Glutamatergic GRIN2B and polyaminergic ODC1 genes in suicide attempts: associations and gene-environment interactions with childhood/adolescent physical assault

The complex etiology of suicidal behavior has frequently been investigated in relation to monoaminergic neurotransmission, but other neurosystems have shown alterations as well, involving excitatory glutamatergic and inhibitory g-aminobutyric acid (GABA) molecular components, together with the modulating polyamines. Sufficiently powered and family-based association studies of glutamatergic and GABAergic genes with suicidal behavior are nonexistent, but several studies have been reported for polyamines. We therefore conducted, for the first time ever, an extensive family-based study of 113 candidate single-nucleotide polymorphisms (SNPs) located in 24 glutamatergic and GABA genes, in addition to interrelated polyaminergic genes, on the outcome of severe suicide attempts (SAs). The family-based analysis (n=660 trios) was supplemented with gene-environment interaction (G x E), (n=519 controls) and subgroup analyses. The main observations were the previously unreported association and linkage of SNPs rs2268115 and rs220557 in GRIN2B, as well as of SNPs rs1049500 and rs2302614 in ODC1 (P<10(-2)). Furthermore, GRIN2B haplotypic associations were observed, in particular with a four-SNP AGGC haplotype (rs1805247-rs1806201-rs1805482-rs2268115; P<10(-5)), and a third SNP rs7559979 in ODC1 showed G X E with serious childhood/adolescent physical assault (P<10(-4)). SA subjects were characterized by transdiagnostic trait anger and past year alcohol-drug use disorders, but not by alcohol-drug use at SA, depression, anxiety or psychosis diagnoses. We also discuss a first ever confirmatory observation of SNP rs6526342 (polyaminergic SAT1) in SA, originally identified in completed suicides. The results suggest that specific genetic variants in a subset of glutamatergic (GRIN2B) and polyaminergic (ODC1) neurosystem genes may be of importance in certain suicidal subjects.