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

Romain Icick,Florence Vorspan,Emily Karsinti,Cynthia Marie-Claire,Nathalie Prince,Frank Bellivier,Stéphane Mouly,Georges Brousse,Vanessa Bloch,Jean-Pierre Lépine,Jean-Louis Laplanche

doi:10.1038/s41398-021-01200-5

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.

Highlights

The burden of suicidal behavior is high among individuals suffering from substance use disorders (SUD)
We considered only single nucleotide polymorphism (SNP), i.e. markers with minor allele frequency (MAF) ≥ 5%, for analysis
Unbiased data classification by hierarchical clustering indicated that both Brain-derived neurotrophic factor (BDNF) SNPs clustered together with ‘serious’ suicide attempt (SA)

Summary

Introduction

The burden of suicidal behavior is high among individuals suffering from substance use disorders (SUD). About one in three individuals seeking treatment in specialized care centers for SUD report at least one lifetime suicide attempt (SA)[1,2] and up to 35% deaths in heroin-dependent subjects have been attributed to suicide[3]. This may arise from people with SUD reporting. Other promising candidate pathways for suicidal behavior have been identified, including the serotonergic, hypothalamic-pituitary-adrenal (HPA) axis and the neurotrophin systems[13]. These pathways require investigation in SUD populations. In cocaine dependence, two studies from the same research group reported significant associations between any SA and variants in the HPA axis gene FKBP5, both alone[14] and with CRHBP15

Methods

Results

Conclusion