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Basic Science and Pathogenesis.

Xinyu Sun1,2, Makaela Mews3, Nicholas R Wheeler1,2

  • 1Case Western Reserve University School of Medicine, Cleveland, OH, USA.

Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 24, 2025
PubMed
Summary
This summary is machine-generated.

Multi-ancestry TWAS identified TREML2 as a gene associated with Alzheimer's disease (AD) across diverse populations. Elevated TREML2 expression may promote inflammation in microglia, suggesting it as a therapeutic target for AD.

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Area of Science:

  • Genetics
  • Neuroscience
  • Genomics

Background:

  • Transcriptome-wide association studies (TWAS) integrate gene expression with genetic data to understand non-coding variant functions.
  • Alzheimer's disease (AD) research benefits from multi-ancestry approaches to identify genetic associations across diverse populations.
  • The Multi-Ancestry Genomics, Epigenomics, and Transcriptomics of Alzheimer's (MAGENTA) Project provides crucial data for this study.

Purpose of the Study:

  • To identify Alzheimer's disease (AD)-associated genes using a multi-ancestry TWAS approach.
  • To leverage the MAGENTA Project's diverse dataset, including African American, European, and Hispanic ancestries.
  • To explore the functional consequences of genetic variants on gene expression in relation to AD.

Main Methods:

  • Applied Sum of Shared Single Effects (SuShiE) to identify variants impacting gene expression across ancestries.
  • Utilized MA-FOCUS (Multi-Ancestry Fine-Mapping of Causal Gene Sets) for fine-mapping TWAS associations in genomic risk regions.
  • Analyzed whole-blood expression and genotype data from 224 African American, 235 European, and 298 Hispanic individuals, adjusting for relevant covariates.

Main Results:

  • Identified five AD-related genes, with TREML2 consistently associated across all three ancestral groups.
  • TREML2 association was robust, confirmed by SSW meta-analysis (FDR < 0.1) and MA-FOCUS posterior inclusion probability (PIP = 0.88).
  • Observed consistent positive effect size directions for TREML2 across African American, European, and Hispanic ancestries.

Conclusions:

  • Multi-ancestry TWAS is crucial for uncovering genetic mechanisms in AD development.
  • Elevated TREML2 expression may promote microglial pro-inflammatory and proliferation effects in AD.
  • TREML2 presents a potential therapeutic target for Alzheimer's disease research, warranting further investigation.