The largest-ever cross-ancestry meta-analysis GWAS for SLE identifies novel biology and potential treatment targets
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We conducted the largest-ever cross-ancestry GWAS meta-analysis for SLE with 25,109 cases and 271,084 controls comprising East Asian (EA), Southeast Asians (SEA) and Europeans (EUR). We identified 279 independent non-MHC associations, including 51 unreported SLE associations, among which EA-driven associations were identified at PIK3AP1, FOXK1, UBASH3A, and CTDSP1. We further identified a significant interactive association between FOXK1 and IRF5 variants. Statistical fine-mapping together with SNP-to-gene inference and functional prediction identified plausible causal non-coding variants in PRKD3 and TSPAN32, as well as variants in enhancers for CD83, IL12A, c-MYC, and l-MYC, along with an EA-specific missense variant rs55882956 in TYK2. Transcription factors (TFs) linked to fine-mapped enhancer variants contributed to trans-acting regulatory mechanisms in SLE, with strong heritability enrichment at their binding sites across various immune cell types. These include a disproportionate representation of B cell TFs that are themselves risk genes. MYC protein showed the largest enrichment at its binding sites in B cells. In addition, Prioritizing MYC binding sites of B cells in polygenic risk score improved SLE prediction. We also identified 67 candidate druggable genes, providing mechanistic insights and highlighting opportunities for therapeutic development in SLE.
