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.

Figure 1

Flowchart of our experimental design. This study followed three stages: in Stage 1, we genotyped three Asian cohorts of SLE patients and controls and identified 578 regions with P<5×10⁻³. Next we performed imputation-based fine-mapping, association tests and conditional analysis on the quality controlled data. We identified 16 statistically independent loci (P<5×10⁻⁵) for replication. In Stage 2, we performed an in silico replication of these 16 loci in an independent Japanese (JAP) cohort, and two independent Chinese cohorts from Shanghai (SHC) and Beijing (BHC). We identified novel regions represented by 10 replicated SNPs that passed the genome-wide significance threshold (P < 5×10⁻⁸). In Stage 3, we performed integrated functional and interaction analyses of SLE loci.

Figure 2

Manhattan plot of the meta-analysis results using discovery sets. Novel significant loci are highlighted in red, “suggestive” loci are in blue and previously known SLE loci are in black.

Fig. 3

Meta-analysis of lead SNPs from 10 novel genes. We identified 10 novel loci in KR, HC and MC cohorts that were replicated in at least 2 independent cohorts. A partial Discovery-meta-analysis is presented in the middle of the plot, and the overall Meta-analysis is presented below the replication cohorts. KR: Korean; HC: Han Chinese; MC: Malaysian Chinese; JAP: Japanese; BHC: Beijing Han Chinese; SHC: Shanghai Han Chinese.

Fig. 4

Cell-specific gene expression analysis of the novel and SLE loci. We estimated enrichment of our gene-set in a set of human (FANTOM5) cell lines. Overrepresented cell types have a high correlation (Pearson’s correlation coefficient) of SLE-loci expression (dark red). P-values (blue bars) that passed the multiple testing threshold (black line) show significant enrichment in SLE loci.