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

Area of Science:

• Genomics
• Human Genetics
• Molecular Biology

Background:

• Interspersed repeat sequences, including Alu elements, constitute a significant portion of the human genome.
• The functional roles of these repetitive DNA elements, particularly Alu short interspersed elements, remain largely uncharacterized.
• New Alu insertions are ongoing in human populations and have been linked to genetic disorders.

Purpose of the Study:

• To investigate whether polymorphic Alu insertion variants contribute to common diseases through a common variant, common disease model.
• To identify specific Alu insertion variants associated with disease risk loci identified by genome-wide association studies (GWAS).

Main Methods:

• Cataloged 809 polymorphic Alu elements.
• Mapped these elements to 1,159 loci previously implicated in disease risk by GWAS (P < 10^-8).
• Assessed linkage disequilibrium (r^2 > 0.7) between Alu elements and trait-associated single nucleotide polymorphisms (SNPs).

Main Results:

• Alu insertion variants were found to occur disproportionately at GWAS loci (P = 0.013).
• Identified 44 polymorphic Alu elements in significant linkage disequilibrium with trait-associated SNPs.
• This represents a greater than 20-fold increase in the number of polymorphic Alu elements associated with human phenotypes.

Conclusions:

• Polymorphic Alu insertion variants are significantly associated with genetic loci linked to human disease risk.
• These findings highlight the underappreciated role of structural variants in repetitive DNA in contributing to common human diseases.
• Provides a new perspective on the functional impact of repetitive DNA elements in the human genome.