Abstract
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.
Highlights
Mosquito-borne viruses such as West Nile virus (WNV) are a major global health threat, with estimates of more than 340 million infections and more than 440,000 fatalities each year [1]
The largest study conducted to date included 560 neuroinvasive case patients and 950 control patients genotyped for 13,371 single-nucleotide polymorphisms (SNPs), and identified SNPs within the genes replication factor C1 (RFC1), sodium channel neuronal type I α subunit (SCN1A), and ananyl aminopeptidase (ANPEP) to be associated with severe disease, with p-values not reaching statistical significance [11]
With only a minority of individuals infected with WNV developing severe, potentially life-threatening disease, it is vital to identify factors associated with susceptibility to disease [33,34]
Summary
Mosquito-borne viruses such as West Nile virus (WNV) are a major global health threat, with estimates of more than 340 million infections and more than 440,000 fatalities each year [1]. The largest study conducted to date included 560 neuroinvasive case patients and 950 control patients genotyped for 13,371 SNPs, and identified SNPs within the genes replication factor C1 (RFC1), sodium channel neuronal type I α subunit (SCN1A), and ananyl aminopeptidase (ANPEP) to be associated with severe disease, with p-values not reaching statistical significance [11] These genes function in several distinct cellular physiology processes with potential relevance to WNV infection and disease progression [11], but did not reveal common immune-related targets as has been noted in genome-wide association studies (GWAS) of related viral infections [12,13]. Using the first WNND GWAS published to date, we used imputation, population controls, and gene-gene interaction analysis to further identify genetic targets and better define genetic architecture for severe WNND, with the ultimate objective of providing guidance for therapeutic and vaccine development [15]
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