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Identification of genetic variants associated with susceptibility to West Nile virus neuroinvasive disease

Genes & Immunity volume 17, pages 298–304 (2016)Cite this article

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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.

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Acknowledgements

We thank Paul Renauer for technical assistance and Amr Sawalha for a critical reading of the manuscript. This work was supported by a grant from Novartis and institutional funds from the Blood Systems Research Institute. DL was supported by the National Center for Research Resources, the National Center for Advancing Translational Sciences and the Office of the Director, National Institutes of Health, through UCSF-CTSI Grant Numbers TL1 RR024129 and TL1 TR000144. ASL was supported by National Institutes of Health K08 AI081754 and a Clinician Scientist Development Award from the Doris Duke Charitable Foundation. ML was supported in part by the NIH Population Genetics Analysis Program.

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Author notes

  1. A S Lauring and M Seielstad: These authors contributed equally to this work.

Authors and Affiliations

  1. School of Medicine, University of California, San Francisco, San Francisco, CA, USA

    D Long

  2. Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA

    X Deng & M Seielstad

  3. Blood Systems Research Institute, San Francisco, CA, USA

    X Deng & M Seielstad

  4. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada

    P Singh & M Loeb

  5. Division of Infectious Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

    A S Lauring

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  1. D Long
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Correspondence to A S Lauring.

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Long, D., Deng, X., Singh, P. et al. Identification of genetic variants associated with susceptibility to West Nile virus neuroinvasive disease. Genes Immun 17, 298–304 (2016). https://doi.org/10.1038/gene.2016.21

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