Genetic and transcriptomic determinants of disseminated coccidioidomycosis risk reveal African ancestry enrichment and rare immune response variants in NLRX1

Coccidioidomycosis, also known as Valley Fever, is a fungal disease endemic to the Americas that kills hundreds annually, yet the host factors that lead to increased risk of life threatening dissemination of coccidioidomycosis, remain poorly understood. We assembled the largest, comprehensively sequenced coccidioidomycosis cohort to date, comprising 795 individuals with laboratory confirmed coccidioidomycosis and clinical disease severity phenotyping, many with paired whole blood genomic and transcriptomic data. Individuals with greater than 50% African genetic ancestry are significantly enriched in disseminated coccidioidomycosis (DCM) cases (OR=13.37, p=1.08 x10-18), reflecting ancestry-associated differences in allele frequencies at immune loci. Transcriptomic profiling (n=267) revealed upregulation of interferon-inducible genes IFI44 and IFI44L, the fungal recognition receptor CLEC4D, and pro-inflammatory protein S100A12, with sex-specific expression differences in immune cell composition. Gene-burden testing identified NOD-like receptor NLRX1 as the only gene carrying significantly more damaging rare variants than expected by chance (p=5.85 x10-4). We identified a rare missense variant, p.Arg252Trp (rs145644388), in five patients with DCM that represents a founder variant: all carriers share African genetic ancestry and carry 0.6-1.1 centimorgans of identical-by-descent sequence, indicating origin from a common ancestor. In gnomAD, p.Arg252Trp shows a 47-fold enrichment in African populations compared to European populations, directly linking this rare variant to the population-level African ancestry enrichment in DCM. We also identified a rare variant in IFI27 (p.Ser63Leu) present exclusively in severe coccidioidomycosis (DCM or CPC), with all five carriers being male. NLRX1 disruption impairs LC3 associated phagocytosis, a key antifungal mechanism in macrophages. Together, these findings reveal both ancestry-linked immune dysregulation and rare-variant architectures, including a novel African ancestry-enriched founder variant, underlying severe coccidioidomycosis, and identify new targets for risk stratification and treatment.