Genotyping TOMM40′523 poly-T polymorphisms using whole-genome sequencing
Summary: The TOMM40′523 poly-T repeat polymorphism (rs10524523) has been associated with cognitive decline and Alzheimer's disease (AD) progression. Challenges in processing whole-genome sequencing (WGS) data traditionally require additional PCR and targeted sequencing assays to genotype these...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-10-01
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| Series: | HGG Advances |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666247725000910 |
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| Summary: | Summary: The TOMM40′523 poly-T repeat polymorphism (rs10524523) has been associated with cognitive decline and Alzheimer's disease (AD) progression. Challenges in processing whole-genome sequencing (WGS) data traditionally require additional PCR and targeted sequencing assays to genotype these polymorphisms. We introduce a computational pipeline that integrates multiple short tandem repeat (STR) detection tools in an ensemble machine learning model using XGBoost. Using a sample of 1,202 participants from 4 cohort studies, we benchmarked our method against PCR-based measures. Our ensemble model outperformed individual STR tools, improving repeat length estimation accuracy (R2 = 0.92) and achieving an accuracy rate of 93.2% compared with PCR-derived genotypes. Additionally, we validated our WGS-derived genotypes by replicating previously reported associations between TOMM40′523 variants and cognitive decline. Our computational genotyping tool is a scalable and reliable alternative to PCR-based assays, enabling broader investigations of TOMM40 variation in studies with WGS data. |
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| ISSN: | 2666-2477 |