Polygenic regression uncovers trait-relevant cellular contexts through pathway activation transformation of single-cell RNA sequencing data

Advances in single-cell RNA sequencing (scRNA-seq) techniques have accelerated functional interpretation of disease-associated variants discovered from genome-wide association studies (GWASs). However, identification of trait-relevant cell populations is often impeded by inherent technical noise and high sparsity in scRNA-seq data. Here, we developed scPagwas, a computational approach that uncovers trait-relevant cellular context by integrating pathway activation transformation of scRNA-seq data and GWAS summary statistics. scPagwas effectively prioritizes trait-relevant genes, which facilitates identification of trait-relevant cell types/populations with high accuracy in extensive simulated and real datasets. Cellular-level association results identified a novel subpopulation of naïve CD8+ T cells related to COVID-19 severity, and oligodendrocyte progenitor cell and microglia subsets with critical pathways by which genetic variants influence Alzheimer’s disease. Overall, our approach provides new insights for the discovery of trait-relevant cell types and improves the mechanistic understanding of disease variants from a pathway perspective. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Protocols ### Funding Statement We acknowledge funding support from the National Natural Science Foundation of China (32200535 to Y.M; 61871294 and 82172882 to J.S), the Scientific Research Foundation for Talents of Wenzhou Medical University (KYQD20201001 to Y.M.), the Science Foundation of Zhejiang Province (LR19C060001 to J.S), Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang (2021R01013 to J.Y.), Research Program of Westlake Laboratory of Life Sciences and Biomedicine (202208013 to J.Y.), and Westlake Education Foundation (101566022001 to J.Y.). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors