Genome-wide association study identifies human genetic variants associated with fatal outcome from Lassa fever
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Date
2024-02-07
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Nature microbiology
Abstract
Infection with Lassa virus (LASV) can cause Lassa fever, a haemorrhagic
illness with an estimated fatality rate of 29.7%, but causes no or mild
symptoms in many individuals. Here, to investigate whether human genetic
variation underlies the heterogeneity of LASV infection, we carried out
genome-wide association studies (GWAS) as well as seroprevalence surveys,
human leukocyte antigen typing and high-throughput variant functional
characterization assays. We analysed Lassa fever susceptibility and fatal
outcomes in 533 cases of Lassa fever and 1,986 population controls recruited
over a 7 year period in Nigeria and Sierra Leone. We detected genome-wide
significant variant associations with Lassa fever fatal outcomes near GRM7
and LIF in the Nigerian cohort. We also show that a haplotype bearing
signatures of positive selection and overlapping LARGE1, a required LASV
entry factor, is associated with decreased risk of Lassa fever in the Nigerian
cohort but not in the Sierra Leone cohort. Overall, we identified variants and
genes that may impact the risk of severe Lassa fever, demonstrating how
GWAS can provide insight into viral pathogenesis.