In-Depth Analysis of Genetic Variation Associated with Severe West Nile Viral Disease

West Nile virus (WNV) is a mosquito-borne virus which causes symptomatic disease in a minority of infected humans. To identify novel genetic variants associated with severe disease, we utilized data from an existing case-control study of WNV and included population controls for an expanded analysis. We conducted imputation and gene-gene interaction analysis in the largest and most comprehensive genetic study conducted to date for West Nile neuroinvasive disease (WNND). Within the imputed West Nile virus dataset (severe cases n = 381 and asymptomatic/mild controls = 441), we found novel loci within the MCF.2 Cell Line Derived Transforming Sequence Like (MCF2L) gene (rs9549655 and rs2297192) through the individual loci analyses, although none reached statistical significance. Incorporating population controls from the Wisconsin Longitudinal Study on Aging (n = 9012) did not identify additional novel variants, a possible reflection of the cohort's inclusion of individuals who could develop mild or severe WNV disease upon infection. Many of the top gene-gene interaction results were intergenic, with currently undefined biological roles, highlighting the need for further investigation into these regions and other identified gene targets in severe WNND. Further studies including larger sample sizes and more diverse populations reflective of those at risk are needed to fully understand the genetic architecture of severe WNDD and provide guidance on viable targets for therapeutic and vaccine development.