Kidney Week

Abstract: TH-OR028

Genome-Wide Association Study for Idiopathic Nephrotic Syndrome Identifies Susceptibility Loci Across the Lifespan, Response to Therapy, and Genetic Ancestry

Session Information

• Genetics of Complex Kidney Traits
  November 06, 2025 | Location: Room 360A, Convention Center
  Abstract Time: 04:30 PM - 04:40 PM

Category: Genetic Diseases of the Kidneys

• 1202 Genetic Diseases of the Kidneys: Complex Kidney Traits

Authors

• Lim, Tze Yin, Columbia University, New York, New York, United States

Tze Yin Lim, MS, MSc

• Gupta, Yask, University of Lubeck, Lubeck, Germany

Yask Gupta, PhD

• Ke, Juntao, Columbia University, New York, New York, United States

Juntao Ke, PhD

• McNulty, Michelle, Boston Children's Hospital, Boston, Massachusetts, United States

Michelle McNulty, MS

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

Chen Wang, PhD

• Ahram, Dina, Quest Diagnostics Nichols Institute, San Juan Capistrano, California, United States

Dina Ahram, PhD

• Mitrotti, Adele, University of Bari Aldo Moro, Bari, Italy

Adele Mitrotti, MD, PhD

• Povysil, Gundula, Waypoint Bio, New York, New York, United States

Gundula Povysil, MD, PhD

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

Matthias Kretzler, MD

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

Krzysztof Kiryluk, MD

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

Ali G. Gharavi, MD

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

Rasheed A. Gbadegesin, MD, MBBS, FASN

• Gale, Daniel P., University College London, London, England, United Kingdom

Daniel P. Gale, MA, MBChB, PhD

• Tokunaga, Katsushi, National Center for Global Health and Medicine, Tokyo, Japan

Katsushi Tokunaga, PhD

• Iijima, Kazumoto, Hyogo Prefectural Kobe Children’s Hospital, Kobe, Japan

Kazumoto Iijima, MD, PhD

• Ronco, Pierre M., Sorbonne Universite, Paris, Île-de-France, France

Pierre M. Ronco, MD, PhD

• Pollak, Martin, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States

Martin Pollak, MD

• Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States

Friedhelm Hildebrandt, MD

• Saleem, Moin A., University of Bristol, Bristol, England, United Kingdom

Moin A. Saleem, MD, MBBS, MBChB, PhD

• Sampson, Matt G., Boston Children's Hospital, Boston, Massachusetts, United States

Matt G. Sampson, MD

• Sanna-Cherchi, Simone, Columbia University, New York, New York, United States

Simone Sanna-Cherchi, MD

Background

The polygenic background of idiopathic nephrotic syndrome (INS) remains elusive: while previous genome-wide association studies (GWAS) identified risk loci for pediatric steroid sensitive nephrotic syndrome (pSSNS), the genetic architecture across different ages of onset and treatment responses is unclear. Here, we conducted a GWAS to characterize the polygenicity of INS across genetic ancestries, age of onset and treatment response.

Methods

This study included 7610 INS cases, across genetic ancestries, ages of onset, and treatment responses, and 29342 controls. The case distribution were: pSSNS (N=3940), aSSNS (N=715), pSRNS (N=1195), aSRNS (N=1449). 70.4% of SRNS cases had paired sequencing data to extract Mendelian FSGS variants. We performed ancestry-specific GWAS on all cases, followed by stratified analyses by age of onset and therapy response. We then repeated these analyses after excluding 758 cases with likely pathogenic variants in FSGS genes, pathogenic CNVs or APOL1 high-risk genotypes (6787 cases and 28934 controls). We used PLINK2, METAL and MR-MEGA for analysis.

Results

Metanalysis of INS irrespective of age of onset and therapy response showed association with HLA-DQB1(P=2.60x10^-97,OR=2.11), and APOL1, driven by individuals of recent African ancestry(P=8.85x10^-51,OR=2.91). Meta-analysis of pSSNS GWASs retrieved all 12 known loci and identified additional 9 new significant loci: chr3p13 (P=1.69x10^-14), chr22q12.3 (P=1.84x10^-13), chr17q21.1 (P=7.43x10^-11), chr12p13.31 (P= 1.26x10^-8), chr4q27 (P= 2.85x10^-8), chr1q32.1 (P= 4.49x10^-8), chr2q31.2 (P =2.97x10^-10), chr7p14.1 (P=1.15x10^-8), chr1q25.1 (P=3.55x10^-8). Non-Mendelian pSRNS showed a strong immune signature with significant association to HLA-DQB1 (P=8.27x10^-16, OR=1.77).

Conclusion

Our GWAS identified novel candidate loci for INS, including pleiotropic risk alleles that predispose to NS across sub-phenotypes, and loci specific to ancestry, age of onset, and response to therapy. Many loci suggest drug targets with existing treatments possibly suggesting indication expansions and genetic-supported therapies.

Funding

• NIDDK Support

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025e4dgpdcz