High-throughput ”pathomic” analysis of Whole Slide Images (WSIs) offers new opportunities to study tissue characteristics and for biomarker discovery. However, the clinical relevance of the tissue characteristics at the micro- and macro-environment level is limited by the lack of tools that facilitate the measurement of the spatial interaction of individual structure characteristics and their association with clinical parameters. To address these challenges, we introduce HistoWAS (Histology-Wide Association Study), a computational framework designed to link tissue spatial organization to clinical outcomes. Specifically, HistoWAS implements (1) a feature space that augments conventional metrics with 30 topological and spatial features, adapted from Geographic Information Systems (GIS) point pattern analysis, to quantify tissue micro-architecture; and (2) an association study engine, inspired by Phenome-Wide Association Studies (PheWAS), that performs mass univariate regression for each feature with statistical correction. As a proof of concept, we applied HistoWAS to analyze a total of 102 features (72 conventional object-level features and our 30 spatial features) using 385 PAS-stained WSIs from 206 participants in the Kidney Precision Medicine Project (KPMP). The code and data have been released to https: // github. com/ hrlblab/ histoWAS .