Whole Genome Variable Number Tandem Repeat Analysis in Alzheimer Disease

Area of Science:

• Genomics
• Neurodegenerative Diseases
• Genetic Epidemiology

Background:

• Late-onset Alzheimer disease (LOAD) prediction can be improved by investigating allelic variants.
• Variable number tandem repeats (VNTRs) are polymorphic genomic elements previously challenging to genotype.
• Novel software enables VNTR genotyping, but its application in large populations requires validation.

Purpose of the Study:

• To assess the feasibility of VNTR genotyping in large-scale whole-genome sequencing data.
• To identify novel VNTRs associated with LOAD risk.
• To explore the utility of VNTRs as potential biomarkers for LOAD.

Main Methods:

• Genotyped over 200,000 tandem repeats in 9,501 LOAD cases and controls using VNTRseek.
• Identified analytical limitations and optimized VNTR analysis in whole-genome sequencing data.
• Conducted a case-control association study in a subset of non-Hispanic White participants.

Main Results:

• VNTRs were found to be enriched in genomic regions with high variant density.
• Nine VNTRs demonstrated significant association between repeat allele length and LOAD diagnosis.
• Associated VNTRs were identified on genes including DSC3, NR2E3, CCNY, PKP4, GRAP, and MAP6.

Conclusions:

• Demonstrated the feasibility of large-scale VNTR analysis using whole-genome sequencing data.
• Identified specific VNTRs as promising genetic markers associated with LOAD.
• These findings pave the way for developing new genetic strategies for LOAD prediction.