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