Heath Alesha, McNerney M Windy, Yesavage Jerome
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, CA.
Department of Veterans Affairs, Sierra-Pacific Mental Illness Research Educational and Clinical Center, Palo Alto, CA.
Neurol Genet. 2025 Feb 14;11(2):e200241. doi: 10.1212/NXG.0000000000200241. eCollection 2025 Apr.
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.
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.
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.
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.
对不同等位基因变异体进行研究可能会产生新的关联基因，以预测晚发型阿尔茨海默病（LOAD）。可变数目串联重复序列（VNTRs）是基因组重要的多态性组成部分；然而，由于其基因分型复杂，此前一直被忽视。现在有新软件可确定VNTRs的不同长度；不过，尚未在大规模病例对照人群中进行测试。
我们使用VNTRseek对来自阿尔茨海默病测序项目的9501例病例和对照中的20多万个串联重复序列进行基因分型。我们首先确定了该分析的限制因素，然后在一部分非西班牙裔白人参与者中研究了VNTRs与AD诊断的关联。
我们发现VNTRs与基因组中先前已鉴定出大量变异体的区域高度相关。通过病例对照分析，我们确定了9个与LOAD相关的重复等位基因长度的VNTRs，包括DSC3、NR2E3、CCNY、PKP4、GRAP和MAP6上的VNTRs。
我们能够证明这种新型分析在大规模全基因组测序数据中的可行性，并确定与LOAD相关的有前景的VNTRs。
