From GWAS Signals to Causal Genes in Chronic Kidney Disease.

Genome-wide association studies (GWAS) have transformed the study of chronic kidney disease (CKD) by identifying hundreds of genetic loci associated with multiple aspects of kidney function, including albuminuria and CKD risk factors, in diverse populations. A major challenge is translating statistically significant signals into causal genes and mechanisms, as most CKD-associated variants lie in non-coding regulatory regions and often act in a cell type- and context-specific manner. In this review, we provide an overview of the current strategies for moving from GWAS signals toward the identification of causal genes for CKD. We discuss advances in four areas: statistical and functional fine-mapping, molecular quantitative trait locus (QTL) mapping, colocalization, and transcriptome-wide associations, highlighting the advantages and disadvantages of each. We further examined how emerging kidney-specific single-cell, single-nucleus, and spatial transcriptomic atlases have enabled the mapping of genetic risk to specific renal cell types and microanatomical niches. By combining these approaches with chromatin interaction data, multi-omics analytics, and clustered regularly interspaced short palindromic repeats (CRISPR)-based studies, the process of generating causal relationships and mechanistic understanding has been further refined. Importantly, this review provides a unifying framework that synthesizes cross-sectional and longitudinal GWAS with kidney-specific functional genomics to distinguish genetic determinants of CKD susceptibility from modifiers of disease progression, thereby highlighting how regulatory variation and disease trajectories inform precision nephrology. As a result, we can provide insights into the role of genetically informed gene prioritization for experimentation, therapeutic target discovery, and the development of a framework for precision nephrology. Together, these advancements highlight how human genetics, in conjunction with functional genomics and experimental biology, can link an association signal to a clinically relevant interpretation of CKD.