Inflamed mind: multiple genetic variants of IL6 influence suicide risk phenotypes in interaction with early and recent adversities in a linkage disequilibrium-based clumping analysis

Background: Understanding and predicting suicide remains a challenge, and a recent paradigm shift regarding the complex relationship between the immune system and the brain brought attention to the involvement of inflammation in neuropsychiatric conditions including suicide. Among cytokines, IL-6 has been most frequently implicated in suicide, yet only a few candidate gene studies and without considering the effect of stress investigated the role of IL6 in suicidal behaviour. Our study aimed to investigate the association of IL6 variation with a linkage disequilibrium-based clumping method in interaction with childhood adversities and recent stress on manifestations along the suicide spectrum. Methods: One thousand seven hundred and sixty-two participants provided information on previous suicide attempts, current suicidal ideation, thoughts of death, and hopelessness, and were genotyped for 186 variants in IL6. Early childhood adversities were recorded with an instrument adapted from the Childhood Trauma Questionnaire, recent life events were registered using the List of Threatening Life Events. Following a 3-step quality control, logistic and linear regression models were run to explore the effect of genotype and gene-environment interactions on suicide phenotypes. All regression models were followed by a clumping process based on empirical estimates of linkage disequilibrium between clumps of intercorrelated SNPs. Interaction effects of distinct types of recent life events were also analysed. Results: No clumps with significant main effects emerged, but we identified several clumps significantly interacting with childhood adversities on lifetime suicide attempts, current suicidal ideation, and current thoughts of death. We also identified clumps significantly interacting with recent negative life events on current suicidal ideation. We reported no clumps with significant effect on hopelessness either as a main effect or in interaction with childhood adversities or recent stress. Conclusion: We identified variant clumps in IL6 influencing suicidal behaviour, but only in interaction with childhood or recent adversities. Our results may bring us a step further in understanding the role of neuroinflammation and specifically of IL-6 in suicide, towards identifying novel biological markers of suicidal behaviour especially in those exposed to stressful experiences, and to fostering the adaptation of a new paradigm and identifying novel approaches and targets in the treatment of suicidal behaviour.