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-as