Genomic convergence of locus-based GWAS meta-analysis identifies DDX11 as a novel Systemic Lupus Erythematosus gene

Abstract

Genome-wide association studies (GWAS) of systemic lupus erythematosus (SLE) explain only [~]15% of genetic risk, indicating genes of modest effect remain to be discovered. Association clustering methods such as OASIS are more apt at identifying modest genetic effects. 410 genes were mapped to previously identified OASIS GWAS SLE loci and investigated for expression in SLE GEO datasets. GSE50395 dataset from Cordoba was used for validation. Blood eQTL for significant SNPs in SLE loci and STRING for functional pathways of differentially expressed genes was used. Confirmatory qPCR on monocytes of 12 SLE patients and controls was performed. We identified 55 genes that were differentially expressed in at least 2 SLE GEO datasets with all probes directionally aligned. DDX11 was downregulated in both GEO (P=3.60E-02) and Cordoba (P=8.02E-03) datasets and confirmed by qPCR (P=0.001). The most significant SNP, rs3741869 (P=3.2E-05) in OASIS locus 12p11.21, containing DDX11, was a cis-eQTL regulating DDX11 expression (P=8.62E-05). DDX11 interacted with multiple genes including STAT1/STAT4. Genomic convergence with OASIS and multiple expression datasets identifies novel genes. DDX11, RNA helicase involved in genome stability, is repressed in SLE. Summary StatementMore than 100 genes for SLE have been identified but they explain only [~]15% of heritability. GWAS are challenged by risk genes of modest effect. Using locus-based GWAS mapping and multiple gene expression replications, DDX11 was identified as a novel SLE gene. DDX11, repressed in SLE, may be used as a clinical diagnostic tool.