02347nas a2200253   4500000000100000008004100001260001200042100001100054700002100065700001300086700002000099700001500119700001200134700001400146700001100160700001200171700001300183245008200196856009900278300001300377490000700390520168200397022001402079       2021                            d  c12/20211 aFava V1 aDallmann-Sauer M1 aOrlova M1 aCorrea-Macedo W1 aVan Thuc N1 aThai VH1 aAlcaïs A1 aAbel L1 aCobat A1 aSchurr E00aDeep resequencing identifies candidate functional genes in leprosy GWAS loci.  uhttps://journals.plos.org/plosntds/article/file?id=10.1371/journal.pntd.0010029&type=printable  ae00100290 v153 a<p>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.</p>
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