Objective:

By adopting whole-exome sequencing (WES) to explore causal variants and corresponding genes of Alzheimer's disease (AD).

Background:

AD possesses a high level of heritability estimated to be between 58% and 79%. Characterizing the genetic architecture of AD would improve our understanding of pathological mechanisms and enabling the identify new therapeutic targets. However, previous genome-wide association studies (GWASs) only focused on common variants. Thus, it is necessary to utilize WES to explore additional AD-related variants and corresponding genes.

Design/Methods:

Here, we conducted gene-based exome-wide association study (ExWAS) of rare variants and single-variant ExWAS of common variants, utilizing data of 54,569 clinically diagnosed/proxy AD and related dementia (ADRD) and 295,421 controls from the UK Biobank. We further explored the biological function of ExWASs-identified genes in phenotype, tissue, cell, pathway, and protein-protein interaction network (PPIN). Third, we tested the causal and longitudinal relationships of ExWASs-identified genes with ADRD by adopting Mendenlian randomization and Cox survival analysis. Finally, for the identified novel genes, we looked up their potential in druggable genome source andDrugBank database.

Results:

We identified 11 genes by gene-based ExWAS of rare variants and 17 genes by single-variant ExWAS of common variants. Among the identified genes, five genes were validated in another independent cohort, including FRMD8, DDX1, DNMT3L, MORC1, and TGM2. Functional annotations found that the identified genes were enriched in brain tissues and microglia as well as in pathways mainly associated with Aβ and lipid metabolism. Additional evidence from differential expression analyses, MR and Cox regression further supported the significance of these genes in ADRD. Druggability investigation of novel genes indicated that DDX1, DNMT3L, TGM2, SLCO1C1, and NDNF were potentially effective drug targets. These findings contribute to the current body of evidence on the genetic etiology of ADRD.

Conclusions:

Our study contributes to the current body of evidence on the genetic etiology of ADRD.