Structural variants caused by <i>Alu</i> insertions are associated with risks for many human diseases.

Abstract

Interspersed repeat sequences comprise much of our DNA, although their functional effects are poorly understood. The most commonly occurring repeat is the <i>Alu</i> short interspersed element. New <i>Alu</i> insertions occur in human populations, and have been responsible for several instances of genetic disease. In this study, we sought to determine if there are instances of polymorphic <i>Alu</i> insertion variants that function in a common variant, common disease paradigm. We cataloged 809 polymorphic <i>Alu</i> elements mapping to 1,159 loci implicated in disease risk by genome-wide association study (GWAS) (<i>P</i> < 10^-8). We found that <i>Alu</i> insertion variants occur disproportionately at GWAS loci (<i>P</i> = 0.013). Moreover, we identified 44 of these <i>Alu</i> elements in linkage disequilibrium (<i>r</i>² > 0.7) with the trait-associated SNP. This figure represents a >20-fold increase in the number of polymorphic <i>Alu</i> elements associated with human phenotypes. This work provides a broader perspective on how structural variants in repetitive DNAs may contribute to human disease.