Deep resequencing identifies candidate functional genes in leprosy GWAS loci.
Leprosy is the second most prevalent mycobacterial disease globally. Despite the existence of an effective therapy, leprosy incidence has consistently remained above 200,000 cases per year since 2010. Numerous host genetic factors have been identified for leprosy that contribute to the persistently...
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ftdoajarticles:oai:doaj.org/article:084d0a397c8542769f79c1fd1fb72f27 2023-05-15T15:11:13+02:00 Deep resequencing identifies candidate functional genes in leprosy GWAS loci. Vinicius M Fava Monica Dallmann-Sauer Marianna Orlova Wilian Correa-Macedo Nguyen Van Thuc Vu Hong Thai Alexandre Alcaïs Laurent Abel Aurélie Cobat Erwin Schurr 2021-12-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0010029 https://doaj.org/article/084d0a397c8542769f79c1fd1fb72f27 EN eng Public Library of Science (PLoS) https://doi.org/10.1371/journal.pntd.0010029 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0010029 https://doaj.org/article/084d0a397c8542769f79c1fd1fb72f27 PLoS Neglected Tropical Diseases, Vol 15, Iss 12, p e0010029 (2021) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2021 ftdoajarticles https://doi.org/10.1371/journal.pntd.0010029 2022-12-31T03:45:24Z Leprosy is the second most prevalent mycobacterial disease globally. Despite the existence of an effective therapy, leprosy incidence has consistently remained above 200,000 cases per year since 2010. Numerous host genetic factors have been identified for leprosy that contribute to the persistently high case numbers. In the past decade, genetic epidemiology approaches, including genome-wide association studies (GWAS), identified more than 30 loci contributing to leprosy susceptibility. However, GWAS loci commonly encompass multiple genes, which poses a challenge to define causal candidates for each locus. To address this problem, we hypothesized that genes contributing to leprosy susceptibility differ in their frequencies of rare protein-altering variants between cases and controls. Using deep resequencing we assessed protein-coding variants for 34 genes located in GWAS or linkage loci in 555 Vietnamese leprosy cases and 500 healthy controls. We observed 234 nonsynonymous mutations in the targeted genes. A significant depletion of protein-altering variants was detected for the IL18R1 and BCL10 genes in leprosy cases. The IL18R1 gene is clustered with IL18RAP and IL1RL1 in the leprosy GWAS locus on chromosome 2q12.1. Moreover, in a recent GWAS we identified an HLA-independent signal of association with leprosy on chromosome 6p21. Here, we report amino acid changes in the CDSN and PSORS1C2 genes depleted in leprosy cases, indicating them as candidate genes in the chromosome 6p21 locus. Our results show that deep resequencing can identify leprosy candidate susceptibility genes that had been missed by classic linkage and association approaches. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 15 12 e0010029 |
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Directory of Open Access Journals: DOAJ Articles |
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English |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Vinicius M Fava Monica Dallmann-Sauer Marianna Orlova Wilian Correa-Macedo Nguyen Van Thuc Vu Hong Thai Alexandre Alcaïs Laurent Abel Aurélie Cobat Erwin Schurr Deep resequencing identifies candidate functional genes in leprosy GWAS loci. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Leprosy is the second most prevalent mycobacterial disease globally. Despite the existence of an effective therapy, leprosy incidence has consistently remained above 200,000 cases per year since 2010. Numerous host genetic factors have been identified for leprosy that contribute to the persistently high case numbers. In the past decade, genetic epidemiology approaches, including genome-wide association studies (GWAS), identified more than 30 loci contributing to leprosy susceptibility. However, GWAS loci commonly encompass multiple genes, which poses a challenge to define causal candidates for each locus. To address this problem, we hypothesized that genes contributing to leprosy susceptibility differ in their frequencies of rare protein-altering variants between cases and controls. Using deep resequencing we assessed protein-coding variants for 34 genes located in GWAS or linkage loci in 555 Vietnamese leprosy cases and 500 healthy controls. We observed 234 nonsynonymous mutations in the targeted genes. A significant depletion of protein-altering variants was detected for the IL18R1 and BCL10 genes in leprosy cases. The IL18R1 gene is clustered with IL18RAP and IL1RL1 in the leprosy GWAS locus on chromosome 2q12.1. Moreover, in a recent GWAS we identified an HLA-independent signal of association with leprosy on chromosome 6p21. Here, we report amino acid changes in the CDSN and PSORS1C2 genes depleted in leprosy cases, indicating them as candidate genes in the chromosome 6p21 locus. Our results show that deep resequencing can identify leprosy candidate susceptibility genes that had been missed by classic linkage and association approaches. |
format |
Article in Journal/Newspaper |
author |
Vinicius M Fava Monica Dallmann-Sauer Marianna Orlova Wilian Correa-Macedo Nguyen Van Thuc Vu Hong Thai Alexandre Alcaïs Laurent Abel Aurélie Cobat Erwin Schurr |
author_facet |
Vinicius M Fava Monica Dallmann-Sauer Marianna Orlova Wilian Correa-Macedo Nguyen Van Thuc Vu Hong Thai Alexandre Alcaïs Laurent Abel Aurélie Cobat Erwin Schurr |
author_sort |
Vinicius M Fava |
title |
Deep resequencing identifies candidate functional genes in leprosy GWAS loci. |
title_short |
Deep resequencing identifies candidate functional genes in leprosy GWAS loci. |
title_full |
Deep resequencing identifies candidate functional genes in leprosy GWAS loci. |
title_fullStr |
Deep resequencing identifies candidate functional genes in leprosy GWAS loci. |
title_full_unstemmed |
Deep resequencing identifies candidate functional genes in leprosy GWAS loci. |
title_sort |
deep resequencing identifies candidate functional genes in leprosy gwas loci. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2021 |
url |
https://doi.org/10.1371/journal.pntd.0010029 https://doaj.org/article/084d0a397c8542769f79c1fd1fb72f27 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 15, Iss 12, p e0010029 (2021) |
op_relation |
https://doi.org/10.1371/journal.pntd.0010029 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0010029 https://doaj.org/article/084d0a397c8542769f79c1fd1fb72f27 |
op_doi |
https://doi.org/10.1371/journal.pntd.0010029 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
15 |
container_issue |
12 |
container_start_page |
e0010029 |
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1766342102366552064 |