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Abstract: FR-PO308

Mapping Genomic Regulation of Kidney Disease and Traits Through High-Resolution and Interpretable Expression Quantitative Trait Loci (eQTLs)

Session Information

Category: Genetic Diseases of the Kidneys

  • 1102 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Mcnulty, Michelle, Boston Children's Hospital, Boston, Massachusetts, United States
  • Han, Seong Kyu, Boston Children's Hospital, Boston, Massachusetts, United States
  • Benway, Christopher, Boston Children's Hospital, Boston, Massachusetts, United States
  • Wen, Pei, University of Maryland School of Medicine, Baltimore, Maryland, United States
  • Greenberg, Anya, Boston Children's Hospital, Boston, Massachusetts, United States
  • Onuchic-Whitford, Ana C., Boston Children's Hospital, Boston, Massachusetts, United States
  • Wilson, Parker C., Washington University in St Louis, St Louis, Missouri, United States
  • Humphreys, Benjamin D., Washington University in St Louis, St Louis, Missouri, United States
  • Wen, Xiaoquan, University of Michigan, Ann Arbor, Michigan, United States
  • Han, Zhe, University of Maryland School of Medicine, Baltimore, Maryland, United States
  • Lee, Dongwon, Boston Children's Hospital, Boston, Massachusetts, United States
  • Sampson, Matt G., Boston Children's Hospital, Boston, Massachusetts, United States

Group or Team Name

  • NEPTUNE
Background

The genomic contributors to kidney diseases and traits extend well beyond rare, pathogenic, exonic variants that typified the initial discoveries in this area. Genome-wide association studies (GWAS) have demonstrated that heritability of diverse kidney traits and diseases are polygenic and primarily non-coding. eQTL studies illuminate genomic variants that regulate specific genes providing biological insight and fine mapping of loci discovered via GWAS. Efforts to maximize eQTL accuracy and precision are ongoing.

Methods

We conducted an eQTL analysis using RNA-seq from micro-dissected glomeruli (N=240) and tubulointerstitial (N=311) kidney tissue and paired whole genome sequencing (WGS) from the nephrotic syndrome cohort NEPTUNE. Single-nuclear open chromatin annotations and the distance to each gene’s transcription start site were combined into an “integrative” Bayesian prior for multi-SNP fine mapping. To validate precision and accuracy of our eQTL maps, we assessed fine-mapping resolution, predicted impact on gene regulation, and heritability of estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR). We highlighted the value of our eQTL maps through colocalization and transcription-wide association studies with eGFR and UACR GWAS. A subset of variants and genes were experimentally validated in vitro and using a Drosophila nephrocyte model.

Results

We discovered 5,371 glomerular and 9,787 tubulointerstitial eGenes. The integrative prior resulted in higher resolution eQTLs illustrated by (1) smaller credible sets with greater confidence, (2) increased enrichment of partitioned heritability for GWAS traits, (3) an increased number of variants colocalized with GWAS loci, and (4) enrichment of computationally predicted functional regulatory variants. We also functionally validated NCOA7 and LARP4B eQTLs on a gene and variant level.

Conclusion

This study demonstrates that tissue-specific eQTL maps informed by single-nucleus open chromatin data have enhanced utility for diverse downstream analyses. Results can be explored and downloaded at www.nephqtl2.org.

Funding

  • NIDDK Support