Unraveling the genetics of gulf war illness in diverse participants enrolled in the million veteran program, 2025, Pathak et al

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

Gita A Pathak, Dora Koller, Brenda Cabrera-Mendoza, Alice B S Nono Djotsa, Frank R Wendt, Antonella De Lillo, Eleni Friligkou, Jun He, Manuela R Kouakou, Linh M Duong, Jacqueline Vahey, Lea Steele, Rachel Quaden, Kelly M Harrington, Sarah T Ahmed, J Michael Gaziano, John Concato, Hongyu Zhao, Krishnan Radhakrishnan, Joel Gelernter, Elizabeth Gifford, Mihaela Aslan, Drew A Helmer, Elizabeth R Hauser, Renato Polimanti

[Line breaks added]

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 ATG4B transcriptomic regulation and with sex hormone-binding globulin levels. Rs138168412 was associated with AOPEP transcriptomic regulation and with respiratory function and physical strength. The TWAS identified five additional loci such as CEMIP in the cerebellum and SNCG in 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.

Link (Human Molecular Genetics) [Paywall]

 

Genes mentioned in the abstract:

AGXT
MAB21L4
ATG4B
AOPEP
CEMIP
SNCG

 

We don't seem to have discussed GWS for a long time. There used to be a lot of focus on it as possibly related to ME/CFS. Is that no longer the view?

 

IIRC a large study looked for PEM in GWS and found that it wasn’t a feature. (Some people criticised the study, but there was a decent amount of discussion as well). No idea when this was, within the past year I think.
(But my timescales are so off I can’t tell if something was a month or eight months ago because every single day is exactly the same).

 

Very little research is being done comparatively. The US and UK governments are just waiting for the veterans to die so the problem "takes care of itself". Just as they always have. Just as they have done with us, even though new cases keep happening.

For sure there is an overlap, but given that there has been so much more ME/CFS research over the last 5 years and it still hasn't amounted to anything, there really isn't much happening with GWI. Especially since even the amount of ME/CFS research is microscopic potatoes anyway.

 

This study?

Exercise does not cause post-exertional malaise Gulf War Illness: A randomized, controlled, dose–response, crossover study, 2024, Boruch et al.

I would hope that didn't cause a decrease in discussion. The thread was almost all criticism.

They possibly showed that not everyone with GWI has PEM, not that no one with GWI has it. It'd be like taking a random group of people with long COVID (who are taking almost 7000 steps/day already), seeing that as a group they don't get worse after exercise, and declaring that PEM isn't an issue in long COVID.

I post any gulf war illness studies that seem relevant. There's just not many compared to ME/CFS or LC.

 

Thanks your memory is clearer than mine!

 

Had a quick glance at the paper itself. Very brief summary of the GWAS results of significance:

* rs145088940 (HAS2) - CDCsevere - only in cross-ancestry meta-analysis of the non-deployed
* rs138168412 (AOPEP) - KSsymptoms in non-deployed veterans / eQTL effects
* rs142258944 (BMPR1B) - CDC definition in African descent deployed
* rs10993846 (VAV2) - CDC definition in African non-deployed
* rs12352243 - CDCsevere in the combined African sample (deployed & non-deployed)
* rs10014935 - CDCsevere in Europeans (whole sample)
* rs4675853 (AGXT / MAB21L4 / ATG4B) - in KSsymptoms; Europeans; phenome-wide analysis showing association with SHBG levels

Spoiler: TWAS hits & GWI definitions

* CEMIP (cerebellum, CDC definition)
* SNCG (adrenal gland, CDC)
* MAML2 (cerebellar hemisphere, CDC - also suggestive sub-Bonferroni signals in coronary artery, minor salivary gland and stomach)
* BAG3 (minor salivary gland; KSGWI)
* H2AJ (breast mammary tissue; CDCsevere).

All five TWAS hits from the European-ancestry analysis; limited sample size for non-European ancestries.

GWI definitions are:
* KSGWI (Kansas definition - cases require symptoms in >= 3 domains)
* KSsymptoms (Kansas without exclusionary conditions)
* CDC (general CDC definition for GWI)
* CDCsevere (CDC & requiring at least one severe symptom in multiple domains)