Genomic interplay between deployment exposures and Gulf War illness in Million Veteran Program participants

Veterans of the 1990–1991 Gulf War (GW) experienced an elevated burden of chronic health conditions, most notably Gulf War Illness (GWI). While the disease etiology remains unclear, it is hypothesized that both genetic susceptibility and deployment exposures contribute to GWI risk. We investigated 6,882 GW-deployed Veterans, assessing genetic and epigenetic interactions with GW exposures (ground combat, insect baits, oil well smoke exposure, pyridostigmine bromide pills, biological/chemical warfare agents, and pesticides). We observed nominal evidence of a genome-wide gene–environment interaction variance component (0.38 ± 0.22) related to biological/chemical warfare-agent exposure and identified three loci showing genome-wide significant interactions (p < 5 × 10− 8; rs78441512, rs145790544, and rs117997207). Also, type-2 diabetes polygenic risk association with GWI is reduced in Veterans exposed to biological/chemical warfare agents, pesticides, and oil well fire smoke during GW deployment. An exploratory computational drug-repurposing analysis highlighted clebopride, rifampicin, and fisetin as compounds potentially targeting GWI-associated molecular pathways. Our GWI epigenome-wide association study identified five sites showing epigenetic interaction with four GW exposures: ground combat, biological/chemical warfare agents, pyridostigmine bromide pill use, and pesticide use. In conclusion, our study demonstrates that both genetic and epigenetic factors interact with GW military exposures to influence GWI vulnerability, highlighting potential druggable pathways to develop novel therapeutic interventions.