Kidney Week

Abstract: TH-OR83

Genome-Wide Glomerular Allele-Specific Expression in Human Proteinuric Kidney Tissue

Session Information

• Non-Cystic Genetic Kidney Diseases: Disease Genes, Modifiers, and Therapies
  October 24, 2024 | Location: Room 23, Convention Center
  Abstract Time: 04:40 PM - 04:50 PM

Category: Genetic Diseases of the Kidneys

• 1202 Genetic Diseases of the Kidneys: Non-Cystic

Authors

• Onuchic-Whitford, Ana C., Brigham and Women's Hospital, Boston, Massachusetts, United States

Ana C. Onuchic-Whitford, MD

• Sung, Junmo, Brigham and Women's Hospital, Boston, Massachusetts, United States

Junmo Sung, MS

• Sakkas, Erotokritos, Boston Children's Hospital, Boston, Massachusetts, United States

Erotokritos Sakkas

• Mcnulty, Michelle, Boston Children's Hospital, Boston, Massachusetts, United States

Michelle Mcnulty, MS

• Greenberg, Anya, Boston Children's Hospital, Boston, Massachusetts, United States

Anya Greenberg

• Yoon, Jihoon, Yonsei University College of Medicine, Seodaemun-gu, Korea (the Republic of)

Jihoon Yoon, MD, PhD

• Badina, Sowmya, Brigham and Women's Hospital, Boston, Massachusetts, United States

Sowmya Badina

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

Matt G. Sampson, MD

• Lee, Dongwon, Boston Children's Hospital, Boston, Massachusetts, United States

Dongwon Lee, PhD

Group or Team Name

• NEPTUNE (Nephrotic Syndrome Study Network).

Background

Regulation of gene expression plays a key role in disease pathophysiology and contributes to penetrance of pathogenic variants. Allele-specific expression (ASE), where each copy of a gene contributes differentially to total gene expression, is a robust measure of cis-regulatory effects. While this phenomenon is well described in other organs, ASE analysis in kidneys is limited, mainly to normal tissue. Here, we successfully generated a genome-wide, high-quality ASE dataset in glomerular tissue from individuals with proteinuric kidney disease in NEPTUNE, using a rigorous computational pipeline.

Methods

We leveraged whole-genome sequencing (WGS) paired with kidney biopsy-derived glomerular RNA-seq from 240 NEPTUNE participants to robustly quantify ASE events across the genome. WGS was population-phased using WhatsHap and SHAPEIT4 with a large reference panel of phased haplotypes (~500K individuals) from UK Biobank. RNA alignment was done with STAR/WASP to address read mapping bias; duplicate reads were removed. phASER was used to integrate phased WGS and RNA-seq to generate SNP- and gene-level allelic expression data for all individuals. We applied the same pipeline to 88 individuals from GTEx with kidney cortex samples and paired WGS/RNA data.

Results

Using an RNA read count >=20 cutoff, we calculated allelic expression for a mean of 7,173 genes per individual. Applying the binomial test with correction for multiple comparisons, we identified genes with significant ASE (FDR<0.05). 19,175 genes had ASE observed in ≥1 person and 14,148 of these genes were protein-coding. Individuals had a mean of 1,433 ASE genes and 55 genes with monoallelic expression. PLA2R1 ranked 8^th (genome-wide) as most common ASE gene among NEPTUNE participants, with PLCG2 ranking 12^th and NPHS2 ranking 13^th. While these key glomerular genes were also significantly expressed in GTEx kidney samples, they had less ASE among individuals, ranking as 954^th (PLA2R1), 1719^th (PLCG2) and 206^th (NPHS2) most common ASE genes.

Conclusion

We generated a genome-wide dataset of ASE in proteinuric glomerular tissue through a rigorous multi-step process integrating several computational tools. Our initial analysis reveals overrepresentation of ASE in known proteinuric kidney disease-related genes among NEPTUNE participants.

Funding

• NIDDK Support