Genetic and transcriptomic determinants of disseminated coccidioidomycosis identify a founder variant in NLRX1 and ancestry-specific rare variants in immune response genes

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ABSTRACT 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 have increased risk for disseminated coccidioidomycosis (DCM) cases (OR=13.37, p=1.08×10 -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=5.85×10⁻⁴). We identified a rare missense variant, NLRX1 p.Arg252Trp (rs145644388), in five patients with DCM that represents a founder variant: all carriers share African local genetic ancestry and carry 0.6–1.1 centimorgans of identical-by-descent sequence, indicating origin from a common ancestor. In gnomAD, NLRX1 p.Arg252Trp shows has higher allele frequency in African (AF=0.00615) compared to European (AF= 2.25x10 -5 ) populations, directly linking this rare variant to population-level African genetic ancestry enrichment in DCM. NLRX1 disruption impairs LC3-associated phagocytosis, an antifungal mechanism in macrophages. Together, these findings reveal both immune gene expression dysregulation and rare-variant architectures associated with African genetic ancestry underlying severe coccidioidomycosis and identify new targets for risk stratification and treatment. Highlights Patients with disseminated coccidioidomycosis are significantly more likely to have African genetic ancestry. Whole-blood transcriptomics identifies upregulation of interferon-inducible genes IFI44 , IFI44L , and fungal pattern-recognition receptor CLEC4D in disseminated disease. Rare missense variants in NLRX1 , a mitochondrial NOD-like receptor involved in LC3-associated phagocytosis, are significantly enriched in disseminated cases by gene-burden testing. Context and Significance Valley fever (coccidioidomycosis) is a fungal infection endemic to the southwestern United States that causes life-threatening disseminated disease in a small fraction of those infected. The biological determinants underlying why some develop severe, disseminated infection remains poorly understood. Epidemiological studies have noted that individuals of African American or Filipino background face disproportionately higher risk for severe disease, but these studies relied on self-reported race, a social construct that is not biologically based. By assembling the largest genomically characterized Valley Fever cohort to date and using genome sequencing to directly quantify genetic ancestry, we show that genetic variation that is more common in populations with African ancestry is associated with risk for dissemination. We further identify disruption of interferon signaling and LC3-associated phagocytosis — a cellular mechanism by which macrophages contain fungal infections — as likely contributors to severe disease. These findings open new avenues for risk stratification and potential therapeutic targeting in this neglected fungal infection.

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