Structural variants caused by Alu insertions are associated with risks for many human diseases

Significance Repetitive sequences comprise a large portion of the genome and are often thought of as “junk DNA.” They are a significant source of genetic variation, particularly Alu elements. Their functional consequence is frequently dismissed. Here, we test the hypothesis that Alu polymorphisms contribute to phenotypic differences between individuals. We identified an enrichment of Alu polymorphisms in regions of the genome associated with human disease risk. Further, we find 44 instances where the trait-associated SNP is a surrogate for presence or absence of an Alu insertion. This finding indicates that the Alu may be the variant effecting disease risk, an intriguing possibility given its size and regulatory potential. This work emphasizes the importance of considering repeat polymorphisms in functional variant analysis.