PathGPS: discover shared genetic architecture using GWAS summary data

Abstract

ABSTRACT The increasing availability and scale of biobanks and “omic” datasets bring new horizons for understanding biological mechanisms. PathGPS is an exploratory data analysis tool to discover genetic architectures using Genome Wide Association Studies (GWAS) summary data. PathGPS is based on a linear structural equation model where traits are regulated by both genetic and environmental pathways. PathGPS decouples the genetic and environmental components by contrasting the GWAS associations of “signal” genes with those of “noise” genes. From the estimated genetic component, PathGPS then extracts genetic pathways via principal component and factor analysis, leveraging the low-rank and sparse properties. In addition, we provide a bootstrap aggregating (“bagging”) algorithm to improve stability under data perturbation and hyperparameter tuning. When applied to a metabolomics dataset and the UK Biobank, PathGPS confirms several known gene–trait clusters and suggests multiple new hypotheses for future investigations.