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

Dylan Kotliar; Siddharth Raju; Shervin Tabrizi; Ikponmwosa Odia; Augustine Goba; Mambu Momoh; John Demby Sandi; Parvathy Nair; Eric Phelan; Ridhi Tariyal; Philomena E Eromon; Samar Mehta; Refugio Robles-Sikisaka; Katherine J Siddle; Matt Stremlau; Simbirie Jalloh; Stephen K Gire; Sarah Winnicki; Bridget Chak; Stephen 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; Pan-Pan Jiang; Nathan Yozwiak; Shannon Heuklom; Lina M Moses; George O Akpede; Danny A Asogun; Kathleen Rubins; Susan Kales; Anise N Happi; Christopher O Iruolagbe; Mercy Dic-Ijiewere; Kelly Iraoyah; Omoregie O Osazuwa; Alexander K Okonkwo; Stefan Kunz; Joseph B McCormick; S Humarr Khan; Anna N Honko; Eric S Lander; Michael B A Oldstone; Lisa Hensley; Onikepe A Folarin; Sylvanus A 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 T Happi; Pardis C Sabeti

doi:10.1038/s41564-023-01589-3

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

Nat Microbiol. 2024 Mar;9(3):751-762. doi: 10.1038/s41564-023-01589-3. Epub 2024 Feb 7.

Authors

Dylan Kotliar^#^{1

2

3}, Siddharth Raju^#^{4

5}, Shervin Tabrizi^#^{4

6

7}, Ikponmwosa Odia^#⁸, Augustine Goba⁹, Mambu Momoh^{9

10}, John Demby Sandi⁹, Parvathy Nair¹¹, Eric Phelan¹², Ridhi Tariyal¹³, Philomena E Eromon^{8

14}, Samar Mehta¹⁵, Refugio Robles-Sikisaka¹⁶, Katherine J Siddle⁴, Matt Stremlau¹⁷, Simbirie Jalloh⁹, Stephen K Gire¹³, Sarah Winnicki⁴, Bridget Chak¹⁸, Stephen F Schaffner^{4

19

20}, Matthias Pauthner²¹, Elinor K Karlsson^{4

22

23}, Sarah R Chapin⁴, Sharon G Kennedy^{4

24}, Luis M Branco²⁵, Lansana Kanneh²⁶, Joseph J Vitti⁴, Nisha Broodie²⁷, Adrianne Gladden-Young²⁸, Omowunmi Omoniwa²⁹, Pan-Pan Jiang³⁰, Nathan Yozwiak³¹, Shannon Heuklom³², Lina M Moses³³, George O Akpede^{8

34}, Danny A Asogun³⁵, Kathleen Rubins³⁶, Susan Kales³⁷, Anise N Happi¹⁴, Christopher O Iruolagbe³⁸, Mercy Dic-Ijiewere³⁸, Kelly Iraoyah³⁸, Omoregie O Osazuwa³⁸, Alexander K Okonkwo³⁸, Stefan Kunz³⁹, Joseph B McCormick⁴⁰, S Humarr Khan⁹, Anna N Honko⁴¹, Eric S Lander^{4

5

42}, Michael B A Oldstone¹⁶, Lisa Hensley⁴³, Onikepe A Folarin^{14

44}, Sylvanus A Okogbenin⁸, Stephan Günther⁴⁵, Hanna M Ollila^{4

46

47

48}, Ryan Tewhey³⁷, Peter O Okokhere^{8

34

38}, John S Schieffelin⁴⁹, Kristian G Andersen¹⁶, Steven K Reilly⁵⁰, Donald S Grant^{9

26}, Robert F Garry⁵¹, Kayla G Barnes^{4

20

52

53}, Christian T Happi^{54

55

56}, Pardis C Sabeti^{57

58

59

60

61

62}

Affiliations

¹ Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA. [email protected].
² Department of Systems Biology, Harvard Medical School, Boston, MA, USA. [email protected].
³ Department of Internal Medicine, Brigham and Women's Hospital, Boston, MA, USA. [email protected].
⁴ Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA.
⁵ Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
⁶ Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA.
⁷ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁸ Institute of Lassa Fever, Research and Control, Irrua Specialist Teaching Hospital, Irrua, Nigeria.
⁹ College of Medicine and Allied Health Sciences, University of Sierra Leone, Freetown, Sierra Leone.
¹⁰ Eastern Polytechnic College, Kenema, Sierra Leone.
¹¹ Howard Hughes Medical Institute, Chevy Chase, MD, USA.
¹² Prospr at Work Inc., Berlin, Germany.
¹³ NextGen Jane, Inc., Oakland, CA, USA.
¹⁴ African Centre of Excellence for Genomics of Infectious Diseases (ACEGID), Redeemer's University, Ede, Nigeria.
¹⁵ Department of Critical Care Medicine, University of Maryland Medical Center, Baltimore, MA, USA.
¹⁶ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA.
¹⁷ Equator Labs Incorporated, Washington, DC, USA.
¹⁸ Biological Sciences Division, University of Chicago, Chicago, IL, USA.
¹⁹ Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, USA.
²⁰ Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
²¹ Vir Biotechnology, San Francisco, CA, USA.
²² Genomics and Computational Biology, UMass Chan Medical School, Worcester, MA, USA.
²³ Program in Molecular Medicine, UMass Chan Medical School, Worcester, MA, USA.
²⁴ Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
²⁵ Zalgen Labs, Frederick, MD, USA.
²⁶ Viral Hemorrhagic Fever Program, Kenema Government Hospital, Ministry of Health and Sanitation, Kenema, Sierra Leone.
²⁷ New York-Presbyterian Hospital-Columbia and Cornell, New York, NY, USA.
²⁸ Molecular Microbiology, Graduate School of Biomedical Sciences, Tufts University, Boston, MA, USA.
²⁹ Malaria Consortium, Abuja, Nigeria.
³⁰ Google Medical Brain, Mountain View, CA, USA.
³¹ Gene and Cell Therapy Institute, Mass General Brigham, Cambridge, MA, USA.
³² San Francisco Community Health Center, San Francisco, CA, USA.
³³ Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA.
³⁴ Department of Medicine, Ambrose Alli University, Ekpoma, Nigeria.
³⁵ Department of Community Medicine, Ambrose Alli University, Ekpoma, Nigeria.
³⁶ National Aeronautics and Space Administration, Houston, TX, USA.
³⁷ The Jackson Laboratory, Bar Harbor, ME, USA.
³⁸ Department of Medicine, Irrua Specialist Teaching Hospital, Irrua, Nigeria.
³⁹ Institute of Microbiology, University Hospital Center and University of Lausanne, Lausanne, Switzerland.
⁴⁰ UTHealth Houston School of Public Health, Brownsville Campus, Brownsville, TX, USA.
⁴¹ Boston University School of Medicine, Boston, MA, USA.
⁴² Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA.
⁴³ National Institutes of Health Integrated Research Facility, Frederick, MA, USA.
⁴⁴ Department of Biological Sciences, Redeemer's University, Ede, Nigeria.
⁴⁵ Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
⁴⁶ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
⁴⁷ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁴⁸ Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁴⁹ Section of Infectious Disease, Department of Pediatrics, Tulane University School of Medicine, New Orleans, LA, USA.
⁵⁰ Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
⁵¹ Tulane University School of Medicine, New Orleans, LA, USA.
⁵² Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Kamuzu University of Health Sciences, Blantyre, Malawi.
⁵³ Department of Vector Biology and Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool, UK.
⁵⁴ African Centre of Excellence for Genomics of Infectious Diseases (ACEGID), Redeemer's University, Ede, Nigeria. [email protected].
⁵⁵ Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA. [email protected].
⁵⁶ Department of Biological Sciences, Redeemer's University, Ede, Nigeria. [email protected].
⁵⁷ Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA. [email protected].
⁵⁸ Howard Hughes Medical Institute, Chevy Chase, MD, USA. [email protected].
⁵⁹ Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, USA. [email protected].
⁶⁰ Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA. [email protected].
⁶¹ Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. [email protected].
⁶² Massachusetts Consortium on Pathogen Readiness, Boston, MA, USA. [email protected].

^# Contributed equally.

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.

MeSH terms

Fever
Genome-Wide Association Study
Human Genetics
Humans
Lassa Fever* / diagnosis
Lassa Fever* / epidemiology
Lassa Fever* / genetics
Lassa virus / genetics
Seroepidemiologic Studies

Abstract

MeSH terms

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