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Abstract: SA-PO394

Multiethnic GWAS for Idiopathic Nephrotic Syndrome in Adults and Children

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Ahram, Dina, Columbia University, New York, New York, United States
  • Mcnulty, Michelle, Univeristy of Michigan, Ann Arbor, Michigan, United States
  • Mitrotti, Adele, Columbia University, New York, New York, United States
  • Krithivasan, Priya, Columbia University, New York, New York, United States
  • Jin, Gina ying, Columbia University, New York, New York, United States
  • Bodria, Monica, Giannina Gaslini Children’s Hospital, Genova, Italy
  • Westland, Rik, VU University Medical Center, Amsterdam, Netherlands
  • Saraga, Marijan, University Hospital in Split, Split, Croatia
  • Milosevic, Danko, Zagreb School of Medicine, Clinical Hospital Centre Zagreb, Zagreb, Croatia
  • Tasic, Velibor, University Children's Hospital, Skopje, Macedonia (the former Yugoslav Republic of)
  • Santoro, Domenico, Policlinico G Martino, Messina, Italy
  • Messa, Piergiorgio, Policlinico Milano, Milano, Italy
  • Weng, Patricia L., UCLA, Los Angeles, California, United States
  • Zaza, Gianluigi, Universita di Verona, Verona, Italy
  • Gesualdo, Loreto, University of Bari, Altamura, Bari, Italy
  • Fiaccadori, Enrico, Universita Degli Studi-Dip. Clinica Medica Nefrologia, Parma, Italy
  • Appel, Gerald B., Columbia University, New York, New York, United States
  • Bomback, Andrew S., Columbia University, New York, New York, United States
  • Scolari, Francesco, University of Brescia, Montichiari (Brescia), Italy
  • Caliskan, Yasar, Division of Nephrology, Saint Louis University School of Medicine, St. Louis, Missouri, United States
  • Gharavi, Ali G., Columbia University, New York, New York, United States
  • Kiryluk, Krzysztof, Columbia University, New York, New York, United States
  • Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States
  • Sampson, Matt G., Univeristy of Michigan, Ann Arbor, Michigan, United States
  • Sanna-Cherchi, Simone, Columbia University, New York, New York, United States

Group or Team Name

  • Sanna-Cherchi Lab
Background

Common HLA variants have been associated with steroid sensitive nephrotic syndrome (NS) in small cohort studies. We conducted a genome-wide association study (GWAS) for NS in different ethnicities, ages of onset and response to steroid therapy.

Methods

We genotyped 2,639 NS cases and 16,765 genetically-matched controls. After imputation, we performed ancestry-specific GWAS using an additive model corrected for population stratification, followed by meta-analysis across 11 populations. Subsequent meta-analyses were performed stratified by: age of onset (Pediatric and Adults), race (Caucasians and Africans) and steroid responsiveness (Sensitive and Resistant) .

Results

In the combined meta-analysis (2,639 cases), we discovered significant associations for the APOL1 (OR=2.87, P= 7.68x10-31), which were driven solely by African individuals (520 cases; OR=2.82, P=1.45x10-37), the HLA-DQA1 locus (OR=1.43, P= 3.2x10-22), and a novel locus on chr.1q42.2 (OR=1.34, P=3.29x10-08). After conditional analysis on the top two SNPs at APOL1 and HLA, a second independent HLA genome-wide significant signal was discovered (OR=1.36, P=2.18x10-10). Among adult onset patients (n=1,391), the strongest signals were for APOL1 (OR=3.14, P=1.82x10-21) and a novel locus on chr.14q21.3 (OR=1.54, P=1.62x10-8). The HLA-DQA1 was the strongest signal among pediatric cases (n=1,195; OR=2.01, P=4.06x10-32). Interestingly, the HLA signal in Caucasians was significant also in adults (OR=1.33; P=1.20x10-8). Additional signals were found in adult and pediatric cohorts stratified by race and response to therapy.

Conclusion

Our results reveal novel NS loci, pleiotropic risk predisposing alleles across different subphenotypes, and signals specific to race and age of onset. Specifically, we can now implicate variation in the HLA locus as a major contributor to NS also in adults. Fine-mapping of HLA in children and adults and integrating these GWAS alleles with other NS-associated genetic factors (Mendelian alleles, CNVs) holds promise in further elucidating the genetic architecture of NS.

Funding

  • Other U.S. Government Support