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. 2025 Feb 14;11(2):e200241.
doi: 10.1212/NXG.0000000000200241. eCollection 2025 Apr.

Whole Genome Variable Number Tandem Repeat Analysis in Alzheimer Disease

Alesha Heath  1   2 , M Windy McNerney  1   2 , Jerome Yesavage  1   2
Affiliations

Whole Genome Variable Number Tandem Repeat Analysis in Alzheimer Disease

Alesha Heath et al. Neurol Genet. .

Erratum in

Abstract

Background and objectives: Investigation into different allelic variants may yield new associative genes to predict late-onset Alzheimer disease (LOAD). Variable number tandem repeats (VNTRs) are important polymorphic components of the genome; however, they have been previously overlooked because of their complex genotyping. New software can now determine differing lengths of VNTRs; however, this has not been tested in a large case-control population.

Methods: We used VNTRseek to genotype over 200,000 tandem repeats in 9,501 cases and controls from the Alzheimer's Disease Sequencing Project. We first identified limiting factors of this analysis and then examined the association of VNTRs with AD diagnosis in a subset of non-Hispanic White participants.

Results: We found that VNTRs were highly associated with areas of the genome with a high number of previously identified variants. From our case-control analysis, we identified 9 VNTRs with a repeat allele length associated with LOAD including VNTRs on DSC3, NR2E3, CCNY, PKP4, GRAP, and MAP6.

Discussion: We were able to show the feasibility of this new type of analysis in large-scale whole-genome sequencing data and identify promising VNTRs that are associated with LOAD.

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Conflict of interest statement

The authors report no relevant disclosures. Go to Neurology.org/NG for full disclosures.

Figures

Figure 1
Figure 1. Properties of VNTRs Across the Genome
(A) Mean (±SEM) number of indels in the dbSNP database that overlapped with TRs with 1–15 alleles. The number of TRs within each allele grouping is shown above each bar. (B) Relationship of the total length of the reference repeat sequence with the percent of VNTRs removed that did not meet the call rate of 95%. The number of VNTRs that were excluded is shown within the bar. VNTR = variable number tandem repeat.
Figure 2
Figure 2. Manhattan and Q-Q Plots of VNTR Associations With LOAD Diagnosis
Manhattan and QQ plots of p values from the logistic model investigating the association of VNTRs with diagnosis of LOAD with no covariates (A, B) and adjusted for sex, APOE4, and 5 PCs (C, D). Genomic inflation indicated by λ. LOAD = late-onset Alzheimer disease; VNTR = variable number tandem repeat.
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