Abstract
Background: Approximately 697,000 members of the U.S. Armed Forces were deployed to the Persian Gulf in support of the 1990–1991 Persian Gulf War (GW). Subsequently, many deployed and some non-deployed veterans developed a chronic multi-symptom illness, now named Gulf War Illness (GWI). This manuscript outlines the methods and rationale for studying the genomics of GWI within the Million Veteran Program (MVP), a VA-based national research program that has linked medical records, surveys, and genomic data, enabling genome-wide association studies (GWASs). Methods: MVP participants who served in the military during the GW era were contacted by mail and invited to participate in the GWI study. A structured health questionnaire, based on a previously tested instrument, was also included in the mailing. Data on deployment locations and exposures, symptoms associated with GWI, clinical diagnoses, personal habits, and health care utilization were collected. Self-reported data will be augmented with chart reviews and structured international classification of disease codes, to classify participants by GWI case status. We will develop a phenotyping algorithm, based on two commonly used case definitions, to determine GWI status, and then conduct a nested case-control GWAS. Genetic variants associated with GWI will be investigated, and gene–gene and gene–environment interactions studied. The genetic overlap of GWI with, and causative mechanisms linking this illness to, other health conditions and the effects of genomic regulatory mechanisms on GWI risk will also be explored. Conclusions: The proposed initial GWAS described in this report will investigate the genomic underpinnings of GWI with a large sample size and state-of-the-art genomic analyses and phenotyping. The data generated will provide a rich and expansive foundation on which to build additional analyses.
Highlights
In response to Iraq’s invasion of Kuwait on 2 August 1990, a multinational coalition force was created to liberate Kuwait [1]
The survey instrument was designed to be consistent with other Gulf War Illness (GWI) questionnaires used within the VA [56], which have collected service details including deployment locations and exposures, health information in the form of symptoms associated with GWI, diagnoses of specific medical and psychiatric illnesses, personal habits, and health care and hospitalization utilization
We will use the PrediXcan approach [70] and GTEx (Genotype-Tissue Expression) data [71] as a reference panel, to impute tissue-specific transcriptomic profiles in GWI cases and controls. The goal of these analyses is to develop risk-prediction models of genetic and genomic predictors, combined with trans-ethnic analysis and phenotypic characterization that can be used to perform genomic structural equation modeling (SEM) [72] and Mendelian randomization (MR) [73]
Summary
In response to Iraq’s invasion of Kuwait on 2 August 1990, a multinational coalition force was created to liberate Kuwait [1]. GWI remains a symptom-based illness, as defined by two generally accepted research case definitions, referred to as CDC [23] and Kansas [24] Both definitions are based on self-reported chronic symptoms (>6 months in duration): in the CDC classification involving any two of three domains (fatigue, musculoskeletal pain, cognitive/mood) [23]; and in the Kansas definition involving any three of six domains (fatigue, musculoskeletal pain, cognitive/neuro/mood, pulmonary, gastrointestinal, skin) [24]. We will examine (i) the genetic overlap of GWI with other physical and mental disorders, (ii) potential causative mechanisms that may link GWI to other health conditions, and (iii) effects of genomic regulatory mechanisms across tissues and cell types on GWI risk These investigations will provide an unprecedented opportunity to classify and understand GWI. We report on several aspects of CSP #2006, focusing on the initial planned genomic analyses
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