Abstract: SA-OR064
Immune Cell Expression Quantitative Trait Loci (eQTL) Analysis of Pediatric Patients with Steroid-Sensitive Nephrotic Syndrome from the CureGN Cohort
Session Information
- Innovations in Pediatric Nephrology and Kidney Development
November 08, 2025 | Location: Room 371A, Convention Center
Abstract Time: 04:30 PM - 04:40 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Complex Kidney Traits
Authors
- McNulty, Michelle, Boston Children's Hospital, Boston, Massachusetts, United States
- Puntambekar, Sidhant N, Boston Children's Hospital, Boston, Massachusetts, United States
- Reynolds, Kaylia M., Boston Children's Hospital, Boston, Massachusetts, United States
- Kiryluk, Krzysztof, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, United States
- Kretzler, Matthias, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
- Sampson, Matt G., Boston Children's Hospital, Boston, Massachusetts, United States
Group or Team Name
- CureGN Consortium, NEPTUNE Consortium.
Background
Recent genome-wide association studies (GWAS) of pediatric steroid-sensitive nephrotic syndrome (pSSNS), one of the most common childhood glomerular diseases, identified 12 genome-wide significant and 20 suggestive associated loci. Multiomics mapping efforts to identify causal pSSNS SNPs and their target genes have not used relevant tissue samples from patients whose disease state and context directly reflect those of the GWAS. Here, we address this first with a whole blood eQTL study of immune cells from children with SSNS, followed by colocalization and transcriptome-wide association studies (TWAS) with the pSSNS GWAS.
Methods
Using 211 pediatric participants with pSSNS from the CureGN study, we built a fine-mapped set of high-resolution whole blood eQTLs. We used FastQTL and Bayesian fine-mapping (TORUS/DAP), which incorporated immune cell open chromatin annotations as a prior. We conducted colocalization between the CureGN whole blood eQTLs and pSSNS GWAS summary statistics using fastENLOC. To construct causal pathways from variants to gene expression to disease, we used a Mendelian randomization method, probabilistic TWAS. We compared the CureGN whole blood TWAS with TWAS of glomerular and tubulointerstitial eQTLs from NEPTUNE.
Results
We discovered 7,126 eQTLs from the CureGN cohort. Comparing the CureGN eQTLs to whole blood eQTLs from GTEx and kidney eQTLs from NEPTUNE, 1,165 eQTLs were unique to the CureGN cohort. Colocalization implicated TNFSF15, HLA-DQB1, AHI1, and ORMDL3/GSDMB. PTWAS using genetic variants as instrumental variables identified 54, 40, and 45 associated genes from CureGN whole blood eQTLs and NEPTUNE glomerular and tubulointerstitial eQTLs respectively. BAD, a positive regulator of programmed cell death, was a unique immune eQTL in CureGN and a significant whole blood PTWAS hit, identifying it as a candidate for future functional assays.
Conclusion
High-resolution whole blood eQTL mapping in a pediatric cohort contributed to the mapping of the genetic risk of pSSNS in ways undetectable by using kidney tissue or healthy adult immune cells. These findings underscore the importance of matching state and context specific factors between GWAS and eQTL cohorts when conducting post-GWAS analyses like colocalization and TWAS.
Funding
- NIDDK Support