Characterizing the genetic mechanisms underlying Alzheimer's disease (AD) dementia is crucial for developing new therapeutics. Proteome-wide association study (PWAS) integrating proteomics data with genome-wide association study (GWAS) summary data was shown as a powerful tool for detecting risk genes. The identified PWAS risk genes can be interpretated as having genetic effects mediated through the genetically regulated protein abundances. Existing PWAS analyses of AD often rely on the availability of individual-level proteomics and genetics data of a reference cohort. Leveraging summary-level protein quantitative trait loci (pQTL) reference data of multiple relevant tissues is expected to improve PWAS findings for studying AD. Here, we applied our recently developed OTTERS tool to conduct PWAS of AD dementia, by leveraging summary-level pQTL data of brain, cerebrospinal fluid (CSF), and plasma tissues, and multiple statistical methods. For each target protein, imputation models of the protein abundance with genetic predictors were trained from summary-level pQTL data, estimating a set of pQTL weights for considered genetic predictors. PWAS p-values were obtained by integrating GWAS summary data of AD dementia with estimated pQTL weights. PWAS p-values from multiple statistical methods were combined by the aggregated Cauchy association test to yield one omnibus PWAS p-value for the target protein. We identified significant PWAS risk genes through omnibus PWAS p-values and analyzed their protein-protein interactions using STRING. Their potential causal effects were assessed by the probabilistic Mendelian randomization (PMR-Egger). As a result, we identified a total of 23 significant PWAS risk genes for AD dementia in brain, CSF, and plasma tissues, including 7 novel findings. We showed that 15 of these risk genes were interconnected within a protein-protein interaction network involving the well-known AD risk gene of APOE and 5 novel findings, and enriched in immune functions and lipids pathways including positive regulation of immune system process, positive regulation of macrophage proliferation, humoral immune response, and high-density lipoprotein particle clearance. Existing biological evidence was found to relate our novel findings with AD. We validated the mediated causal effects of 14 risk genes (60.8%). In conclusion, we identified both known and novel PWAS risk genes, providing novel insights into the genetic mechanisms in brain, CSF, and plasma tissues, and targeted therapeutics development of AD dementia. Our study also demonstrated the effectiveness of integrating public available summary-level pQTL data with GWAS summary data for mapping risk genes of complex human diseases.
Keywords: Alzheimer’s disease dementia; GWAS; OTTERS; PWAS; pQTL summary data.