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논문분류	춘계학술대회 초록집
제목	Understanding cell-type convergence of kidney disease and traits through interpretable eQTLs informed by single-cell epigenomic data
저자	Seong Kyu Han
출판정보	2023; 2023(1):
키워드
초록	Objectives: Genomic contributors to kidney traits extend beyond rare, pathogenic, exonic variants. Genome-wide association studies (GWAS) have demonstrated that heritability of diverse kidney traits are polygenic and primarily non-coding.Expression quantitative trait locus (eQTL) studies illuminate genomic variants that regulate specific genes providing biological insight and fine mapping of GWAS loci.Single-cell epigenomic data can aid fine-mapping of eQTLs to identify kidney regulatory variants from tag-SNPs within same haplotype block. Methods: Using 240 glomerular (GLOM) and 311 tubulointerstitial (TUBE) micro-dissected samples from human kidney biopsies, we discovered 5,371 GLOM and 9,787 TUBE genes with at least one variant significantly associated with expression (eGene) by incorporating kidney single-nucleus open chromatin data and transcription start site distance as an “integrative prior” for Bayesian statistical fine-mapping. Results: Theuse of an integrative prior resulted in higher resolution eQTLs illustrated by (1) smaller numbers of variants in credible sets with greater confidence, (2) increased enrichment of partitioned heritability for GWAS of two kidney traits, (3) an increased number of variants colocalized with the GWAS loci, and (4) enrichment of computationally predicted functional regulatory variants.A subset of variants and genes were validated experimentallyin vitroand using aDrosophilanephrocyte model. Conclusions: The eQTLs augmented by cell-type CREs make the results of downstream analyses interpretable in terms of (1) mechanistic insight into transcriptional regulation and (2) contributing cell-types orcis-regulatory elements. Interactive visualizations of eQTLs provided in www.nephqtl2.org will be a novel resource to narrow down potential mechanisms and elucidate the regulatory landscape of kidney phenotypes.
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