insertion variants alter gene transcript levels.

are high copy number interspersed repeats that have accumulated near genes during primate and human evolution. They are a pervasive source of structural variation in modern humans. Impacts that insertions may have on gene expression are not well understood, although some have been associated with expression quantitative trait loci (eQTLs). Here, we directly test regulatory effects of polymorphic insertions in isolation of other variants on the same haplotype. To screen insertion variants for those with such effects, we used ectopic luciferase reporter assays and evaluated 110 insertion variants, including more than 40 with a potential role in disease risk. We observed a continuum of effects with significant outliers that up- or down-regulate luciferase activity. Using a series of reporter constructs, which included genomic context surrounding the , we can distinguish between instances in which the disrupts another regulator and those in which the introduces new regulatory sequence. We next focused on three polymorphic loci associated with breast cancer that display significant effects in the reporter assay. We used CRISPR to modify the endogenous sequences, establishing cell lines varying in the genotype. Our findings indicate that genotype can alter expression of genes implicated in cancer risk, including , , and These data show that commonly occurring polymorphic elements can alter transcript levels and potentially contribute to disease risk.