Clustering suicidal phenotypes and genetic associations with brain-derived neurotrophic factor in patients with substance use disorders

Abstract

Suicide attempts (SA), especially recurrent SA or serious SA, are common in substance use disorders (SUD). However, the genetic component of SA in SUD samples remains unclear. Brain-derived neurotrophic factor (BDNF) alleles and levels have been repeatedly involved in stress-related psychopathology. This investigation uses a within-cases study of BDNF and associated factors in three suicidal phenotypes (‘any’, ‘recurrent’, and ‘serious’) of outpatients seeking treatment for opiate and/or cocaine use disorder. Phenotypic characterization was ascertained using a semi-structured interview. After thorough quality control, 98 SNPs of BDNF and associated factors (the BDNF pathway) were extracted from whole-genome data, leaving 411 patients of Caucasian ancestry, who had reliable data regarding their SA history. Binary and multinomial regression with the three suicidal phenotypes were further performed to adjust for possible confounders, along with hierarchical clustering and compared to controls (N = 2504). Bayesian analyses were conducted to detect pleiotropy across the suicidal phenotypes. Among 154 (37%) ever suicide attempters, 104 (68%) reported at least one serious SA and 96 (57%) two SA or more. The median number of non-tobacco SUDs was three. The BDNF gene remained associated with lifetime SA in SNP-based (rs7934165, rs10835210) and gene-based tests within the clinical sample. rs10835210 clustered with serious SA. Bayesian analysis identified genetic correlation between ‘any’ and ‘serious’ SA regarding rs7934165. Despite limitations, ‘serious’ SA was shown to share both clinical and genetic risk factors of SA—not otherwise specified, suggesting a shared BDNF-related pathophysiology of SA in this population with multiple SUDs.

An epigenetic candidate–gene association study of parental styles in suicide attempters with substance use disorders

“…55 It is noticeable that our group previously reported associations between severe suicidal behaviour and an SNP from another gene in the neurotrophin pathway (BDNF rs10835210) in SUD-highlighting its potential role in suicidal behaviour in this population. 36 Although they were obtained after multivariate imputation of MOPS score that may have been missing due to the absence of the corresponding parent, our findings of altered methylation in FKBP5…”

“…Finally, as regards NTF3 , we could only identify one study where NTF3 levels in the hippocampus were lower for suicide victims compared with controls 55 . It is noticeable that our group previously reported associations between severe suicidal behaviour and an SNP from another gene in the neurotrophin pathway ( BDNF rs10835210) in SUD—highlighting its potential role in suicidal behaviour in this population 36 …”

“…We referred to reviews involving in the epigenetics of suicidal behaviour and childhood maltreatment 33 and specific articles in the different pathways: for the BDNF pathway: KEGG neurotrophin signalling pathway (map 04722), genes encoding extracellular proteins, only main ligand neurotrophins (BDNF, NTF3, NTF4, CNTF, NTF) and their receptors (NTRK2, NTRK3, CNTFR), one of the major genes regulating BDNF (SORT1) and SKA2. 34 , 35 The same selection was also applied in a previous study from our group 36 focusing on suicidal behaviour; for the HPA axis: we have selected from a review of the genetic HPA regulation: various signalling (CRH, CRHR1, CRHR2, AVP and POMC), regulatory (CRHBP, FKBP5, FKBP4, PROP1, NR3C1 and NR3C2) and inflammatory (SOCS3, STAT3, LIF and ANXA1) targets associated with the HPA axis 37 ; for the oxytocin pathway: we have selected from a review of the oxytocin pathway gene network 38 in the human brain: OXT, OXTR, CD38, TRPM2, EGFR, 39 NPR1, NPR2 and NPR3. 40 …”

“…for the BDNF pathway: KEGG neurotrophin signalling pathway (map 04722), genes encoding extracellular proteins, only main ligand neurotrophins (BDNF, NTF3, NTF4, CNTF, NTF) and their receptors (NTRK2, NTRK3, CNTFR), one of the major genes regulating BDNF (SORT1) and SKA2. 34 , 35 The same selection was also applied in a previous study from our group 36 focusing on suicidal behaviour;…”

Prevalence of benzodiazepine use disorder during hospitalization for alcohol detoxification

“…These medications were categorized as follows: (i) non‐BZD psychotropic medication, further categorized into antidepressants, mood‐stabilizers, antipsychotics (both first and second generation), medication for opioid use disorder (MOUD), and AUD medications not aimed at detoxification and available in France at the time of the study (i.e., acamprosate, baclofene, disulfirame, nalmefene, and naltrexone) [25] and (ii) nonpsychotropic drugs. Psychotropics all belonged to the category “N” from the Anatomical Therapeutic Chemical (ATC) Classification, limited to medications used in psychiatric disorders, as summarized in various recommendations from the HAS and reported in previous studies from our group [26]. Antipsychotics of the first and second generation were mixed altogether, thus, this category also included neuroleptics, which are mostly used for symptomatic treatment.…”