Kidney multiome-based genetic scorecard reveals convergent coding and regulatory variants

Abstract

Kidney dysfunction is a major cause of mortality, but its genetic architecture remains elusive. In this study, we conducted a multiancestry genome-wide association study in 2.2 million individuals and identified 1026 (97 previously unknown) independent loci. Ancestry-specific analysis indicated an attenuation of newly identified signals on common variants in European ancestry populations and the power of population diversity for further discoveries. We defined genotype effects on allele-specific gene expression and regulatory circuitries in more than 700 human kidneys and 237,000 cells. We found 1363 coding variants disrupting 782 genes, with 601 genes also targeted by regulatory variants and convergence in 161 genes. Integrating 32 types of genetic information, we present the "Kidney Disease Genetic Scorecard" for prioritizing potentially causal genes, cell types, and druggable targets for kidney disease.