Kidney Week

Abstract: TH-PO0349

Cross-Phenotype Genome-Wide Association Study Identifies Shared Genetic Susceptibility Across Glomerular Disorders

Session Information

• Glomerular Diseases: Omics
  October 22, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Shanbhog, Shreya, University of Michigan, Ann Arbor, Michigan, United States

Shreya Shanbhog, MS

• Fermin, Damian, University of Michigan, Ann Arbor, Michigan, United States

Damian Fermin, PhD

• Wang, Chen, Columbia University, New York, New York, United States

Chen Wang, PhD

• Sampson, Matt G., Harvard Medical School, Boston, Massachusetts, United States

Matt G. Sampson, MD

• Gbadegesin, Rasheed A., Duke University, Durham, North Carolina, United States

Rasheed A. Gbadegesin, MD, MBBS, FASN

• Ju, Wenjun, University of Michigan, Ann Arbor, Michigan, United States

Wenjun Ju, PhD

• Eddy, Sean, University of Michigan, Ann Arbor, Michigan, United States

Sean Eddy, PhD

• Gharavi, Ali G., Columbia University, New York, New York, United States

Ali G. Gharavi, MD

• Kiryluk, Krzysztof, Columbia University, New York, New York, United States

Krzysztof Kiryluk, MD

• Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States

Matthias Kretzler, MD

• Liu, Lili, University of Michigan, Ann Arbor, Michigan, United States

Lili Liu, PhD

Background

Although primary glomerulonephropathies (GN) - including IgA nephropathy (IgAN), IgA vasculitis (IgAV), membranous nephropathy (MN), and minimal change disease (MCD), share clinical features such as proteinuria and reduced kidney function, their shared genetic susceptibility remains poorly studied.

Methods

We conducted a cross-phenotype meta-GWAS across 4 GN forms, including IgAN (10,146 cases and 28,751 controls), IgAV (2,170 cases and 5,928 controls), MN (3,782 cases, 9,038 controls) and MCD (2,440 cases and 36,023 controls). The meta-GWAS was performed using both METAL and METASOFT framework, followed by fine-mapping of genome-wide significant loci. Shared genetic determinants between traits were examined by COLOC. We further investigated candidate gene expression across kidney cell types in NEPTUNE and KPMP to identify potential causal cell types.

Results

Cross-phenotype meta-GWAS identified 31 genome-wide significant loci, including 7 novel signals for glomerular disorders. Seven loci showed concordant effects across all four forms of GN, whereas the remaining loci showed opposing effects across at least two GN forms. The lead intronic SNP at the novel MAGI2 locus (OR = 1.13; P = 3.43x10^-08) is located within the MAGI2 transcript and shows consistent effects across GN subtypes. MAGI2 is extensively expressed in podocytes, and the GN risk allele is associated with increased MAGI2 expression in podocytes in both KPMP and NEPTUNE. Consistently, MAGI2 expression was higher in podocytes from patients with GN than in those from living donors. A significant tubular eQTL (FDR = 0.015) links the GN-risk allele to increased MAGI2 expression. These highlight a potential link from genetic regulation of MAGI2 expression to GN risk. Colocalization analyses indicated shared causal variants between IgAN and MCD at the CD28, TNFSF8, and FCRL2 loci, and between IgAN and IgAV at the INPP5D, ANKRD55, ITGAM, and DEFA5 loci. Fine-mapping and integration with QTL signals at genome-wide significant loci further prioritized functional variants and candidate genes.

Conclusion

This study identified shared and disease-specific genetic determinants across glomerular disorders. Through cross-phenotype analysis, we uncovered novel genetic risk factors and candidate genes associated with GN risk, providing novel insights into their underlying genetic architecture.