Unraveling the genetics of gulf war illness in diverse participants enrolled in the million veteran program
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.
Authors
- John Concato (ORCID: https://orcid.org/0000-0003-2846-0503)
- Sarah T. Ahmed (ORCID: https://orcid.org/0000-0001-5495-545X)
- Brenda Cabrera‐Mendoza (ORCID: https://orcid.org/0000-0003-4729-9997)
- Kelly Harrington (ORCID: https://orcid.org/0000-0001-9668-183X)
- Renato A Polimanti (ORCID: https://orcid.org/0000-0003-0745-6046)
- Alice B. S. Nono Djotsa (ORCID: https://orcid.org/0000-0001-9779-9522)
- Krishnan Radhakrishnan (ORCID: https://orcid.org/0000-0001-9243-7733)
- Mihaela Aslan (ORCID: https://orcid.org/0000-0002-5041-010X)
- Jacqueline Vahey (ORCID: https://orcid.org/0000-0002-0449-295X)
- Joel Gelernter (ORCID: https://orcid.org/0000-0002-4067-1859)
- Dóra Koller (ORCID: https://orcid.org/0000-0002-0415-0466)
- Antonella De Lillo (ORCID: https://orcid.org/0000-0003-0746-5209)
- Lea Steele (ORCID: https://orcid.org/0000-0003-4940-069X)
- Frank R. Wendt (ORCID: https://orcid.org/0000-0002-2108-6822)
- Eleni Friligkou (ORCID: https://orcid.org/0009-0003-3682-0991)
- Jun He (ORCID: https://orcid.org/0000-0003-4467-7649)
- Elizabeth R. Hauser (ORCID: https://orcid.org/0000-0003-0367-9189)
- Manuela R. Kouakou
- Drew A. Helmer (ORCID: https://orcid.org/0000-0003-0385-432X)
- Elizabeth J. Gifford (ORCID: https://orcid.org/0000-0002-1488-0286)
- Gita A. Pathak (ORCID: https://orcid.org/0000-0003-3943-0895)
- Linh M. Duong (ORCID: https://orcid.org/0000-0002-2569-5326)
- Hongyu Zhao (ORCID: https://orcid.org/0009-0004-0091-8281)
- J. Michael Gaziano
- Rachel Quaden
Institutions
- Boston University (US)
- Brigham and Women's Hospital (US)
- Michael E. DeBakey VA Medical Center (US)
- United States Food and Drug Administration (US)
- Substance Abuse and Mental Health Services Administration (US)
- 3M (United States) (US)
- Harvard University (US)
- Duke University (US)
- Baylor College of Medicine (US)
- University of Toronto (CA)
- VA Boston Healthcare System (US)
- Center for Child and Family Health (US)
- Yale University (US)
- VA Connecticut Healthcare System (US)
- Center for Innovation (US)
- Durham VA Medical Center (US)
Publication Details
- Journal
- Human Molecular Genetics
- Published
- 2025-05-14
- DOI
- https://doi.org/10.1093/hmg/ddaf075
- Citations
- 1
- Primary Topic
- Fibromyalgia and Chronic Fatigue Syndrome Research
- Type
- article
- Field-Weighted Citation Impact
- 1.47