Abstract
Functional enrichment results typically implicate tissue or cell-type-specific biological pathways in disease pathogenesis and as therapeutic targets. We propose generalized linkage disequilibrium score regression (g-LDSC) that requires only genome-wide association studies (GWASs) summary-level data to estimate functional enrichment. The method adopts the same assumptions and regression model formulation as stratified linkage disequilibrium score regression (s-LDSC). Although s-LDSC only partially uses LD information, our method uses the whole LD matrix, which accounts for possible correlated error structure via a feasible generalized least-squares estimation. We demonstrate through simulation studies under various scenarios that g-LDSC provides more precise estimates of functional enrichment than s-LDSC, regardless of model misspecification. In an application to GWAS summary statistics of 15 traits from the UK Biobank, estimates of functional enrichment using g-LDSC were lower and more realistic than those obtained from s-LDSC. In addition, g-LDSC detected more significantly enriched functional annotations among 24 functional annotations for the 15 traits than s-LDSC (118 vs. 51).