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High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry

Abstract

Systemic lupus erythematosus (SLE) has a strong but incompletely understood genetic architecture. We conducted an association study with replication in 4,478 SLE cases and 12,656 controls from six East Asian cohorts to identify new SLE susceptibility loci and better localize known loci. We identified ten new loci and confirmed 20 known loci with genome-wide significance. Among the new loci, the most significant locus was GTF2IRD1-GTF2I at 7q11.23 (rs73366469, Pmeta = 3.75 × 10−117, odds ratio (OR) = 2.38), followed by DEF6, IL12B, TCF7, TERT, CD226, PCNXL3, RASGRP1, SYNGR1 and SIGLEC6. We identified the most likely functional variants at each locus by analyzing epigenetic marks and gene expression data. Ten candidate variants are known to alter gene expression in cis or in trans. Enrichment analysis highlights the importance of these loci in B cell and T cell biology. The new loci, together with previously known loci, increase the explained heritability of SLE to 24%. The new loci share functional and ontological characteristics with previously reported loci and are possible drug targets for SLE therapeutics.

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Figure 1: Flowchart of our experimental design.
Figure 2: Manhattan plot of the meta-analysis results using the discovery sets.
Figure 3: Meta-analysis of the lead SNPs from the ten newly identified loci.
Figure 4: Cell type–specific gene expression analysis of SLE susceptibility loci.

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Acknowledgements

We are grateful to the affected and unaffected individuals who participated in this study. We thank the research assistants, coordinators and physicians who helped in the recruitment of subjects, including the individuals in the coordinating projects. A part of the Korean control data was provided from the Korean Biobank Project supported by the Korea Center for Disease Control and Prevention at the Korea National Institute of Health. Genomic DNA from 100 Korean patients with SLE was obtained from the Korean National Biobank at Wonkwang University Hospital, which is supported by the Ministry of Health and Welfare, Republic of Korea.

This work was supported by grants from the US National Institutes of Health (AR060366, MD007909, AI103399, AI024717, AI083194, AI107176, TR001425, HG008666 and HG006828), the US Department of Defense (PR094002), the US Department of Veterans Affairs, the National Basic Research Program of China (973 program) (2014CB541902), the Research Fund of Beijing Municipal Science and Technology for the Outstanding PhD Program (20121000110), the National Natural Science Foundation of China (81200524, 81230072) and High-Impact Research Ministry of Education Grant UM.C/625/1/HIR/MoE/E000044-20001, Malaysia. This study was also supported by a grant from the Korea Healthcare Technology R&D Project (HI13C2124), Ministry for Health and Welfare, Republic of Korea.

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Contributions

S.K.N., J.B.H. and S.-C.B. conceived and initiated the study. S.K.N. designed, coordinated and supervised the overall study. C.S., X.Z., P.M., K.B., A.A. and X.K.-H. prepared samples, performed genotyping, cleaned the data, combined various data sets and maintained the database. C.S., J.E.M., K.K. and Y.O. performed data imputation, association analysis and various statistical analyses on the data. L.L.L., J.E.M., M.D. and J.D.W. performed the bioinformatic analysis. S.-C.B., H.Z., K.H.C., X.Z., K.K., S.-Y.B., H.-S.L., T.-H.K., Y.M.K., C.-H.S., W.T.C., Y.-B.P., J.-Y.C., S.C.S., S.-S.L., Y.J.K., B.-G.H., Y.K., A.S., M.K., T.S., K.Y., J.M., Y.Q., K.M.K. and N.S. recruited and characterized patients with SLE and controls and supplied the demographic and clinical data. C.S., J.E.M., X.K.-H., K.K., S.-C.B., L.L.L. and S.K.N. drafted the manuscript. All authors approved the study, reviewed the manuscript, commented and helped in revising the manuscript.

Corresponding authors

Correspondence to Sang-Cheol Bae or Swapan K Nath.

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Supplementary Tables 1–29

Supplementary Tables 1–29. (XLSX 2075 kb)

Supplementary Data Set

Summary-level association data for the discovery sets. (XLSX 18647 kb)

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Sun, C., Molineros, J., Looger, L. et al. High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry. Nat Genet 48, 323–330 (2016). https://doi.org/10.1038/ng.3496

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