From GWAS to Translational Insights: Comprehensive Genetic Analysis of Nephrotic Syndrome from Multiple Populations
Year: 2025
Type: preprint
Study design: Observational Study
Abstract: Nephrotic syndrome is a rare, heterogeneous kidney disorder characterized by proteinuria, hypoalbuminemia, and edema. To elucidate its genetic architecture, we conducted a large-scale, electronic health record (EHR)-linked, multi-ancestry genome-wide association study comprising 5,214 cases and 1,601,060 controls. We identified 37 distinct loci associated with disease risk, including novel associations at JAML and STPG2 , and confirmed prior signals at PLA2R1 , HMCN1 , and APOL1 . Fine-mapping of the major histocompatibility complex (MHC) revealed the strongest association at DRB103:01:01G in individuals of European ancestry (OR = 2.01, P = 1.4×10⁻²⁰), alongside nominal ancestry-specific associations in African ( DOA01:01:05 ) and Latino ( DPB1*14:01:01G ) populations. Transcriptome-wide association analysis (TWAS) identified 484 significant gene-tissue associations, including C4A in kidney cortex. Expression quantitative trait locus (eQTL) mapping revealed numerous cis-eQTLs in glomerular and tubular renal tissues, largely within the MHC region. We observed significant genetic correlation between adult and pediatric nephrotic syndrome (Rg = 0.63, P = 3.5x10 -11 ), suggesting shared genetic etiology. Pathway analyses implicated estrogen receptor signaling and histone modification. Mendelian randomization implicated APOM expression and apomorphine exposure with increased disease risk (OR = 4.93, P = 1.8x10 -19 ). These results expand the understanding of nephrotic syndrome pathogenesis and highlight ancestry-informed targets for therapeutic development.
Source: Research Square
Authors: Joseph H. Breeyear, Hannah M. Seagle, Alexis T. Akerele, Nikhil K. Khankari, Kwangmi Ahn, Adam B. Burkholder, Eric S. Torstenson, John S. House, Yanfei Zhang, Gail P. Jarvik, Ozan Dikiltas, Ming Ta Michael Lee, Iftikhar J. Kullo, David C. Fargo, Robb Rowley, Krzysztof Kiryluk, Richard P. Woychik, Alison A. Motsinger-Reif, Katalin Susztak, Todd L. Edwards, Jacklyn N. Hellwege
Institutions: National Institutes of Health, National Institute of Environmental Health Sciences, Vanderbilt University, Vanderbilt University Medical Center, Geisinger Health System, University of Washington Medical Center, Mayo Clinic, National Human Genome Research Institute, Columbia University, Children's Hospital of Philadelphia, University of Pennsylvania
Language: English
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Award: G2209161966
OpenAlex ID: W4414931799