Deep resequencing identifies candidate functional genes in leprosy GWAS loci

Abstract

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.

Leprosy: treatment, prevention, immune response and gene function

“…The identification of individuals at risk for DHS becomes feasible through testing for the presence of HLA-B13:01 and TCR clones. In addition, the methods allow for a more precise and effective screening process, enabling timely interventions and personalized medical strategies for those susceptible to DHS ( 119 ). Moreover, five amino acid variants in HLA-DRB1 are also closely related to the DHS in Chinese patients.…”

Genome‐wide meta‐analysis and fine‐mapping prioritize potential causal variants and genes related to leprosy

“…16 For example, 65.7% (23 out of 35) of the established GWAS variants of leprosy are located in the noncoding regions of the genome. [6][7][8][9][10][11][12][13][14]17,18 Thus, post-GWASs mainly focus on finemapping research, which could enable to identify causal genes or variants and establish a foundation for further functional exploration and interpretation of the pathogenesis of diseases. 19,20 Large-scale genetic fine-mapping analyses have been conducted for infectious and autoimmune diseases.…”

“…GWAS loci often harbor many variants and genes, and most of the significantly associated variants are located in the nonprotein‐coding regions of the genome 16 . For example, 65.7% (23 out of 35) of the established GWAS variants of leprosy are located in the noncoding regions of the genome 6–14,17,18 . Thus, post‐GWASs mainly focus on fine‐mapping research, which could enable to identify causal genes or variants and establish a foundation for further functional exploration and interpretation of the pathogenesis of diseases 19,20 .…”