Journal Article

Genome-wide association study identifies human genetic variants associated with fatal outcome from Lassa fever

Tariyal, Ridhi, Jiang, Pan-Pan, Tewhey, Ryan, Robles-Sikisaka, Refugio, Siddle, Katherine J., Iruolagbe, Christopher O., Kotliar, Dylan, Heuklom, Shannon, Vitti, Joseph J., Omoniwa, Omowunmi, Happi, Christian T., Asogun, Danny A., Kales, Susan, Schieffelin, John S., Happi, Anise N., Folarin, Onikepe A., Okokhere, Peter O., Günther, Stephan, Nair, Parvathy, Stremlau, Matt, Gladden-Young, Adrianne, Sabeti, Pardis C., Eromon, Philomena E., Karlsson, Elinor K., Lander, Eric S., Moses, Lina M., Khan, S. Humarr, Sandi, John Demby, Broodie, Nisha, Dic-Ijiewere, Mercy, Kunz, Stefan, Ollila, Hanna M., Phelan, Eric, Okogbenin, Sylvanus A., Reilly, Steven K., Yozwiak, Nathan, Okonkwo, Alexander K., Garry, Robert F., Andersen, Kristian G., Mehta, Samar, Grant, Donald S., Winnicki, Sarah, Tabrizi, Shervin, Raju, Siddharth, Momoh, Mambu, Iraoyah, Kelly, Goba, Augustine, Oldstone, Michael B. A., Rubins, Kathleen, Kennedy, Sharon G., Schaffner, Stephen F., Kanneh, Lansana, Honko, Anna N., Odia, Ikponmwosa, Gire, Stephen K., McCormick, Joseph B., Hensley, Lisa, Akpede, George O., Branco, Luis M., Osazuwa, Omoregie O., B

2024

Overview

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. GWAS in difficult-to-recruit populations identifies variants associated with Lassa fever outcome and susceptibility at loci proximal to LIF, GRM7 and LARGE1.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 45/43 / 631/208/205/2138 / 631/208/212/2301 / 631/326/596/2557 / Biomedical and Life Sciences / Fever / Genetic diversity / genetic variation / Genome-wide association studies / Genome-Wide Association Study / Genomes / Haplotypes / Hemorrhagic fever / Histocompatibility antigen HLA / HLA antigens / Human Genetics / Humans / Infectious Diseases / Lassa fever / Lassa Fever - diagnosis / Lassa Fever - epidemiology / Lassa Fever - genetics / Lassa mammarenavirus / Lassa virus - genetics / Lassa virus fever / Life Sciences / Medical Microbiology / Microbiology / mortality / Nigeria / Parasitology / pathogenesis / Positive selection / risk / risk reduction / Seroepidemiologic Studies / Serology / seroprevalence / Sierra Leone / Tissue typing / Virology