Related Experiment Video
Updated: Apr 11, 2026
04:41
Mapping Alzheimer's Disease Variants to Their Target Genes Using Computational Analysis of Chromatin Configuration
Published on: January 9, 2020
19.6K
Rare coding variants from ADSP R5 whole-genome sequencing implicate novel genes in Alzheimer's disease
Wan-Ping Lee, Hui Wang1, Yuk Yee Leung1
1University of Pennsylvania.
Research Square
|April 10, 2026
Summary
This study analyzed whole-genome sequencing data from over 58,000 individuals to find rare genetic variants linked to Alzheimer's disease (AD). Researchers identified 40 significant genes, offering a valuable resource for future AD gene discovery.
Area of Science:
- Genetics
- Neuroscience
- Genomics
Background:
- Alzheimer's disease (AD) poses a significant global health challenge.
- Identifying genetic factors, especially rare variants, is crucial for understanding AD pathogenesis.
- Large-scale sequencing initiatives are essential for comprehensive genetic discovery.
Purpose of the Study:
- To leverage whole-genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP) Release 5.
- To discover rare coding variants and genes associated with Alzheimer's disease and related traits across diverse ancestries.
- To provide a valuable resource for advancing Alzheimer's disease gene discovery.
Main Methods:
- Analysis of whole-genome sequencing data from 58,507 individuals.
- Application of gene-based aggregation tests and Bonferroni correction for significance.
- Replication analyses using UK Biobank and Alzheimer's Disease Genetics Consortium (ADGC) cohorts.
- Carrier-based analyses for AD-related traits and coalescent analyses for allele age.
Main Results:
- Identified 40 genes exceeding the significance threshold, including known (TREM2, PSEN1) and novel candidates.
- Eight genes (TREM2, ACADS, MFSD12, NUP210L, PIEZO2, PSEN1, SMURF2, AKAP13) showed strong replication.
- Linked rare variants to age at onset, neuropathology, cognition, and cerebrospinal fluid biomarkers.
- Observed that AD-enriched variants are often ancestry-concentrated and AD risk alleles are relatively young.
Conclusions:
- The ADSP Release 5 provides a powerful multi-ancestry resource for rare variant discovery in Alzheimer's disease.
- Findings highlight key genes and pathways involved in AD pathogenesis.
- This dataset will accelerate the identification of novel therapeutic targets for Alzheimer's disease.
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