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

Dylan Kotliar ^1,2,3, Siddharth Raju ^4,5, Shervin Tabrizi ^4,6,7

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

⁰Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA. dkotliar@mgb.org.

Nature Microbiology +

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February 7, 2024

View abstract on PubMed

Summary

Human genetic variations influence Lassa fever severity. Genome-wide association studies identified specific gene variants linked to Lassa virus (LASV) infection outcomes, offering insights into disease pathogenesis.

Area Of Science

Genetics
Virology
Immunology

Background

Lassa virus (LASV) causes Lassa fever, a hemorrhagic illness with significant mortality, yet disease presentation varies widely.
The heterogeneity in Lassa fever outcomes suggests a potential role for human genetic factors in disease susceptibility and severity.

Purpose Of The Study

To investigate the influence of human genetic variation on Lassa fever susceptibility and fatal outcomes.
To identify specific genetic variants and genes associated with differential LASV infection responses.

Main Methods

Genome-wide association studies (GWAS) were conducted on Lassa fever cases and population controls.
Seroprevalence surveys, human leukocyte antigen (HLA) typing, and high-throughput variant functional characterization assays were employed.
Analysis included 533 Lassa fever cases and 1,986 controls from Nigeria and Sierra Leone over a 7-year period.

Main Results

Genome-wide significant variant associations with fatal Lassa fever outcomes were detected near the GRM7 and LIF genes in the Nigerian cohort.
A positively selected haplotype overlapping LARGE1, a LASV entry factor, was associated with reduced Lassa fever risk in Nigerians but not in Sierra Leoneans.
Identified genetic variants suggest an impact on the risk of severe Lassa fever.

Conclusions

Human genetic variation plays a role in determining the severity of Lassa fever.
GWAS can uncover genetic factors contributing to viral pathogenesis and inform strategies for managing LASV infections.
Specific genetic loci and factors like LARGE1 may influence Lassa fever risk differently across populations.

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