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<p>Most existing transcriptome wide association studies (TWASs) of Alzheimer’s Disease (AD) dementia only use bulk RNA-seq data and a single statistical method. Here, we utilize an omnibus TWAS (TWAS-O) pipeline that leverages multiple complementary statistical methods to integrate the snRNA-seq dataset (<i>n</i> = 415) of the dorsolateral prefrontal cortex (DLPFC) and the latest GWAS data of AD dementia. We fine-map TWAS risk genes by gene-based conditional analysis and conducted validation analyses by the analogous omnibus proteome-wide association studies (PWAS-O) using bulk proteomics data of DLPFC (<i>n</i> = 716). We identify 223 unique cell-type-aware TWAS risk genes from 350 associations across six major brain cell-types, including 91 fine-mapped independent associations, 11 of which are novel. By PWAS-O, we identify 21 significant PWAS risk genes, including 13 independent associations, which validated 31.9% independent cell-type-aware TWAS associations. By protein-protein interaction network analyses, our novel cell-type-aware TWAS findings are linked to established AD risk genes such as <i>APOE, BIN1</i>, and <i>MAPT</i>.</p>

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Cell-type-aware transcriptome-wide association studies identify 91 independent risk genes for Alzheimer’s disease dementia

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月22日

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  • Qiang Liu,
  • Randy L. Parrish,
  • Shizhen Tang,
  • Shinya Tasaki,
  • David A. Bennett,
  • Nicholas T. Seyfried,
  • Philip L. De Jager,
  • Vilas Menon,
  • Aron S. Buchman,
  • Jingjing Yang

摘要

Most existing transcriptome wide association studies (TWASs) of Alzheimer’s Disease (AD) dementia only use bulk RNA-seq data and a single statistical method. Here, we utilize an omnibus TWAS (TWAS-O) pipeline that leverages multiple complementary statistical methods to integrate the snRNA-seq dataset (n = 415) of the dorsolateral prefrontal cortex (DLPFC) and the latest GWAS data of AD dementia. We fine-map TWAS risk genes by gene-based conditional analysis and conducted validation analyses by the analogous omnibus proteome-wide association studies (PWAS-O) using bulk proteomics data of DLPFC (n = 716). We identify 223 unique cell-type-aware TWAS risk genes from 350 associations across six major brain cell-types, including 91 fine-mapped independent associations, 11 of which are novel. By PWAS-O, we identify 21 significant PWAS risk genes, including 13 independent associations, which validated 31.9% independent cell-type-aware TWAS associations. By protein-protein interaction network analyses, our novel cell-type-aware TWAS findings are linked to established AD risk genes such as APOE, BIN1, and MAPT.