Haplotype-based Association Analysis Reveals a Novel Risk Locus for Systemic Lupus Erythematosus in Chinese Han Populations

Abstract

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with strong genetic contribution, characterized by recurrent inflammatory response and multiple-organ damage. Single SNP-based association studies have identified more than 40 susceptibility loci reaching genome-wide significance for SLE, but only explained a small portion of heritability. Analysis methods based on haplotypes comprising multiple SNPs within LD blocks may provide additional power to uncover some of missing susceptibility variants. Therefore, in this study, we implemented a haplotype-based association study using two published SLE GWAS data from southern and northern China respectively, and then combined summary statistics of each cohort under weighted Z-score model. Eventually, we identified a novel SLE risk locus with combined haplotype p-value 6E-07 in chromosome 2q22.1 (upstream of CXCR4). The regional haplotype P value is better than any single-SNP P values within the region, suggesting haplotypes were more informative than single SNPs in this case. In conclusion, this strategy was demonstrated to be helpful to partially explain the missing inheritability of the complex diseases including SLE and move us forward towards a better understanding of its genetic architecture and molecular diagnosis for prototype autoimmune disease.