A transcriptome-wide association study of Alzheimer’s disease using prediction models of relevant tissues identifies novel candidate susceptibility genes

BACKGROUND: Genome-wide association studies (GWAS) have identified over 56 susceptibility loci associated with Alzheimer’s disease (AD), but the genes responsible for these associations remain largely unknown. METHODS: We performed a large transcriptome-wide association study (TWAS) leveraging modified UTMOST (Unified Test for MOlecular SignaTures) prediction models of ten brain tissues that are potentially related to AD to discover novel AD genetic loci and putative target genes in 71,880 (proxy) cases and 383,378 (proxy) controls of European ancestry. RESULTS: We identified 53 genes with predicted expression associations with AD risk at Bonferroni correction threshold (P value < 3.38 × 10(−6)). Based on fine-mapping analyses, 21 genes at nine loci showed strong support for being causal. CONCLUSIONS: Our study provides new insights into the etiology and underlying genetic architecture of AD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13073-021-00959-y.