Multi-ancestry meta-analysis of host genetic susceptibility to tuberculosis identifies shared genetic architecture

Haiko Schurz; Vivek Naranbhai; Tom A Yates; James J Gilchrist; Tom Parks; Peter J Dodd; Marlo Möller; Eileen G Hoal; Andrew P Morris; Adrian V S Hill; International Tuberculosis Host Genetics Consortium

doi:10.7554/eLife.84394

Multi-ancestry meta-analysis of host genetic susceptibility to tuberculosis identifies shared genetic architecture

Elife. 2024 Jan 15:13:e84394. doi: 10.7554/eLife.84394.

Authors

Haiko Schurz¹, Vivek Naranbhai^{2

3

4

5

6}, Tom A Yates⁷, James J Gilchrist^{2

8}, Tom Parks^{2

9}, Peter J Dodd¹⁰, Marlo Möller¹, Eileen G Hoal¹, Andrew P Morris¹¹, Adrian V S Hill^{2

12}; International Tuberculosis Host Genetics Consortium

Collaborators

International Tuberculosis Host Genetics Consortium:
Haiko Schurz¹³, Vivek Naranbhai^{2

3

4

5

6}, Tom A Yates¹⁴, James J Gilchrist^{2

8}, Tom Parks^{2

9}, Peter J Dodd¹¹, Marlo Möller¹³, Eileen G Hoal¹³, Andrew P Morris¹¹, Adrian V S Hill^{2

12}, Reinout van Crevel^{15

16}, Arjan van Laarhoven¹⁵, Tom H M Ottenhoff¹⁷, Andres Metspalu¹⁸, Reedik Magi¹⁸, Christian G Meyer^{19

20}, Magda Ellis²¹, Thorsten Thye¹⁰, Surakameth Mahasirimongkol²², Ekawat Pasomsub²³, Katsushi Tokunaga²⁴, Yosuke Omae²⁴, Hideki Yanai²⁵, Taisei Mushiroda²⁶, Michiaki Kubo²⁶, Atsushi Takahashi^{26

27

28}, Yoichiro Kamatani^{26

27}, Bachti Alisjahbana²⁹, Wei Liu^{30

31}, A-Dong Sheng^{32

33

34

35}, Yurong Yang³⁶

Affiliations

¹ DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
² Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
³ Massachusetts General Hospital, Boston, United States.
⁴ Dana-Farber Cancer Institute, Boston, United States.
⁵ Centre for the AIDS Programme of Research in South Africa, Durban, South Africa.
⁶ Harvard Medical School, Boston, United States.
⁷ Division of Infection and Immunity, Faculty of Medical Sciences, University College London, London, United Kingdom.
⁸ Department of Paediatrics, University of Oxford, Oxford, United Kingdom.
⁹ Department of Infectious Diseases Imperial College London, London, United Kingdom.
¹⁰ School of Health and Related Research, University of Sheffield, Sheffield, United Kingdom.
¹¹ Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, The University of Manchester, Manchester, United Kingdom.
¹² Jenner Institute, University of Oxford, Oxford, United Kingdom.
¹³ DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University,, Cape Town, South Africa.
¹⁴ Division of Infection and Immunity, Faculty of Medical Sciences, University College, London, United Kingdom.
¹⁵ Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands.
¹⁶ Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
¹⁷ Head Lab Dept of Infectious Diseases; Head Group Immunology and Immunogenetics of Bacterial Infectious Diseases Leiden University Medical Center, Leiden, Netherlands.
¹⁸ Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.
¹⁹ Institute of Tropical Medicine, Eberhard-Karls University Tübingen, Tübingen, Germany.
²⁰ Faculty of Medicine, Duy Tan University, Da Nang, Viet Nam.
²¹ Tuberculosis Research Group, Centenary Institute, Sydney, Australia.
²² Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand.
²³ Virology Laboratory, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
²⁴ Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan.
²⁵ Fukujuji Hospital and Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association, Kiyose, Japan.
²⁶ RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
²⁷ Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
²⁸ Department of Genomic Medicine, Research Institute, National Cerebral and Cardiovascular Center, Suita, Japan.
²⁹ Faculty of Medicine, Universitas Padjdjaran - Hasan Sadikin Hospital, Bandung, Indonesia.
³⁰ Department of Plastic and Reconstructive Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University - School of Medicine, Shanghai, China.
³¹ National Tissue Engineering Center of China, Shanghai, China.
³² National Clinical Research Center for Respiratory Diseases, National Key Discipline of Pediatrics, Capital Medical University, Beijing, China.
³³ Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, China.
³⁴ Beijing Key Laboratory of Pediatric Respiratory Infection Diseases, Beijing Pediatric Research Institute, Beijing, China.
³⁵ Children's Hospital Affiliated to Zhengzhou University, Henan Children's Hospital, Zhengzhou Children's Hospital, Zhengzhou, China.
³⁶ Ningxia Medical University, Ningxia Hui Autonomous Region, Ningxia, China.

Abstract

The heritability of susceptibility to tuberculosis (TB) disease has been well recognized. Over 100 genes have been studied as candidates for TB susceptibility, and several variants were identified by genome-wide association studies (GWAS), but few replicate. We established the International Tuberculosis Host Genetics Consortium to perform a multi-ancestry meta-analysis of GWAS, including 14,153 cases and 19,536 controls of African, Asian, and European ancestry. Our analyses demonstrate a substantial degree of heritability (pooled polygenic h² = 26.3%, 95% CI 23.7-29.0%) for susceptibility to TB that is shared across ancestries, highlighting an important host genetic influence on disease. We identified one global host genetic correlate for TB at genome-wide significance (p<5 × 10^-8) in the human leukocyte antigen (HLA)-II region (rs28383206, p-value=5.2 × 10^-9) but failed to replicate variants previously associated with TB susceptibility. These data demonstrate the complex shared genetic architecture of susceptibility to TB and the importance of large-scale GWAS analysis across multiple ancestries experiencing different levels of infection pressure.

Keywords: GWAS; HLA; genetics; genomics; human; meta-analysis; multi-ancestry; tuberculosis.

Publication types

Meta-Analysis

MeSH terms

Genetic Predisposition to Disease*
Genome-Wide Association Study
Humans
Polymorphism, Single Nucleotide
Racial Groups / genetics
Tuberculosis* / genetics

Associated data

Dryad/10.5061/dryad.6wwpzgn2s

Abstract

Publication types

MeSH terms

Associated data

Grants and funding