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Kidney Week

Abstract: TH-PO770

Multi-Ethnic Genome-Wide Association Study (GWAS) for Idiopathic Nephrotic Syndrome Identifies Susceptibility Loci Across the Life Span, Response to Therapy, and Genetic Ancestry

Session Information

Category: Glomerular Diseases

  • 1403 Podocyte Biology

Authors

  • Gupta, Yask, Columbia University, New York, New York, United States
  • Ke, Juntao, Columbia University, New York, New York, United States
  • Povysil, Gundula, Columbia University, New York, New York, United States
  • Mcnulty, Michelle, Boston Children's Hospital, Boston, Massachusetts, United States
  • Jin, Gina, Columbia University, New York, New York, United States
  • Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States
  • Kiryluk, Krzysztof, Columbia University, New York, New York, United States
  • Gharavi, Ali G., Columbia University, New York, New York, United States
  • Gbadegesin, Rasheed A., Duke University, Durham, North Carolina, United States
  • Saleem, Moin, University of Bristol, Bristol, Bristol, United Kingdom
  • Pollak, Martin, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
  • Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States
  • Sampson, Matt G., Boston Children's Hospital, Boston, Massachusetts, United States
  • Sanna-Cherchi, Simone, Columbia University, New York, New York, United States
Background

Large-scale genetic association studies for idiopathic nephrotic syndrome cause by focal segmental glomerulosclerosis and minimal change disease are lacking, especially for forms of disease that are unresponsive to immunosuppressive treatment.
To address this knowledge gap, we conducted a large-scale genome-wide association study (GWAS) for common variants with paired exome sequencing in order to assess the complex polygenic architecture of non-Mendelian INS.

Methods

This study consists of 5,600 INS cases across the life span, genetic ancestry, and response to therapy, compared to over 50,000 genetically matched controls. More than 80% of cases had paired exome or genome sequencing. GWAS was conducted first on the entire cohort and then in subgroups based on age of onset, ancestry, and response to therapy. Analyses were conducted again after removal of cases harboring diagnostic/pathogenic Mendelian mutations in known FSGS genes and APOL1 high-risk genotypes. Ancestry specific GWAS were conducted using Regenie and Saige, metanalyses were conducted using Metal and TransMeta.

Results

Trans-ethnic metanalysis of all cases irrespective of age of onset and response to therapy showed the known association of APOL1, driven by individuals of recent African ancestry (OR= 2.67, P= 4.24 x 10-61), association with the HLA-DQA1 locus (OR=1.49, P= 5.91 x 10-24) and with chromosome 4 (LDB2; OR=1.34, P= 4.48 x 10-9). After removal of cases harboring pathogenic mutations causing Mendelian forms of FSGS and APOL1 HR genotypes, the strength for association to chromosome 4 increased and a novel locus on chromosome 15 reached genome-wide significance (ADAMTSL3; OR=1.53, P=2.73 x 10-08). Ancestry-specific and sub-phenotype analyses according to the age of onset and response to glucocorticoid treatment resulted in validation and replication of loci for SSNS (e.g. CALHM6, CLEC16A), and several novel HLA loci (for adult SSNS and non-Mendelian SRNS).

Conclusion

Interim results demonstrate multiple novel loci for INS, including pleiotropic risk alleles that predispose to NS across different sub-phenotypes, and loci specific to ancestry, age of onset, and response to therapy.

Funding

  • NIDDK Support