GENETIC OR POLYGENIC RISK SCORES IN KIDNEY FIELD: A SCOPING REVIEW

Chronic kidney disease (CKD) and other kidney disorders pose a growing global health burden, with substantial variation in susceptibility, progression, and outcomes. Traditional risk factors such as diabetes, hypertension, and lifestyle do not fully explain disease heterogeneity. Genome-wide association studies (GWAS) have identified numerous common variants associated with kidney function and related traits, but individual effect sizes are small. Genetic risk scores (GRSs) and polygenic risk scores (PRSs), which aggregate multiple variants, offer a promising approach to quantify genetic predisposition. In nephrology, GRSs/PRSs are increasingly studied for risk stratification, early detection, and guiding interventions. However, their clinical utility remains uncertain due to differences in study design, population ancestry, phenotype definitions, and statistical methods. To address this, we conducted a scoping review to map the literature on GRSs/PRSs in kidney disease, summarizing their development, validation, and application across populations and clinical contexts.

We searched MEDLINE, Embase, Web of Science, and Scopus up to April 2025, and screened grey literature via preprint servers such as BioRxiv and MedRxiv, following the PRISMA-ScR guidelines. Studies in any language were included if they addressed CKD, acute kidney injury, end-stage kidney disease, or related conditions, and examined GRSs/PRSs. Non-kidney disease studies were excluded. Basic study information and metrics were summarized.

Of 1,953 articles identified, 108 met the inclusion criteria, encompassing 128 GRSs/PRSs. Studies on GRSs/PRSs in nephrology have appeared since 2010, with a marked increase after 2019. Continuous phenotypes included eGFR (n=49/128, 38.3%), urinary albumin-to-creatinine ratio (UACR; n=14/128, 10.9%), and eGFR slope (n=5/128, 3.9%). Binary phenotypes included CKD (n=24/128, 18.8%), IgA nephropathy (n=10/128, 7.8%), membranous nephropathy (n=6/128, 4.7%), diabetes-related kidney disease (n=4/128, 3.1%), and rapid kidney function decline (n=3/128, 2.3%). GWAS ancestry was predominantly European (n=44/108, 40.7%), followed by multi-ancestry studies (n=29/108, 26.7%) and East Asian–only (n=11/108, 10.2%). African, South Asian, and American population–specific studies were rare. Among the studies that applied the constructed GRSs/PRSs to external cohorts to evaluate their utility, 36/81 studies (44.4%) validated the scores in populations of the same ancestry as the original construction, while 33/81 studies (40.7%) tested them in populations of different ancestry (12 studies could not be classified). Recent studies included a larger number of single nucleotide polymorphisms in score construction, and many combined GRSs/PRSs with clinical indicators when assessing their predictive ability.

Numerous GRSs/PRSs have been developed in nephrology, primarily focusing on eGFR and overall CKD, with few addressing other phenotypes. A bias toward European ancestry was evident in the datasets used. As GRS/PRS methodologies evolve, further studies are needed to improve their applicability and generalizability across diverse populations. Acknowledgement: This work was supported by the Japan Agency for Medical Research and Development (AMED, 25tm0424230h0002).