Genetic association of the kynurenine pathway to suicidal behavior

Abstract

Suicidal behavior has been associated with dysfunctions in the kynurenine pathway, including alterations in the levels of neuroprotective and neurotoxic metabolites. Changes in the catalytic activity of enzymes within the pathway may contribute significantly. Variations in the genes encoding enzymes within the pathway can significantly affect their catalytic activity, playing a crucial role in the process. To explore this possibility, we hypothesized that these genetic variations would occur more frequently in patients with a history of suicidal behavior compared to non-suicidal individuals. Thus, we investigated the relationship between a history of suicide attempts and five single nucleotide polymorphisms (SNPs) within genes involved in the kynurenine pathway: IDO1 (rs7820268), IDO2 (rs10109853), KMO (rs1053230), KAT1 (rs10988134), and ACSMD (rs2121337). Our sample comprised 849 subjects: 325 individuals who had attempted suicide in their lifetime (SAs), 99 individuals with a history of major depression disorder but no previous suicide attempts (non-SAs), and 425 non-psychiatric controls (CTRL). We performed SNP association analyses using codominant, dominant, and recessive models. Adjustment for sex and multiple comparisons was applied. After adjustment, the analysis revealed that SAs showed a significantly higher frequency of T alleles and TT genotypes of the rs1053230 SNP compared to CTRL across nearly all models. Furthermore, in the recessive model, non-SAs displayed a higher prevalence of the TT genotype of the rs10109853 SNP compared to CTRL. The rs1053230 and rs10109853 SNPs could play a role in the previously observed metabolic dysregulation among SAs and non-SAs, respectively. To validate our findings, it is crucial to conduct functional analyses to investigate the impact of rs10109853 and rs1053230 SNPs on the expression and/or catalytic activity of the corresponding enzymes.

Fig. 1

Simplified diagram of the kynurenine pathway. The kynurenine pathway consists of two branches with opposite actions. A neuroprotective branch (in green) represented by KYNA and a neurotoxic branch (in red) represented by QUIN. KYNA is a non-competitive NMDA receptor antagonist that reduces extracellular glutamate and acts as a ROS scavenger. QUIN is a potent NMDA receptor agonist that increases glutamate extracellular release by neurons and inhibits its uptake by astrocytes. IDO: idoleamine-2,3- dioxygenase, TDO: tryptophan 2,3-dioxygenase, KATs: kynurenine aminostransferases, KMO: kynurenine 3-monooxygenase, KYNU: kynureninase, 3-HAAO: 3-hydoxyanthranillic acid dioxygenase, ACMSD: 2-Amino-3-carboxymuconic-6-semiladehyde decarboxylase, QPRT: quinolonate phosphoribosyl transferase, NMDAr: N-methyl-D-aspartate receptor, ROS: reactive oxygen species, NAD: Nicotinamide adenine dinucleotide, IFNγ: Interferon gamma, IL-6: interleukin 6, IL-1β: interleukin 1beta, TNFα: tumor necrosis factor alpha, TGFβ: transforming growth factor beta. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)