ABSTRACT Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by high morbidity and mortality, and largely ineffective treatments. SLE is genetically complex with strong familial aggregation and high heritability. Most of the risk alleles for SLE are not protein-coding sequence changes, suggesting that a significant portion of disease risk is mediated by regulatory variants in the noncoding genome. At a recently identified intergenic SLE risk locus on chromosome 12q12, our in silico analyses implicate the risk variants as eQTLs that impact transcription of genes in multiple biological pathways that contribute to SLE immunopathology, including type I interferon (IFN) and anti-viral genes. This intergenic SLE risk locus is enriched in regulatory elements and resides adjacent to several long non-coding RNA (lncRNA) genes. In this proposal, we outline a comprehensive set of mechanistic and functional experiments to understand the role of the 12q12 risk locus in human immune cells. We hypothesize that several variants within cis-regulatory elements at the 12q12 locus alter the expression of adjacent lncRNAs, which in turn exert cis and trans effects on immune system genes resulting in increased SLE risk. An alternate hypothesis is that the 12q12 locus could be a long-range enhancer for nearby protein- coding and/or non-coding genes. These hypotheses are not mutually exclusive, and our experimental design will detect each possibility. In Aim 1, we will determine the overall impact of the intergenic 12q12 locus on gene regulation in primary immune cells and selected cell lines. Integrative analyses will be used to infer lncRNA influences on mRNA networks. Candidate lncRNAs from these analyses will be knocked down with siRNAs to confirm their function. In Aim 2, we will identify causal cis-regulatory elements in the intergenic 12q12 region. We will use complementary methods to identify likely regulatory elements, and putative causal elements will be knocked out in cell lines to confirm function and reversion to a non-risk cellular phenotype. We expect to find that the intergenic 12q12 locus influences the expression of adjacent lncRNAs and/or neighboring protein-coding or non-coding genes in a cell type-specific manner, resulting in simultaneous modulation of multiple biological pathways involved in SLE pathogenesis. This knowledge could suggest novel therapeutic targets for SLE that would influence multiple pathogenic pathways. This represents a novel mechanism of disease in SLE and provides an illustration of how intergenic risk variants can function in complex disease pathogenesis.