Kidney multiome-based genetic scorecard reveals convergent coding and regulatory variants
Hongbo Liu1,2,3,4, Amin Abedini1,2,3, Eunji Ha1,2,3
1Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA.
Science (New York, N.Y.)
|February 6, 2025
Summary
This study identified 1026 genetic loci linked to kidney dysfunction, including 97 novel ones, using a large genome-wide association study. Findings highlight the importance of population diversity for future kidney disease genetic discoveries.
Area of Science:
- Genetics
- Nephrology
- Genomics
Background:
- Kidney dysfunction represents a significant global health challenge, contributing substantially to mortality.
- The underlying genetic architecture of kidney disease remains incompletely understood, hindering targeted therapeutic development.
Purpose of the Study:
- To elucidate the genetic basis of kidney dysfunction through a large-scale, multiancestry genome-wide association study.
- To identify novel genetic loci and understand the role of genetic variation in kidney disease etiology and gene regulation.
Main Methods:
- Conducted a multiancestry genome-wide association study (GWAS) involving 2.2 million individuals.
- Performed ancestry-specific analyses and integrated genotype data with allele-specific gene expression and regulatory information from human kidney tissues and cells.
- Utilized 32 types of genetic information to develop a comprehensive prioritization tool.
Main Results:
- Identified 1026 independent genetic loci associated with kidney dysfunction, with 97 previously unknown.
- Observed an attenuation of newly identified signals in European ancestry populations, underscoring the value of population diversity.
- Discovered 1363 coding variants impacting 782 genes and identified regulatory variants targeting 601 of these genes, with convergence in 161 genes.
Conclusions:
- The study significantly expands the known genetic landscape of kidney dysfunction.
- Highlights the critical role of diverse ancestries in uncovering novel genetic associations for kidney disease.
- Introduced the "Kidney Disease Genetic Scorecard" to prioritize causal genes, cell types, and therapeutic targets for kidney disease.
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