Mapping genomic regulation of kidney disease and traits through high-resolution and interpretable eQTLs
Year: 2023
Type: article
Study design: Observational Study
Abstract: Expression quantitative trait locus (eQTL) studies illuminate genomic variants that regulate specific genes and contribute to fine-mapped loci discovered via genome-wide association studies (GWAS). Efforts to maximize their accuracy are ongoing. Using 240 glomerular (GLOM) and 311 tubulointerstitial (TUBE) micro-dissected samples from human kidney biopsies, we discovered 5371 GLOM and 9787 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. The use 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 experimentally in vitro and using a Drosophila nephrocyte model. More broadly, this study demonstrates that tissue-specific eQTL maps informed by single-nucleus open chromatin data have enhanced utility for diverse downstream analyses.
Source: Nature Communications
Authors: Seong Kyu Han, Michelle T. McNulty, Christopher J. Benway, Pei Wen, Anya Greenberg, Ana C. Onuchic-Whitford, Nephrotic Syndrome Study Network (NEPTUNE), Dongkeun Jang, Jason Flannick, Noël P. Burtt, Parker C. Wilson, Benjamin D. Humphreys, Xiaoquan Wen, Zhe Han, Dongwon Lee, Matthew G. Sampson
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,290
Funders: U.S. Department of Health and Human Services, Nephcure Foundation, University of Michigan, Rare Diseases Clinical Research Network, Halpin Foundation, Massachusetts Green High Performance Computing Center, National Institutes of Health, Manton Center for Orphan Disease Research, Boston Children's Hospital, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute on Drug Abuse, National Human Genome Research Institute, NIH Office of the Director, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences, National Center for Advancing Translational Sciences, Common Fund
Awards: G114959187, G1179255120, G195356861, Mutations in TBC1D8B as a potential new cause of nephrotic syndrome, G2721278807, G3257198934, G3315116511, G3496055938, G355220204, G3596025055, G3673222578, G3729289465, G4279768677, The Association to Function Knowledge Portal: a genomic data resource for translating GWAS associations to biological effects, G4622112869, Modeling Nephrotic Syndrome in Drosophila Nephrocytes, Integrating large scale genomics and functional studies to accelerate FSGS/NS discovery, G6363222580, G6630320530, G7086166731, G8027454555, G9000029571, G9000047882, G9000114733, G9000123151, The next iteration of the AMP-T2D Knowledge Portal, Data Management and Coordinating Center: Rare Diseases Clinical Research Network
OpenAlex ID: W4366405447