Cell-type-specific Transcriptomic-wide Association Studies Detected 91 Independent Risk Genes for Alzheimer’s Disease Dementia

Existing TWASs of AD dementia typically use a single statistical method to identify cell-type-specific risk genes. Here we sought to improve on existing approaches and utilized an omnibus xWAS pipeline to integrate snRNA-seq dataset (n=415) of dorsolateral prefrontal cortex (DLPFC) and the latest GWAS data of AD dementia to detect cell-type-specific risk genes. We identified 223 cell-type-specific TWAS risk genes across six major brain cell types, including 91 independent associations of which 11 are novel. Integrating proteomics data (n=716) of DLPFC and GWAS data, we identified 21 significant PWAS risk genes including 13 independent associations, overlapping with 32% independent cell-type-specific TWAS associations. Protein-protein interaction network analyses showed that our TWAS findings are functionally linked to established AD risk genes such as APOE, BIN1 , and MAPT . These results underscore the value of leveraging large-scale snRNA-seq and proteomics data to uncover novel cell-type-specific mechanisms underlying AD dementia.