Gene regulatory mechanisms of non-coding autoimmune risk loci in primary B cells

Genome-wide association studies have discovered thousands of genetic variants linked to autoimmune disease, and yet the underlying molecular pathways have remained elusive. We curated risk loci across >30 autoimmune traits to reveal overlapping genetic signatures, before performing a high-throughput single-cell multi-omic CRISPR activation screen in primary human B cells to experimentally map 362 target genes regulated by risk loci. Direct measurement of cis-regulatory element transcription revealed how coordinated activation of distal risk loci may mediate pleiotropy between autoimmune traits. Finally, we identify a gain-of-function lupus-associated variant that regulates the transcription factor REL that subsequently binds dozens of risk loci and target genes. Our study provides a valuable resource linking risk loci with cis-regulatory targets and advances our understanding of the shared genetic mechanisms in autoimmunity.