Genome-wide meta-analysis with 1,590,596 individuals identifies 12 novel risk loci for systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic life-threatening and relapsing-remitting multisystem autoimmune disease. However, the genetic susceptibility of SLE has not been fully elucidated. This study will explore the genetic risk loci of SLE. We performed the larger multi-ancestry meta-analysis of genome-wide association study (GWAS) including 22,494 cases with SLE and 1,568,102 healthy controls. Multi-ancestry meta-analysis identified 101 risk loci including 12 novel loci. Across 101 loci, 2,209 likely causal genes are indicated and 265 genes are prioritized, based on eight biological prioritization criteria. The most significantly locus were located on 6p21.32, whereas the highest-ranked candidate causal gene was BLK. Heritability analyses demonstrated a liability scale of the heritability is 25.49%, whereas an estimated 1.25 million effective sample sizes would be necessary to explain 90% of phenotypic variance. Gene enrichment, gene-set analyses, and the genetic correlation revealed that SLE-related genes were enriched in whole blood and spleen, promoted MHCII-related pathways, JAK-STAT signaling, abnormal activation of T and B cells, autoantibodies such as anti-nuclear antibody and anti-neutrophil antibody production, and had a positive genetic correlation with autoimmune diseases (e.g., rheumatoid arthritis), mental and neurological disorders (e.g., schizophrenia), and cardiovascular diseases (e.g., hypertension). Finally, druggable, gene-drug interaction, drug target, and drug repurposing analysis suggested some potential targets (e.g., BLK) and drug (e.g., riboflavin) repurposing for SLE. In conclusion, we identified 101 risk loci including 12 novel loci for SLE. Based on 101 loci, we provided new biological insights, some potential targets, and drug repurposing for SLE.