title: Fine mapping of the GWAS loci identifies SLC35D1 and IL23R as potential risk genes for leprosy.
abstract: BACKGROUND
  Previous genome-wide association study (GWAS) identified two new leprosy associated loci (1p31.3 [rs3762318] and 6q24.3 [rs2275606]). However, there were insufficient validations in independent populations.
  
  
  OBJECTIVE
  To validate the association and to map the potentially causal variants/genes underlying the association between the confirmed GWAS hit and leprosy.
  
  
  METHODS
  We genotyped 10 variants in the regions encompassing the two loci in 1110 Han Chinese subjects with and without leprosy, followed by expression quantitative trait loci (eQTL), mRNA expression profiling, and network analysis. We further sequenced the exon region of four genes that were located in the confirmed GWAS hit region in 80 leprosy patients and 99 individuals without leprosy.
  
  
  RESULTS
  We validated the positive association of rs3762318 with multibacillary leprosy (P=7.5×10-4), whereas the association of rs2275606 could not be validated. eQTL analysis showed that both the GWAS locus rs3762318 and one surrounding positively associated SNP rs2144658 (P=1.8×10-3) significantly affected the mRNA expression of a nearby gene SLC35D1, which might be involved in metabolism. Moreover, SLC35D1 was differentially expressed in skin tissues of leprosy patients, and the differential expression pattern was consistent among leprosy subtypes. Rare damaging missense variants in IL23R were significantly enriched in leprosy patients.
  
  
  CONCLUSIONS
  Our results supported the positive association between the GWAS reported rs3762318 and leprosy, and SLC35D1 and IL23R might be the causal genes.
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China.
authors.forename: Guo-Dong
authors.initials: GD
authors.lastname: Li
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China.
authors.forename: Deng-Feng
authors.initials: DF
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Xiang
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China; Department of Dermatology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China.
authors.forename: Jia-Qi
authors.initials: JQ
authors.lastname: Feng
authors.affiliation: Yuxi City Center for Disease Control and Prevention, Yuxi, Yunnan 653100, China.
authors.forename: Xiao-An
authors.initials: XA
authors.lastname: Li
authors.affiliation: Department of Dermatology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China.
authors.forename: Yu-Ye
authors.initials: YY
authors.lastname: Li
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China. Electronic address: yaoyg@mail.kiz.ac.cn.
authors.forename: Yong-Gang
authors.initials: YG
authors.lastname: Yao
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002648:Child; D002681:China; D002874:Chromosome Mapping; D005091:Exons; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D056006:Leprosy, Multibacillary / Q000235:genetics*; D056005:Leprosy, Paucibacillary / Q000235:genetics*; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000235:genetics*; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012333:RNA, Messenger / Q000378:metabolism; D018123:Receptors, Interleukin / Q000235:genetics*; D012307:Risk Factors; D055815:Young Adult
chemical_list: C515500:IL23R protein, human; D009004:Monosaccharide Transport Proteins; D012333:RNA, Messenger; D018123:Receptors, Interleukin; C425807:SLC35D1 protein, human
keywords: GWAS; IL23R; Leprosy; SLC35D1; Susceptibility; eQTL