Kidney Week

Abstract: FR-OR44

Genome Sequencing and Genetic Association Analyses of Primary Glomerular Disorders in CureGN, NEPTUNE, and Columbia CKD Biobank

Session Information

• Glomerular Diseases: Mechanisms and More
  October 25, 2024 | Location: Room 1, Convention Center
  Abstract Time: 05:40 PM - 05:50 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Wang, Chen, Columbia University, New York, New York, United States

Chen Wang, PhD

• Sanna-Cherchi, Simone, Columbia University, New York, New York, United States

Simone Sanna-Cherchi, MD

• Sampson, Matt G., Boston Children's Hospital, Boston, Massachusetts, United States

Matt G. Sampson, MD

• Gbadegesin, Rasheed A., Duke University, Durham, North Carolina, United States

Rasheed A. Gbadegesin, MD, MBBS, FASN

• Gharavi, Ali G., Columbia University, New York, New York, United States

Ali G. Gharavi, MD

• Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States

Matthias Kretzler, MD

• Kiryluk, Krzysztof, Columbia University, New York, New York, United States

Krzysztof Kiryluk, MD

Group or Team Name

• CureGN Genomics Workgroup.

Background

Glomerular disorders (GD) represent a heterogenous group of kidney diseases with known inherited risk contributions from genetic variants. Whole genome sequencing (WGS) provides the most comprehensive method for profiling common and rare variants. In this study, we generated the largest WGS dataset for patients with primary GD. The aim was to identify common variants (CVs) associated with GD and to comprehensively test for associations of rare variants (RVs) collapsed over genes and/or their regulatory regions.

Methods

WGS (30x) was conducted for 4,307 GD cases and 3,845 controls from the CureGN and NEPTUNE studies and the Columbia CKD Biobank. Variant calling was performed with DRAGEN for individual samples and GATK for cross-sample joint calls. Principal component (PC) analysis was used to estimate genetic ancestry and divide the cohort into 3 ancestral groups (EUR, AFR, EAS). Genome-wide association studies (GWAS) for CVs with adjustment for sex and PCs were performed within each ancestry using PLINK and meta-analyzed across ancestries with METAL. RV collapsing analyses with REGENIE included rare loss-of-function and deleterious missense variants within coding genes; and functional variants within cis-regulatory elements based on the ABC model and ENCODE annotations.

Results

The combined cohort included 1,513 participants with IgA nephropathy (IgAN), 377 with IgA vasculitis (IgAV), 1,023 with membranous nephropathy (MN), 745 with minimal change disease (MCD), 649 with focal segmental glomerulosclerosis (FSGS) and 3,845 controls. GWAS of each GD type identified genome-wide significant associations in the MHC region (IgAN, IgAV, MN, MCD), PLA2R1 (MN), and APOL1 (FSGS). Among the 45 known risk loci previously identified by GWASes, 41 had the same effect direction and 22 replicated with at least nominal significance. Due to limited power, RV collapsing analyses demonstrated no exome-wide significant signals but nominated new candidate genes and regions for follow up studies.

Conclusion

Jointly called WGS data enhanced the resolution of genetic discovery for GD. We replicated most of the known disease associations, indicating substantial potential for a planned meta-analysis incorporating the published studies. The WGS data is accessible via dbGAP (phs002480).