Genome-wide LD scores enable robust heritability and genetic correlation estimation from summary statistics across genetic ancestries

Abstract

Our knowledge of human complex trait architecture across diverse populations remains limited. Estimating SNP heritability and genetic correlation from GWAS summary statistics - successful in revealing genetic architecture in homogeneous cohorts - is challenging in structured and admixed populations due, in part, to the difficulty of representing long-range LD. We present SUMMIT, a statistical framework that combines genome-wide LD scores, efficiently estimated using random projections, with GWAS summary statistics to estimate genome-wide and annotation-specific heritability and genetic correlation. In simulations that explore diverse aspects of genetic architecture across European (EUR), South Asian (SAS), and admixed African-European cohorts (AFR) in the UK Biobank (UKB), SUMMIT had increased accuracy and reduced bias compared to prior methods, with the largest gains in non-European ancestries reflecting improved modeling of long-range LD. Across 40 UKB traits, SUMMIT produced estimates of genome-wide common-SNP heritability (h_g^2) and heritability enrichments in genomic annotations that were broadly concordant across ancestries with the SUMMIT h_g^2 estimates more closely matching recent whole-genome sequencing based estimates. SUMMIT substantially improved genetic correlation analysis recovering more significant findings across ancestries (23 SAS and 3 AFR at FDR < 0.05 compared with none and two for cov-LDSC) with the non-European discoveries showing concordant effects in Europeans suggesting that, like heritability, global patterns of pleiotropy are largely shared across ancestries. By combining accurate genome-wide LD and efficient moment estimation, SUMMIT enables investigation into how heritability and genetic correlation vary across populations and genomic annotations, including in structured and admixed cohorts, at the genome-wide, annotation-specific, and cross-trait levels.