Multimodal Analysis of Transcriptional Regulation in the Dorsolateral Prefrontal Cortex Enhances Alzheimer's Disease Risk Gene Discovery

Cross-modality xQTL and TWAS in dorsolateral prefrontal cortex RNA-seq (n=1,035) identifies 161 independent Alzheimer’s disease risk genes, with 59% detected via non-expression modalities.

• Why it matters: TWAS for AD dementia can miss genetic effects mediated by other transcriptomic regulatory layers beyond gene expression, limiting discovery and mechanistic interpretation.
• What they did: Using 396,344 transcriptomic quantitative traits across six modalities (expression, RNA stability, isoform ratios, splice junction usage, alternative TSS, polyA usage), the study performed xQTL mapping and AD TWAS, then tested proteomic support in DLPFC data.
• The result: Cross-modality mapping increased signal detection by 42%, colocalized 55 of 75 AD GWAS risk loci (including 15 found only with non-expression modalities), and proteome-wide association supported 26 xTWAS risk genes.

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