Unraveling the genetics of gulf war illness in diverse participants enrolled in the million veteran program.

Pathak GA, Koller D, Cabrera-Mendoza B, Nono Djotsa ABS, Wendt FR, De Lillo A, Friligkou E, He J, Kouakou MR, Duong LM, Vahey J, Steele L, Quaden R, Harrington KM, Ahmed ST, Gaziano JM, Concato J, Zhao H, Zhao H, Radhakrishnan K, Gelernter J, Radhakrishnan K, Gelernter J, Gifford E, Aslan M, Gifford E, Aslan M, Helmer DA, Helmer DA, Hauser ER, Hauser ER, Polimanti R, Polimanti R. Unraveling the genetics of gulf war illness in diverse participants enrolled in the million veteran program. Human Molecular Genetics. 2025 May 14 DOI: 10.1093/hmg/ddaf075.

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Abstract:

Gulf War Illness (GWI) is a multi-symptom chronic condition that affects Veterans who served in the 1990-1991 Gulf War (GW). To generate novel information about GWI pathogenesis, we used genome-wide data available from 33 523 Veterans of diverse ancestral backgrounds who served during the 1990-1991 Gulf War era (34% deployed). Polygenic score (PGS) analysis showed GWI pleiotropy for several traits with the strongest evidence for type-2 diabetes (T2D), anxiety, and depression. While T2D PGS was associated with higher GWI odds in GW Veterans, anxiety and depression PGSs were associated with higher odds of GWI in non-deployed GW-era Veterans. Seven independent variants were identified (P < 5 × 10-8). Two of them were supported by independent transcriptomic and phenome-wide analyses. Rs4675853 was associated with AGXT, MAB21L4, and ATG4Btranscriptomic regulation and with sex hormone-binding globulin levels. Rs138168412 was associated with AOPEPtranscriptomic regulation and with respiratory function and physical strength. The TWAS identified five additional loci such as CEMIPin the cerebellum and SNCGin the adrenal gland. The results provide a comprehensive assessment of the polygenic architecture of GWI research definitions, identifying mechanisms potentially relevant to the disease pathogenesis.