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Kidney Week

Abstract: FR-PO1030

Exome-Wide Association Study for C3 Glomerulopathies

Session Information

Category: Genetic Diseases of the Kidney

  • 1002 Genetic Diseases of the Kidney: Non-Cystic

Authors

  • Na, Young-Ji, Columbia University, New York, New York, United States
  • Li, Yifu, Columbia University, New York, New York, United States
  • Marasa, Maddalena, Columbia University, New York, New York, United States
  • Krithivasan, Priya, Columbia University, New York, New York, United States
  • Steers, Nicholas J., Columbia University, New York, New York, United States
  • Sanchez, Elena, Columbia University, New York, New York, United States
  • Goicoechea de jorge, Elena, Complutense University Madrid, Madrid, Spain
  • Praga, Manuel, Hospital 12 de Octubre, Pozuelo De Alarcon, Spain
  • Bomback, Andrew S., Columbia University, New York, New York, United States
  • Kiryluk, Krzysztof, Columbia University, New York, New York, United States
  • Rodriguez de Cordoba, Santiago, Consejo Superior de Investigaciones Cientificas, Madrid, Spain
  • Appel, Gerald B., Columbia University College of Physicians and Surgeons, Scarsdale, New York, United States
  • Gharavi, Ali G., Columbia University, New York, New York, United States
Background

C3 glomerulopathies (C3Gs) include a spectrum of rare diseases such as C3 glomerulonephritis (C3GN) and dense deposit disease (DDD), which share phenotypic similarities and underlying genetic commonalities. Mutations in components of the complement pathway have been implicated, but the genetic underpinnings are largely unknown. The aim of this study is to use whole-exome sequencing to improve understanding of the genetic architecture of C3G.

Methods

We performed a case-control exome-wide collapsing analysis using 282 case subjects with C3Gs [C3GN, DDD, and immune complex-mediated MPGN] and 9,825 control subjects with no known kidney diseases. To identify risk signals, we tested all protein-coding genes for an excess of ultra-rare genetic variation among the cases, compared with control samples. We tested multiple models, including loss-of-function variants and non-benign nonsynonymous variants. We also applied regional intolerance model based on missense tolerance ratio (MTR).

Results

In multiple model, patients with C3G had a higher frequency of loss-of-function variants and non-benign nonsynonymous variants in Complement Factor H (P = 6.51 X 10-07), C3 (P = 1.04 X 10-04) in the dominant models and C5 (P = 0.0279) and CFB (P = 0.0279) in the recessive models. Rare putatively pathogenic variants were detected mainly among C3GN cases. In addition, we identified many signals that did not reach exome-wide significance but represent interesting candidate genes for C3Gs.

Conclusion

We identified excess ultra-rare variation in several known C3G genes under both dominant and recessive models. These data suggest that exome sequencing can discover rare risk alleles for C3Gs enhancing the established gene-mapping paradigms.

Funding

  • NIDDK Support