Meta-analysis of GWAS on two Chinese populations followed by replication identifies novel genetic variants on the X chromosome associated with systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that affects mainly females. What role the X chromosome plays in the disease has always been an intriguing question. In this study, we examined the genetic variants on the X chromosome through meta-analysis of two genome-wide association studies (GWAS) on SLE on Chinese Han populations. Prominent association signals from the meta-analysis were replicated in 4 additional Asian cohorts, with a total of 5373 cases and 9166 matched controls. We identified a novel variant in PRPS2 on Xp22.3 as associated with SLE with genome-wide significance (rs7062536, OR = 0.84, P = 1.00E-08). Association of the L1CAM-MECP2 region with SLE was reported previously. In this study, we identified independent contributors in this region in NAA10 (rs2071128, OR = 0.81, P = 2.19E-13) and TMEM187 (rs17422, OR = 0.75, P = 1.47E-15), in addition to replicating the association from IRAK1-MECP2 region (rs1059702, OR = 0.71, P = 2.40E-18) in Asian cohorts. The X-linked susceptibility variants showed higher effect size in males than that in females, similar to results from a genome-wide survey of associated SNPs on the autosomes. These results suggest that susceptibility genes identified on the X chromosome, while contributing to disease predisposition, might not contribute significantly to the female predominance of this prototype autoimmune disease.

When the balance is broken: X-linked gene dosage from two X chromosomes and female-biased autoimmunity

“…SNPs in the MECP2/IRAK1 locus on Xq28 have been associated with risk for developing SLE (Fig. ) . Because IRAK1 and MECP2 are located less than 2 kilobases apart, it has been challenging to parse out which of the 2 genes are affected by the SNPs.…”

Genetic studies on systemic lupus erythematosus in East Asia point to population differences in disease susceptibility

“…Another replication effort identified ANXA6 as associated with the disease (Zhang et al, ). Focusing on X chromosome variants, Zhang et al elucidated PRPS2 as a novel SLE locus, while elucidating independent variants in the L1CAM‐MECP2 region (Zhang et al, ). More recently, we identified another locus, GPR173 on X chromosome as associated with the disease (Zhang et al, ).…”

Genetic Profiles for Systemic Lupus Erythematosus in Han Chinese Population: From Genome-Wide Association Study to Exome-Wide Association Study

“…Therefore, the genetics community has widely adopted the approach of combining summary statistics from multiple GWAS into a single meta-analysis to increase the statistical power of the analysis by augmenting the effective sample size. In order to further find new SLE susceptibility genes, we performed a series of meta-analysis of GWASs on SLE in Chinese population by collaborating with other SLE teams and found multiple new SLE susceptibility genes (CDKN1B, TET3, CD80, DRAM1, ARID5B, independent SNPs in 11q23.3, PRPS2, and L1CAM-MECP2) (Yang et al, 2013;Zhang et al, 2015aZhang et al, , 2015b. In 2016, we performed the largest SLE GWAS meta-analysis study by combining three GWAS datasets from Chinese (1,659 cases and 3,398 controls) and European (4,036 cases and 6,959 controls) populations.…”