Disentangling associations between complex traits and cell types with seismic

Integrating single-cell RNA sequencing (scRNA-seq) with Genome-Wide Association Studies (GWAS) can help reveal GWAS-associated cell types, furthering our understanding of the cell-type-specific biological processes underlying complex traits and disease. However, current methods have technical limitations that hinder them from making systematic, scalable, interpretable disease-cell-type associations. In order to rapidly and accurately pinpoint associations, we develop a novel framework, seismic, which characterizes cell types using a new specificity score. We compare seismic with alternative methods across over 1,000 cell type characterizations at different granularities and 28 traits, demonstrating that seismic both corroborates findings and identifies trait-relevant cell groups which are not apparent through other methodologies. Furthermore, as part of the seismic framework, the specific genes driving cell type-trait associations can easily be accessed and analyzed, enabling further biological insights. The advantages of seismic are particularly salient in neurodegenerative diseases such as Parkinson's and Alzheimer's, where disease pathology has not only cell-specific manifestations, but also brain region-specific differences. Interestingly, a case study of Alzheimer's disease reveals the importance of considering GWAS endpoints, as studies relying on clinical diagnoses consistently identify microglial associations, while GWAS with a tau biomarker endpoint reveals neuronal associations. In general, seismic is a computationally efficient, powerful, and interpretable approach for identifying associations between complex traits and cell type-specific expression.