Multi-ancestry meta-analysis of host genetic susceptibility to tuberculosis identifies shared genetic architecture
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 Tubercul...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2024-01-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/84394 |
| _version_ | 1797353777192239104 |
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| author | Haiko Schurz Vivek Naranbhai Tom A Yates James J Gilchrist Tom Parks Peter J Dodd Marlo Möller Eileen G Hoal Andrew P Morris Adrian VS Hill International Tuberculosis Host Genetics Consortium |
| author_facet | Haiko Schurz Vivek Naranbhai Tom A Yates James J Gilchrist Tom Parks Peter J Dodd Marlo Möller Eileen G Hoal Andrew P Morris Adrian VS Hill International Tuberculosis Host Genetics Consortium |
| author_sort | Haiko Schurz |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T13:35:56Z |
| format | Article |
| id | doaj.art-00c3c9bd8aaa466cb16976111e168c78 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-03-08T13:35:56Z |
| publishDate | 2024-01-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-00c3c9bd8aaa466cb16976111e168c782024-01-16T18:07:19ZengeLife Sciences Publications LtdeLife2050-084X2024-01-011310.7554/eLife.84394Multi-ancestry meta-analysis of host genetic susceptibility to tuberculosis identifies shared genetic architectureHaiko Schurz0https://orcid.org/0000-0002-0009-3409Vivek Naranbhai1Tom A Yates2https://orcid.org/0000-0002-6081-1767James J Gilchrist3https://orcid.org/0000-0003-2045-6788Tom Parks4Peter J Dodd5Marlo Möller6https://orcid.org/0000-0002-0805-6741Eileen G Hoal7Andrew P Morris8https://orcid.org/0000-0002-6805-6014Adrian VS Hill9International Tuberculosis Host Genetics ConsortiumDSI-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 AfricaWellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Massachusetts General Hospital, Boston, United States; Dana-Farber Cancer Institute, Boston, United States; Centre for the AIDS Programme of Research in South Africa, Durban, South Africa; Harvard Medical School, Boston, United StatesDivision of Infection and Immunity, Faculty of Medical Sciences, University College London, London, United KingdomWellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Department of Paediatrics, University of Oxford, Oxford, United KingdomWellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Department of Infectious Diseases Imperial College London, London, United KingdomSchool of Health and Related Research, University of Sheffield, Sheffield, United KingdomDSI-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 AfricaDSI-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 AfricaCentre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, The University of Manchester, Manchester, United KingdomWellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Jenner Institute, University of Oxford, Oxford, United KingdomThe 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.https://elifesciences.org/articles/84394tuberculosisGWASmulti-ancestrymeta-analysisHLA |
| spellingShingle | Haiko Schurz Vivek Naranbhai Tom A Yates James J Gilchrist Tom Parks Peter J Dodd Marlo Möller Eileen G Hoal Andrew P Morris Adrian VS Hill International Tuberculosis Host Genetics Consortium Multi-ancestry meta-analysis of host genetic susceptibility to tuberculosis identifies shared genetic architecture eLife tuberculosis GWAS multi-ancestry meta-analysis HLA |
| title | Multi-ancestry meta-analysis of host genetic susceptibility to tuberculosis identifies shared genetic architecture |
| title_full | Multi-ancestry meta-analysis of host genetic susceptibility to tuberculosis identifies shared genetic architecture |
| title_fullStr | Multi-ancestry meta-analysis of host genetic susceptibility to tuberculosis identifies shared genetic architecture |
| title_full_unstemmed | Multi-ancestry meta-analysis of host genetic susceptibility to tuberculosis identifies shared genetic architecture |
| title_short | Multi-ancestry meta-analysis of host genetic susceptibility to tuberculosis identifies shared genetic architecture |
| title_sort | multi ancestry meta analysis of host genetic susceptibility to tuberculosis identifies shared genetic architecture |
| topic | tuberculosis GWAS multi-ancestry meta-analysis HLA |
| url | https://elifesciences.org/articles/84394 |
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