Date Published: October 11, 2018
Publisher: Public Library of Science
Author(s): Eric Deflesselle, Romain Colle, Laurent Rigal, Denis J. David, Albane Vievard, Séverine Martin, Laurent Becquemont, Céline Verstuyft, Emmanuelle Corruble, Kenji Hashimoto.
Suicide Attempts (SA) are the main complications of Major Depressive Episodes (MDE) and are difficult to predict. Suicide is associated with the expression of Receptor Tyrosin-Kinase B (TRKB), the receptor of the Brain Derived Neurotrophic Factor (BDNF) involved in MDE. However, the impact of its genetic polymorphisms as predictive factors of SA should be clarified. Our main aim is to assess the association of 8 TRKB genetic polymorphisms and SA in depressed patients.
In 624 patients currently experiencing an MDE in the context of Major Depressive Disorder (MDD) (METADAP study), we assessed the association between 8 TRKB genetic polymorphisms (rs1778933, rs1187352, rs2289658, rs2289657, rs2289656, rs3824519, rs56142442 and rs1439050) and acute (previous month) or past (older than one month) SA. Bonferroni corrections and multivariate analysis adjusted for age, sex, level of education, marital status, Hamilton Depression Rating Scale score and previous MDE were used.
The rs2289656 was associated with acute SA (CC = 28.5%, CT = 15.0% and TT = 11.5%, p = 0.0008). However, the other SNPs were not. Patients with the CC genotype had a higher rate of acute SA (28.5%) as compared to T carriers (14.6%) (adjusted OR = 2.2, CI95% [1.4; 3.5], p<0.0001). The TRKB rs2289656 CC genotype is associated with a 2.2 fold higher risk of acute SA in depressed patients. If this result could be confirmed, this TRKB SNP may be assessed to contribute to the prediction of SA in depressed patients.
Suicide Attempts (SA) are the main complications of Major Depressive Episodes (MDE). 15% of patients with MDE attempt suicide during their life . Their risk of SA and of suicide death is respectively about 20 fold (odds ratio [OR] = 7.8–29.9)  and 6 fold higher than the general population . Major Depressive Disorder (MDD) is the leading cause of SA and suicide deaths (40% of SA and 60% of the suicide deaths) . The prediction of SA during MDE is difficult for clinicians and is a major public health issue. Thus, it could be useful to identify biomarkers that could improve the prediction of SA. Genetic biomarkers are of interest since heritability of suicidal behavior is high . So, the purpose of this study is to identify genetic biomarkers of SA in depressed patients that may contribute to prevent SA in depressed patients.
The present study showed an association between the rs2289656 TRKB genetic polymorphism and acute SA in depressed patients. Indeed, patients with the CC genotype had 2.3 fold higher risk of acute SA as compared to T allele carriers. This SNP was not associated with MDD clinical features and remained significantly associated with acute SA after adjustment on MDD clinical and socio-demographical characteristics. Interestingly, in Kohli’s study , rs2289656 was not in linkage disequilibrium with the five TRKB SNPs significantly associated with lifetime SA. The rs2289656 was associated with Alzheimer disease (CC genotype is 3-fold more frequent in sporadic Alzheimer’s disease than the CT genotype) . Some studies show an association between suicide attempts and the neurogenesis pathway genes such as BDNF, of which TRKB is the main receptor . The neurotrophin genes (BDNF, NGF and TRKB) have the strongest evidence for a role in SA . As depression is associated with neurotrophins , it could potentiate the effect of genetics on suicide attempts. A previous study  found a trend (p = 0.11) between this rs2289656 and lifetime SA in a German MDD sample (n = 394). Here, we show a significant association between this SNP and acute SA in a larger French MDD-MDE cohort. There were previous published GWAS of suicide attempts that did not catch TRKB SNPs [11,14,15,17,35,37,38]. Considering the large number of SNPs studied, in order to have sufficient statistical power, at least ten thousands patients should have been included . Actually, these previous GWAS on SA did not have this sample size.
This study in depressed patients showed an association between the rs2289656 TRKB SNP and acute SA. If it could be confirmed, there could be a benefit to genotype this TRKB SNP in daily practice to predict SA in depressed patients.