Leveraging functional annotations to map rare variants associated with Alzheimer disease with gruyere.

Increased availability of whole-genome sequencing (WGS) has facilitated the study of rare variants (RVs) in complex diseases. Multiple RV association tests are available to study the relationship between genotype and phenotype, but most do not fully leverage the availability of variant-level functional annotations. We propose genome-wide rare variant enrichment evaluation (gruyere), an empirical Bayesian framework that complements existing methods by learning global, trait-specific weights for functional annotations to improve variant prioritization. We apply gruyere to WGS data from the Alzheimer's Disease Sequencing Project to identify Alzheimer disease (AD)-associated genes and annotations. Growing evidence suggests that the disruption of microglial regulation is a key contributor to AD risk, yet existing methods have not examined rare non-coding effects that incorporate such cell-type-specific information. To address this gap, we (1) define per-gene non-coding RV test sets using predicted enhancer and promoter regions in microglia and other brain cell types (oligodendrocytes, astrocytes, and neurons) and (2) include cell-type-specific variant effect predictions (VEPs) as functional annotations. gruyere identifies 13 significant genetic associations not detected by other RV methods, four of which remain significant in omnibus tests. We find that deep-learning-based VEPs for splicing, transcription factor binding, and chromatin state are highly predictive of functional non-coding RVs. Our study establishes a robust framework incorporating functional annotations, coding RVs, and cell-type-associated non-coding RVs to perform genome-wide association tests, uncovering AD-relevant genes and annotations.