Abstract: TH-PO447
Large-Scale Case-Control Exome-Wide Association Study Identifies Known and Novel Susceptibility Genes for Idiopathic Nephrotic Syndrome
Session Information
- Genetic Diseases: Glomerulopathies - I
November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Ke, Juntao, Columbia University, New York, New York, United States
- Povysil, Gundula, Columbia University, New York, New York, United States
- Shril, Shirlee, Boston Children's Hospital, Boston, Massachusetts, United States
- Gupta, Yask, 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
- Saleem, Moin, University of Bristol, Bristol, Bristol, United Kingdom
- Gbadegesin, Rasheed A., Duke University, Durham, North Carolina, United States
- Sampson, Matt G., Boston Children's Hospital, Boston, Massachusetts, United States
- Gharavi, Ali G., Columbia University, New York, New York, United States
- Pollak, Martin, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
- Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States
- Sanna-Cherchi, Simone, Columbia University, New York, New York, United States
Background
The genetic causes of idiopathic nephrotic syndrome (INS) have traditionally been studies using family-based approaches and comprehensive association studies across the age of onset, response to therapy, and ancestries are lacking.
Methods
We conducted an exome sequencing (ES) study on 5,262 children and adult cases with INS caused by focal segmental glomerulosclerosis or minimal change disease, including 1,998 steroid sensitive cases (SSNS) and 3,264 cases that were not known to be responsive to steroids (either steroid resistant or untreated/unknown). Per-gene burden of rare coding variants was assessed by exome-wide collapsing analysis comparing the above 5,262 cases and 28,637 population controls with ES data under dominant and recessive models. Analyses were conducted on the entire dataset and then again after removal of cases harboring diagnostic/pathogenic Mendelian mutations in known FSGS genes and APOL1 high-risk genotypes.
Results
In the analysis on the entire cohort, we identified and retrieved association for many of the known FSGS genes, including WT1 ( best P= 1.09 × 10-23; OR= 15.64), COL4A5 (best P= 2.37 × 10-17; OR= 9.83), INF2 (best P= 1.87 × 10-11; OR= 12.22), and several others, under dominant models, and NPHS1 (best P= 1.56 × 10-21; OR= 25.18), NPHS2 (best P= 3.93 × 10-15; OR= 30.58), SMARCAL1 (best P= 9.91 x 10-9; OR= 31.97) and several others, under a recessive model. This analysis re-classified CD2AP as an autosomal recessive cause of INS, and points to mutations in CLN5 and OCRL as common causes of FSGS phenocopies. Removal of solved cases and re-analysis prioritized 5 novel genes that exceeded the 5% false discovery rate (FDR), one gene that represented a phenotypic expansion of a known Mendelian neurodevelopmental disease, and three genes for which mouse models of the orthologues display glomerulopathy. Three of them are novel candidates for steroid resistant NS and two for SSNS.
Conclusion
These findings expand our understanding of the genetic underpinning of INS, identify novel candidate genes, and highlight the high genetic heterogeneity of disease. Genetic and functional validation studies of these results are ongoing.