Kidney Week

Abstract: PO1673

Using Clustering to Facilitate Gene-Based Rare-Variant Collapsing for a Diverse Cohort of FSGS Patients

Session Information

• Genetic Diseases of the Kidneys: Non-Cystic - 2
  October 22, 2020 | Location: On-Demand
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

• Povysil, Gundula, Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, US, New York, New York, United States

Gundula Povysil,

• Ahram, Dina, Division of Nephrology, Columbia University Irving Medical Center, New York, NY, US, New York, New York, United States

Dina Ahram,

• Mitrotti, Adele, Division of Nephrology, Columbia University Irving Medical Center, New York, NY, US, New York, United States

Adele Mitrotti,

• Jin, Gina Ying, Division of Nephrology, Columbia University Irving Medical Center, New York, NY, US, New York, New York, United States

Gina Ying Jin,

• Scolari, Francesco, Cattedra di Nefrologia, Università di Brescia, Seconda Divisione di Nefrologia, Azienda Ospedaliera Spedali Civili di Brescia Presidio di Montichiari, Brescia, Italy, Brescia, Italy

Francesco Scolari,

• Santoro, Domenico, Department of Nephrology, University of Messina, Messina, Italy, Messina, Italy

Domenico Santoro,

• Gesualdo, Loreto, Section of Nephrology, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy, Bari, Italy

Loreto Gesualdo,

• Fiaccadori, Enrico, Internal Medicine and Nephrology Dept., Parma University Medical School, Parma, Italy, Parma, Italy

Enrico Fiaccadori,

• Milosevic, Danko, Department of Pediatric Nephrology, Dialysis and Transplantation, University Hospital Center Zagreb, Zagreb, Croatia, Zagreb, Croatia

Danko Milosevic,

• Tasic, Velibor, University Children's Hospital, Medical Faculty of Skopje, Skopje, Macedonia, Skopje, Macedonia (the former Yugoslav Republic of)

Velibor Tasic,

• Saraga, Marijan, Department of Pediatrics, University Hospital of Split, Split, Croatia, Split, Croatia

Marijan Saraga,

• Zaza, Gianluigi, Renal and Dialysis Unit, Department of Medicine, School of Medicine, University of Verona, Verona, Italy, Verona, Italy

Gianluigi Zaza,

• Westland, Rik, Division of Nephrology, Columbia University Irving Medical Center, New York, NY, US, New York, United States

Rik Westland,

• Simões e silva, Ana cristina, Faculty of Medicine, Federal University of Minas Gerais, Minas Gerais, Brazil, Minas Gerais, Brazil

Ana cristina Simões e silva,

• Gharavi, Ali G., Division of Nephrology, Columbia University Irving Medical Center, New York, NY, US, New York, New York, United States

Ali G. Gharavi,

• Armisen, Javier, Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK, Cambridge, United Kingdom

Javier Armisen,

• Paul, Dirk S., Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK, Cambridge, United Kingdom

Dirk S. Paul,

• Haefliger, Carolina, Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK, Cambridge, United Kingdom

Carolina Haefliger,

• Ghiggeri, Gian Marco, Division of Nephrology, Dialysis, Transplantation, and Laboratory on Pathophysiology of Uremia, Istituto G. Gaslini, Genoa, Italy, Genoa, Italy

Gian Marco Ghiggeri,

• Goldstein, David B., Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, US, New York, New York, United States

David B. Goldstein,

• Sanna-Cherchi, Simone, Division of Nephrology, Columbia University Irving Medical Center, New York, NY, US, New York, New York, United States

Simone Sanna-Cherchi,

Background

Several focal segmental glomerulosclerosis (FSGS) genes have been discovered through family studies. Rare-variant case-control studies, however, have been largely underpowered and/or restricted to a single ancestry.

Methods

We performed exome sequencing of 1,989 cases with FSGS and compared them to 18,835 controls. Using gene-based collapsing, we looked for genes with an excess of rare qualifying variants (QVs) in cases or controls. Standard collapsing was complicated by the diverse ancestry of our cases that not only included African, Asian, and Hispanic samples, but also Caucasian subpopulations not well represented in public databases or our controls. Therefore, we extended our collapsing workflow by a clustering step based on principal components reflecting ancestry. We performed coverage harmonization and frequency filtering within the clusters to capture population-specific differences. We used the Cochran-Mantel-Haenszel test to test for an association between disease status and QV status while controlling for cluster membership.

Results

Collapsing analyses were conducted on all cases together and on pediatric, adult, steroid-resistant, and steroid-sensitive subgroups. We detected a significant enrichment of QVs in known FSGS genes WT1, INF2, and NPHS2; additional signals in other FSGS genes (e.g. PAX2, COL4A3, COL4A5, CD2AP); and two novel ones that did not reach study-wide significance due to the limited sample size and phenotype heterogeneity. In several models and subgroups, the majority of the top 10 genes was formed by known FSGS genes, confirming the robustness of our novel approach.

Conclusion

We show that our new collapsing approach decreases inflation when samples with different ancestries are analyzed together, while preserving the underlying disease signals. We are currently more than doubling our case cohort, which should increase the power to detect significant signals in known FSGS genes, clarify the suggestive signal in two new genes, and allow well-powered sub-phenotype analyses.

Funding

• Commercial Support – AstraZeneca