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Discovery of six new susceptibility loci and analysis of pleiotropic effects in leprosy

Nature Genetics volume 47, pages 267–271 (2015)Cite this article

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Abstract

Genome-wide association studies (GWAS) have led to the discovery of several susceptibility loci for leprosy with robust evidence, providing biological insight into the role of host genetic factors in mycobacterial infection. However, the identified loci only partially explain disease heritability, and additional genetic risk factors remain to be discovered. We performed a 3-stage GWAS of leprosy in the Chinese population using 8,313 cases and 16,017 controls. Besides confirming all previously published loci, we discovered six new susceptibility loci, and further gene prioritization analysis of these loci implicated BATF3, CCDC88B and CIITA-SOCS1 as new susceptibility genes for leprosy. A systematic evaluation of pleiotropic effects demonstrated a high tendency for leprosy susceptibility loci to show association with autoimmunity and inflammatory diseases. Further analysis suggests that molecular sensing of infection might have a similar pathogenic role across these diseases, whereas immune responses have discordant roles in infectious and inflammatory diseases.

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Figure 1: Forest plots of newly discovered leprosy risk loci.
Figure 2: Regional association plots of newly discovered leprosy risk loci.
Figure 3: Association plot of the MHC region.

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Acknowledgements

We thank the individuals who participated in this project. This work was funded by grants from the National Natural Science Foundation of China (81371721, 81271746, 31200933 and 81101187), the National 863 Program of China (2014AA020505), the Shandong Provincial Advanced Taishan Scholar Construction Project and the Agency for Science, Technology and Research of Singapore. A.I. was supported by the Singapore International Graduate Award.

Author information

Author notes

  1. Hong Liu and Astrid Irwanto: These authors contributed equally to this work.

  2. Xuejun Zhang, Jianjun Liu and Furen Zhang: These authors jointly supervised this work.

Authors and Affiliations

  1. Shandong Provincial Hospital for Skin Diseases, Shandong University, Jinan, China

    Hong Liu & Hongqing Tian

  2. Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, China

    Hong Liu, Xi'an Fu, Gongqi Yu, Yongxiang Yu, Yonghu Sun, Chuan Wang, Zhenzhen Wang, Mingfei Chen, Fangfang Bao, Jinghui Li, Jiabao You, Jian Liu, Tongsheng Chu, Na Wang, Guiye Niu, Dianchang Liu, Xiulu Yu, Lin Zhang, Guizhi Zhou, Shumin Chen & Furen Zhang

  3. School of Medicine, Shandong University, Jinan, China

    Hong Liu, Qilin Zhang & Furen Zhang

  4. Shandong Provincial Key Laboratory for Dermatovenereology, Jinan, China

    Hong Liu, Xi'an Fu, Gongqi Yu, Yongxiang Yu, Yonghu Sun, Chuan Wang, Zhenzhen Wang, Mingfei Chen, Fangfang Bao, Jinghui Li, Jiabao You, Jian Liu, Tongsheng Chu, Na Wang, Guiye Niu, Dianchang Liu, Xiulu Yu, Lin Zhang, Guizhi Zhou, Shumin Chen & Furen Zhang

  5. Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research of Singapore, Singapore

    Astrid Irwanto, Huiqi Low, Yi Li, Herty Liany & Jianjun Liu

  6. Saw Swee Hock School of Public Health, National University of Singapore, Singapore

    Astrid Irwanto & Jianjun Liu

  7. Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Yukinori Okada

  8. Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Yukinori Okada

  9. Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA

    Yukinori Okada

  10. Singapore Immunology Network, Singapore

    Anand Kumar Andiappan & Olaf Rotzschke

  11. National Clinical Key Project of Dermatology and Venereology, Jinan, China

    Hongqing Tian & Furen Zhang

  12. Department of Dermatology, First Affiliated Hospital, Anhui Medical University, Hefei, China

    Xuejun Zhang

  13. Key Laboratory of Gene Resource Utilization for Severe Diseases, Ministry of Education and Anhui Province, Hefei, China

    Xuejun Zhang

Authors
  1. Hong Liu
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  2. Astrid Irwanto
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  3. Xi'an Fu
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  32. Furen Zhang
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Contributions

F.Z. obtained financial support and conceived the study. F.Z. and Jianjun Liu designed the study. H. Liu was responsible for sample selection, genotyping and project management. A.I. was responsible for all the statistical analysis. S.C., T.C., X.Y., L.Z. and D.L. undertook recruitment and collected phenotype data. X.F., G.Y., Y.Y., C.W., F.B., Q.Z., H.T., M.C., J. Li, J.Y., Jian Liu, G.Z., N.W. and G.N. conducted sample selection and performed genotyping for the validation study. A.I., Z.W., Y.S., Y.L., H. Low, H. Liany and Y.O. undertook data checking, statistical analysis and bioinformatics interrogations. A.K.A. and O.R. shared their eQTL database. X.Z. provided a portion of the control data in the discovery stage. A.I., H. Liu, F.Z. and Jianjun Liu wrote the manuscript. All the authors contributed to the final manuscript, with F.Z., Jianjun Liu, H. Liu and A.I. having key roles.

Corresponding author

Correspondence to Furen Zhang.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Principal-components analysis (PCA) of all samples analyzed in the discovery phase.

Colors represent study populations, including northern Chinese samples from the first independent study (red), northern Chinese Han samples from the second study (yellow), southern Chinese Han samples from the second study (blue) and southern Chinese minority samples from the second study (white).

Supplementary Figure 2 Quantile-quantile plot of the association.

Left, before removal of SNPs located within known leprosy loci. Right, after removal of SNPs located within known leprosy loci. The dotted vertical line in the right panel shows the point where the statistics lift off from the expected null distribution (–log10 (P) of 3 to 4), which becomes the statistical threshold for our SNP selection (P < 5 × 10−4).

Supplementary Figure 3 Chromosomal plot of the genome-wide association analysis.

Known loci are defined as loci previously published with genome-wide significance (P < 5 × 10−8). Suggestive loci are defined as loci with suggestive evidence of association (1 × 10−6 < P < 5 × 10−8). Novel loci are defined as loci in the current study validated at genome-wide significance (P < 5 × 10−8).

Supplementary Figure 4 Map of regions where samples were collected.

Different colors represent the different provinces in China. Grouping of samples for analysis is based on the circled regions, namely, north Chinese Han, west Chinese Han, southeast Chinese Han, southwest Chinese Han and southern minorities.

Supplementary Figure 5 Association at BCL10 (rs2735591) in the combined analysis.

Odds ratios (ORs) are presented with their 95% confidence intervals (brackets). Phet, P value from the Cochran's Q heterogeneity test without any adjustments for multiple testing.

Supplementary Figure 6 Evidence of eQTL signals for rs9271100 in the lymphoblastoid cell lines of HapMap samples.

The association of the SNP with HLA-DRB1 gene expression is highlighted in the black box. Colors represent different populations. CEU, Utah residents with Northern and Western European ancestry from the CEPH collection; CHB, Han Chinese in Beijing, China; GIH, Gujarati Indians in Houston, Texas; JPT, Japanese in Tokyo, Japan; LWK, Luhya in Webuye, Kenya; MEX, Mexican ancestry in Los Angeles, California; MKK, Maasai in Kinyawa, Kenya; YRI, Yoruba in Ibadan, Nigeria. Data were obtained from the Genevar eQTL database (Bioinformatics 26, 2474–2476, 2010).

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Liu, H., Irwanto, A., Fu, X. et al. Discovery of six new susceptibility loci and analysis of pleiotropic effects in leprosy. Nat Genet 47, 267–271 (2015). https://doi.org/10.1038/ng.3212

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