Mapping the genetic architecture of human traits to cell types in the kidney identifies mechanisms of disease and potential treatments.
Xin Sheng,Yuting Guan,Ziyuan Ma,Junnan Wu,Hongbo Liu,Chengxiang Qiu,Steven Vitale,Zhen Miao,Matthew J. Seasock,Matthew Palmer,Myung K. Shin,Kevin L. Duffin,Steven S. Pullen,Todd L. Edwards,Jacklyn N. Hellwege,Adriana M. Hung,Mingyao Li,Benjamin F. Voight,Thomas M. Coffman,Christopher D. Brown,Katalin Susztak +20 more
TLDR
In this paper, the authors generated comprehensive maps of expression quantitative trait loci (eQTLs) for 659 microdissected human kidney samples and identified cell-type eQTL by mapping interactions between cell type abundances and genotypes.Abstract:
The functional interpretation of genome-wide association studies (GWAS) is challenging due to the cell-type-dependent influences of genetic variants. Here, we generated comprehensive maps of expression quantitative trait loci (eQTLs) for 659 microdissected human kidney samples and identified cell-type-eQTLs by mapping interactions between cell type abundances and genotypes. By partitioning heritability using stratified linkage disequilibrium score regression to integrate GWAS with single-cell RNA sequencing and single-nucleus assay for transposase-accessible chromatin with high-throughput sequencing data, we prioritized proximal tubules for kidney function and endothelial cells and distal tubule segments for blood pressure pathogenesis. Bayesian colocalization analysis nominated more than 200 genes for kidney function and hypertension. Our study clarifies the mechanism of commonly used antihypertensive and renal-protective drugs and identifies drug repurposing opportunities for kidney disease.read more
Citations
More filters
Journal ArticleDOI
Heart Disease and Stroke Statistics—2023 Update: A Report From the American Heart Association
TL;DR: The 2023 Statistical Update as mentioned in this paper provides the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health.
Journal ArticleDOI
Heart Disease and Stroke Statistics—2023 Update: A Report From the American Heart Association
TL;DR: The 2023 Statistical Update as mentioned in this paper provides the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health.
Journal ArticleDOI
Characterizing cis-regulatory elements using single-cell epigenomics
TL;DR: Recent advances in single-cell epigenomic methods and analytical tools are highlighted and discussed and their readiness for human tissue profiling is discussed.
Journal ArticleDOI
Epigenomic and transcriptomic analyses define core cell types, genes and targetable mechanisms for kidney disease
Hongbo Liu,Tomohito Doke,Dong Guo,Xin Sheng,Ziyu Ma,Joseph Park,Ha My T. Vy,Girish N. Nadkarni,Amin Abedini,Zhen Miao,Matthew Palmer,Benjamin F. Voight,Hongzhe Li,Christopher D. Brown,Marylyn D. Ritchie,Yan Shu,Katalin Susztak +16 more
TL;DR: The causal role of SLC47A1 in kidney disease is defined in mice with genetic loss of Slc47a1 and in human individuals carrying loss-of-function variants and the key role of bulk and single-cell epigenomic information is emphasized in translating genome-wide association studies into identifying causal genes, cellular origins and mechanisms of complex traits.
Journal ArticleDOI
A single genetic locus controls both expression of DPEP1/CHMP1A and kidney disease development via ferroptosis.
Yuting Guan,Xiujie Liang,Ziyuan Ma,Hailong Hu,Hongbo Liu,Zhen Miao,Andreas Linkermann,Jacklyn N. Hellwege,Benjamin F. Voight,Katalin Susztak +9 more
TL;DR: In this article, the authors identify two kidney disease genes Dipeptidase 1 (DPEP1) and Charged Multivesicular Body Protein 1 A (CHMP1A) via the triangulation of kidney function GWAS, human kidney expression, and methylation quantitative trait loci.
References
More filters
Journal ArticleDOI
edgeR: a Bioconductor package for differential expression analysis of digital gene expression data.
TL;DR: EdgeR as mentioned in this paper is a Bioconductor software package for examining differential expression of replicated count data, which uses an overdispersed Poisson model to account for both biological and technical variability and empirical Bayes methods are used to moderate the degree of overdispersion across transcripts, improving the reliability of inference.
Journal ArticleDOI
Model-based Analysis of ChIP-Seq (MACS)
Yong Zhang,Tao Liu,Clifford A. Meyer,Jérôme Eeckhoute,David S. Johnson,Bradley E. Bernstein,Bradley E. Bernstein,Chad Nusbaum,Richard M. Myers,Myles Brown,Wei Li,X. Shirley Liu +11 more
TL;DR: This work presents Model-based Analysis of ChIP-Seq data, MACS, which analyzes data generated by short read sequencers such as Solexa's Genome Analyzer, and uses a dynamic Poisson distribution to effectively capture local biases in the genome, allowing for more robust predictions.
Journal ArticleDOI
Simple Combinations of Lineage-Determining Transcription Factors Prime cis-Regulatory Elements Required for Macrophage and B Cell Identities
Sven Heinz,Christopher Benner,Nathanael J. Spann,Eric Bertolino,Yin C. Lin,Peter Laslo,Jason X. Cheng,Cornelis Murre,Harinder Singh,Harinder Singh,Christopher K. Glass +10 more
TL;DR: It is demonstrated in macrophages and B cells that collaborative interactions of the common factor PU.1 with small sets of macrophage- or B cell lineage-determining transcription factors establish cell-specific binding sites that are associated with the majority of promoter-distal H3K4me1-marked genomic regions.
Journal ArticleDOI
Statistical significance for genomewide studies
John D. Storey,Robert Tibshirani +1 more
TL;DR: This work proposes an approach to measuring statistical significance in genomewide studies based on the concept of the false discovery rate, which offers a sensible balance between the number of true and false positives that is automatically calibrated and easily interpreted.
Journal ArticleDOI
DAVID: Database for Annotation, Visualization, and Integrated Discovery
Glynn Dennis,Brad T. Sherman,Douglas A. Hosack,Jun Jun Yang,Wei Gao,H. Clifford Lane,Richard A. Lempicki +6 more
TL;DR: DAMID is a web-accessible program that integrates functional genomic annotations with intuitive graphical summaries that assists in the interpretation of genome-scale datasets by facilitating the transition from data collection to biological meaning.
Related Papers (5)
A catalog of genetic loci associated with kidney function from analyses of a million individuals
Integrated genome-wide analysis of expression quantitative trait loci aids interpretation of genomic association studies.
Roby Joehanes,Roby Joehanes,Roby Joehanes,Xiaoling Zhang,Xiaoling Zhang,Tianxiao Huan,Chen Yao,Saixia Ying,Quang Tri Nguyen,Cumhur Y Demirkale,Michael Feolo,Nataliya Sharopova,Anne Sturcke,Alejandro A. Schäffer,Nancy L. Heard-Costa,Han Chen,Han Chen,Poching Liu,Richard J. Wang,Kimberly Woodhouse,Kahraman Tanriverdi,Jane E. Freedman,Nalini Raghavachari,Josée Dupuis,Josée Dupuis,Andrew D. Johnson,Christopher J. O'Donnell,Daniel Levy,Peter J. Munson,Peter J. Munson +29 more
Single-cell RNA-sequencing of differentiating iPS cells reveals dynamic genetic effects on gene expression
Anna S E Cuomo,Daniel D Seaton,Davis J. McCarthy,Davis J. McCarthy,Iker Martinez,Marc Jan Bonder,Marc Jan Bonder,Jose Garcia-Bernardo,Shradha Amatya,Pedro Madrigal,Abigail Isaacson,Florian Buettner,Andrew J Knights,Kedar Nath Natarajan,Kedar Nath Natarajan,Ludovic Vallier,Ludovic Vallier,John C. Marioni,John C. Marioni,John C. Marioni,Mariya Chhatriwala,Oliver Stegle,Oliver Stegle +22 more