title: Identification of genetic variants associated with susceptibility to West Nile virus neuroinvasive disease.
abstract: West Nile virus (WNV) infection results in a diverse spectrum of outcomes, and host genetics are likely to influence susceptibility to neuroinvasive disease (West Nile neuroinvasive disease (WNND)). We performed whole-exome sequencing of 44 individuals with WNND and identified alleles associated with severe disease by variant filtration in cases, kernel association testing in cases and controls and single-nucleotide polymorphism (SNP) imputation into a larger cohort of WNND cases and seropositive controls followed by genome-wide association analysis. Variant filtration prioritized genes based on the enrichment of otherwise rare variants, but did not unambiguously implicate variants shared by a majority of cases. Kernel association demonstrated enrichment for risk and protective alleles in the human leukocyte antigen (HLA)-A and HLA-DQB1 loci that have well understood roles in antiviral immunity. Two loci, HERC5 and an intergenic region between CD83 and JARID2, were implicated by multiple imputed SNPs and exceeded genome-wide significance in a discovery cohort (n=862). SNPs at two additional loci, TFCP2L1 and CACNA1H, achieved genome-wide significance after association testing of directly genotyped and imputed SNPs in a discovery cohort (n=862) and a separate replication cohort (n=1387). The context of these loci suggests that immunoregulatory, ion channel and endothelial barrier functions may be important elements of the host response to WNV.
authors.affiliation: School of Medicine, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Long
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA.|Blood Systems Research Institute, San Francisco, CA, USA.
authors.forename: X
authors.initials: X
authors.lastname: Deng
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Singh
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Loeb
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Lauring
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA.|Blood Systems Research Institute, San Francisco, CA, USA.
authors.forename: M
authors.identifier: 0000-0001-5783-1401
authors.initials: M
authors.lastname: Seielstad
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000235:genetics; D020747:Calcium Channels, T-Type / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D056426:Genetic Loci; D059866:HLA-DQ beta-Chains / Q000235:genetics; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D008875:Middle Aged; D063151:Polycomb Repressive Complex 2 / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012097:Repressor Proteins / Q000235:genetics; D014901:West Nile Fever / Q000235:genetics*; D000097802:CD83 Antigen
chemical_list: D015703:Antigens, CD; D020747:Calcium Channels, T-Type; D059866:HLA-DQ beta-Chains; D007136:Immunoglobulins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D063151:Polycomb Repressive Complex 2; D012097:Repressor Proteins; D000097802:CD83 Antigen; C479952:CACNA1H protein, human; C402395:HERC5 protein, human; C069051:HLA-DQB1 antigen; C547777:JARID2 protein, human; C428128:TFCP2L1 protein, human