was not in equilibrium for the rs2269272 locus, which is likely due to the fact that our control group is not "disease-free" but rather consists of individuals with underlying psychiatric conditions. However, the possibility that some other factor may be influencing the over-representation of T allele homozygotes in the non-attempter group cannot be ruled out. Therefore, further investigation in a larger cohort of patients is warranted. Taken together, our findings support the glial hypothesis of mood abnormalities  and concur with the literature on a putative role of glutamate dysregulation in suicidal behaviour.
The serotonin (5-HT) system is the most widely studied area of neurobiological suicide research . Aberrant 5-HT receptor binding has been implicated in suicide and SA . 5-HTR1B binding is decreased in the prefrontal cortex of suicide brains . Previously a 5-HTR1B promoter CpG island genetic variant, rs6296, was associated with SA . However, findings are inconsistent and a number of studies have found no evidence of association [33, 34]. Rs6296 has also been associated with substance use disorders, major depression and inconsistently with alcohol abuse [33, 35]. Here we report a significant association between the rs6296 locus and SA. In addition, persons with a C/G genotype and a history of abuse or dependence on alcohol were significantly associated with SA, but a gene × alcohol interaction was not evident, suggesting that they represent additive risk factors. These findings provide the impetus for future studies in a cohort of alcohol abuse/dependence patients to further understand the relevance of rs6296 genetic variants and SA in patients with a history of alcohol abuse/dependence.
NTRK2 (TRKB) encodes the receptor for BDNF. Aberrant neurotrophic signalling has been implicated in suicide risk by various studies [36, 37]. BDNF and NTRK2 mRNA and protein expression are reported downregulated in the prefrontal cortex and hippocampus of suicide victims compared to controls [36, 37]. The majority of studies have focused on functional BDNF variant, rs6265, which has been inconsistently implicated in suicide and MDD [38, 39]. In this study, we found no evidence of association between rs6265 and SA, consistent with a previous report . Previously, a number of genetic variants within the NTRK2 gene have been associated with SA among depressed patients . We observed a significant association with NTRK2 intronic genetic variant, rs1659404, and SA in females. Rs1659400 is in strong LD with several other SNPs within the NTRK1 gene, some of which have been implicated in alcohol dependence and depression [42, 43].
To date a number of gene × childhood adversity interactions have been reported in psychiatric patients [44–46]. Childhood trauma (including abuse) has been reported to interact with low expressing 5-HTTLPR genotypes and moderate the risk of suicidal behaviour . Recently, an interaction between child maltreatment and 5-HTT polymorphisms and suicidal ideation among children was described . Here we report, for the first time, a possible moderation effect of a NTRK2 polymorphism on childhood abuse and risk for future suicidal acts. It is important to note that a history of childhood abuse was assessed in this study by a trained clinician as opposed to self-report questionnaires. Recent research has demonstrated that clinician ratings of developmental histories, such as childhood sexual and physical abuse, are in agreement with patient's self-reports and thus supports the validity of clinician reports for numerous clinical variables, including childhood abuse assessment . Future studies could investigate the putative interaction of this genetic variant with childhood trauma score, which would include sexual, physical and emotional abuse and neglect. Such a study would provide a more comprehensive assessment of gene × childhood adversity interaction and risk for SA at this locus.
A number of limitations are apparent in the current study. Firstly, case/control samples were not age-matched, with the SA group having a significantly younger mean age. The SA group also contained a greater number of individuals with a family history of SA and a history of childhood abuse. In addition, rates of MDD diagnoses were different in SA and non-attempter psychiatric controls. However, the genetic variants identified in this study were not associated with either MDD, a family history of SA or abuse. Moreover, our sample size may have reduced power to detect small genetic effects, or alternative interactions between genetic and environmental risk factors. In this study, multiple testing correction, such as Bonferroni correction, was not applied. Bonferroni correction can be regarded as ultraconservative  and ignores the functional candidate gene study design utilised, which is likely to increase the prior probability of detecting an association. In addition, given our modest sample size, Bonferroni correction is likely to result in large type II error rates. Arguably the best solution to type I error is replication .