Genome-wide assessment of genetic risk for systemic lupus erythematosus and disease severity.

Using three European and two Chinese genome-wide association studies (GWAS), we investigated the performance of genetic risk scores (GRSs) for predicting the susceptibility and severity of systemic lupus erythematosus (SLE), using renal disease as a proxy for severity. We used four GWASs to test the performance of GRS both cross validating within the European population and between European and Chinese populations. The performance of GRS in SLE risk prediction was evaluated by receiver operating characteristic (ROC) curves. We then analyzed the polygenic nature of SLE statistically. We also partitioned patients according to their age-of-onset and evaluated the predictability of GRS in disease severity in each age group. We found consistently that the best GRS in the prediction of SLE used SNPs associated at the level of P < 1e-05 in all GWAS data sets and that SNPs with P-values above 0.2 were inflated for SLE true positive signals. The GRS results in an area under the ROC curve ranging between 0.64 and 0.72, within European and between the European and Chinese populations. We further showed a significant positive correlation between a GRS and renal disease in two independent European GWAS (Pcohort1 = 2.44e-08; Pcohort2 = 0.00205) and a significant negative correlation with age of SLE onset (Pcohort1 = 1.76e-12; Pcohort2 = 0.00384). We found that the GRS performed better in the prediction of renal disease in the 'later onset' compared with the 'earlier onset' group. The GRS predicts SLE in both European and Chinese populations and correlates with poorer prognostic factors: young age-of-onset and lupus nephritis.China Scholarship Council (CSC) & National Science Foundation of China grant 8180163

Meta-analysis of GWAS on both Chinese and European populations identifies GPR173 as a novel X chromosome susceptibility gene for SLE

Abstract Background Systemic lupus erythematous (SLE) is a complex autoimmune disease with female predominance, particularly affecting those of childbearing age. We performed analysis of three genome-wide genotyping datasets of populations of both Chinese and European origin. Methods This study involved 5695 cases and 10,357 controls in the discovery stage. The lead signal on chromosome X was followed by replication in three additional Asian cohorts, with 2300 cases and 4244 controls in total. Conditional analysis of the known associated loci on chromosome X was also performed to further explore independent signals. Results Single-nucleotide polymorphism rs13440883 in GPR173 was found to be significantly associated with SLE (P meta = 7.53 × 10− 9, ORmeta= 1.16), whereas conditional analysis provided evidence of a potential independent signal in the L1CAM-IRAK1-MECP2 region in Asian populations (rs5987175 [LCA10]). Conclusions We identified a novel SLE susceptibility locus on the X chromosome. This finding emphasizes the importance of the X chromosome in disease pathogenesis and highlights the role of sex chromosomes in the female bias of SLE

Additional file 1: of Meta-analysis of GWAS on both Chinese and European populations identifies GPR173 as a novel X chromosome susceptibility gene for SLE

Table S1. Complete list of ChIP-seq files used in Intragenomic Replicates (IGR) analysis. Table S2. List of the 48 SNPs with association P value smaller than 1 × 10-4. Table S3. List of the candidate X-linked SLE susceptibility genes. Table S4. List of the 88 SNPs surpassing genome wide significance in L1CAM-MECP2 region. Table S5. Conditional logistic regression results in both Asian GWAS and European GWAS. Table S6. The list of SNVs used in Figure S3A. Figure S1. QQ plot for the cross-population X chromosome meta-analysis data. Figure S2. The LocusZoom Plot showing association significance and local LD for the region around rs13440883 (±200kb). Figure S3. Identification of functional risk-associated SNV shared between Europeans and Asians. Figure S4. LD patterns of the risk-associated SNPs in L1CAM-MECP2 region. (PDF 2421 kb

Identification of 38 novel loci for systemic lupus erythematosus and genetic heterogeneity between ancestral groups

The presentation of systemic lupus erythematosus has been known to differ by ancestry, but the underlying genetic factors remain unclear. Here, the authors report ancestry-specific susceptibility loci and better risk prediction when using data from matched ancestral groups