---
title: "Whole Genome Sequencing of Over 13,000 Diverse Individuals Reveals Shared and Distinct Genetic Associations With Alzheimer’s Disease Across Subpopulations "
id: "8118"
type: "post"
slug: "whole-genome-sequencing-of-over-13000-diverse-individuals-reveals-shared-and-distinct-genetic-associations-with-alzheimers-disease-across-subpopulations"
published_at: "2025-04-17T16:29:44+00:00"
modified_at: "2025-04-17T16:29:45+00:00"
url: "https://dss.niagads.org/whole-genome-sequencing-of-over-13000-diverse-individuals-reveals-shared-and-distinct-genetic-associations-with-alzheimers-disease-across-subpopulations/"
markdown_url: "https://dss.niagads.org/whole-genome-sequencing-of-over-13000-diverse-individuals-reveals-shared-and-distinct-genetic-associations-with-alzheimers-disease-across-subpopulations.md"
excerpt: "Dr. Wan-Ping Lee leads a study investigating genetic associations with Alzheimer’s Disease (AD) within and across African American, Hispanic, and Non-Hispanic White ancestry groups, spanning 13,371 individuals. Here we highlight some key methods and results from this exciting work. The..."
taxonomy_category:
  - "ADSP"
---

## Dr. Wan-Ping Lee leads a study investigating genetic associations with Alzheimer’s Disease (AD) within and across African American, Hispanic, and Non-Hispanic White ancestry groups, spanning 13,371 individuals. Here we highlight some key methods and results from this exciting work.

The Alzheimer’s Disease Sequencing Project (ADSP) is a highly collaborative project investigating genetic factors contributing to Alzheimer’s Disease (AD) risk and protection. In this paper, Dr. Wan-Ping Lee and co-authors investigate the results of new whole-genome sequencing (WGS) data, using statistical methods to highlight associations within and across human population subgroups.

Upon its release in June 2023, ADSP Release 3 was the largest WGS study focusing on AD to date, including 6519 AD cases and 6852 controls (subgroup counts shown in Figure 1 below). Across ancestries, the greatest single-variant associations were found in the *APOE*and *BIN1*regions, and within-subgroup genetic variation associated with AD was found in *LINC00320*for African Americans (AA), on 14q24 for Hispanics (HIS), and in *BIN1*for Non-Hispanic whites (NHW).

Figure 1 from this publication, describing the number of input samples and statistical approaches carried out. Ancestry sub-groups are defined in detail in the manuscript.

Testing for common single nucleotide variants (SNVs) yielded several significant associations. The well-known *APOE* locus, or Apolipoprotein-E on chromosome 19, had the strongest associations in the pooled samples, and these variants were also significant within the three subgroups. Additionally, the *APOE*ɛ2 and ɛ4 alleles were enriched in controls and cases respectively, confirming previous results indicating *APOE*ɛ2 as protective and *APOE*ɛ4 as conferring risk. Notably, both alleles were most common in the AA subgroup.

The rare variant (RV) analysis demonstrated a complex interplay between variants. For example, after controlling for a coding mutation in *PSEN1* (p.G206A), *PSEN1*non-codingRVs were no longer significant, suggesting these RVs share a haplotype and are inherited together. Aggregates of non-coding RVs near *TOMM40*were also significant, even after controlling for effects of *APOE*ɛ2 and ɛ4.

These results demonstrate both the complexity of genetic associations with AD and the importance of WGS across population subgroups to detect such complexities. Unlike conventional genome arrays, WGS is uniquely able to detect RVs and has demonstrated their importance to understanding the genetics of AD. To continue this work, the authors look forward to functional validation of the detected variants.

In conclusion, this study utilized whole genome sequencing across population subgroups and identified common and rare genetic variants linked to AD in genes such as *APOE*, *BIN1*, *PSEN1*, *TOMM40*, and *LINC00320*. For more information on the innovative methods and intriguing results from this work, [please visit the original publication in Alzheimer’s and Dementia](https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.14283)
.

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