Enhancing nonlinear transcriptome- and proteome-wide association studies via trait imputation with applications to...

Genome-wide association studies (GWAS) performed on large cohort and biobank datasets have identified many genetic loci associated with Alzheimer's disease (AD). However, the younger demographic of biobank participants relative to the typical age of late-onset AD has resulted in an insufficient number of AD cases, limiting the statistical power of GWAS and any downstream analyses. To mitigate this limitation, several trait imputation methods have been proposed to impute the expected future AD status of individuals who may not have yet developed the disease. This paper explores the use of imputed AD status in nonlinear transcriptome/proteome-wide association studies (TWAS/PWAS) to identify genes and proteins whose genetically regulated expression is associated with AD risk. In particular, we considered the TWAS/PWAS method DeLIVR, which utilizes deep learning to model the nonlinear effects of expression on disease. We trained transcriptome and proteome imputation models for DeLIVR on data from the Genotype-Tissue Expression (GTEx) Project and the UK Biobank (UKB), respectively, with imputed AD status in UKB participants as the outcome. Next, we performed hypothesis testing for the DeLIVR models using clinically diagnosed AD cases from the Alzheimer's Disease Sequencing Project (ADSP). Our results demonstrate that nonlinear TWAS/PWAS trained with imputed AD outcomes successfully identifies known and putative AD risk genes and proteins. Notably, we found that training with imputed outcomes can increase statistical power without inflating false positives, enabling the discovery of molecular exposures with potentially nonlinear effects on neurodegeneration.