Mapping eGFR loci to the renal transcriptome and phenome in the VA Million Veteran Program

Jacklyn N. Hellwege, Digna R. Velez Edwards, Ayush Giri, Chengxiang Qiu, Jihwan Park, Eric S. Torstenson, Jacob M. Keaton, O. D. Wilson, Cassianne Robinson-Cohen, Cecilia P. Chung, Christianne L. Roumie, Derek Klarin, Scott M. Damrauer, Scott L. DuVall, Edward Siew, Elvis A. Akwo, Matthias Wuttke, Mathias Gorski, Man Li, Yong Li, J. Michael Gaziano, Peter W. F. Wilson, Philip S. Tsao, Christopher J. O’Donnell, Csaba P. Kovesdy, Cristian Pattaro, Anna Köttgen, Katalin Susztak, Todd L. Edwards () and Adriana M. Hung ()
Additional contact information
Jacklyn N. Hellwege: Tennessee Valley Healthcare System (626)/Vanderbilt University
Digna R. Velez Edwards: Tennessee Valley Healthcare System (626)/Vanderbilt University
Ayush Giri: Tennessee Valley Healthcare System (626)/Vanderbilt University
Chengxiang Qiu: University of Pennsylvania
Jihwan Park: University of Pennsylvania
Eric S. Torstenson: Tennessee Valley Healthcare System (626)/Vanderbilt University
Jacob M. Keaton: Tennessee Valley Healthcare System (626)/Vanderbilt University
O. D. Wilson: Vanderbilt University Medical Center
Cassianne Robinson-Cohen: Vanderbilt University Medical Center
Cecilia P. Chung: Tennessee Valley Healthcare System (626)/Vanderbilt University
Christianne L. Roumie: Veteran Affairs Administration Tennessee Valley VA Health Care System Geriatric Research Education Clinical Center (GRECC)
Derek Klarin: VA Boston Health Care System
Scott M. Damrauer: Corporal Michael Crescenz VA Medical Center
Scott L. DuVall: VA Salt Lake City Health Care System
Edward Siew: Vanderbilt University Medical Center
Elvis A. Akwo: Vanderbilt University Medical Center
Matthias Wuttke: Epidemiology and Medical Bioinformatics, Faculty of Medicine and Medical Centre—University of Freiburg
Mathias Gorski: University of Regensburg
Man Li: VA Boston Health Care System
Yong Li: Epidemiology and Medical Bioinformatics, Faculty of Medicine and Medical Centre—University of Freiburg
J. Michael Gaziano: Broad Institute of Harvard and MIT
Peter W. F. Wilson: Atlanta VA Medical Center
Philip S. Tsao: VA Palo Alto Health Care System
Christopher J. O’Donnell: VA Boston Health Care System
Csaba P. Kovesdy: Memphis VA Medical Center
Cristian Pattaro: Eurac Research
Anna Köttgen: Epidemiology and Medical Bioinformatics, Faculty of Medicine and Medical Centre—University of Freiburg
Katalin Susztak: University of Pennsylvania
Todd L. Edwards: Tennessee Valley Healthcare System (626)/Vanderbilt University
Adriana M. Hung: Tennessee Valley Healthcare System (626)/Vanderbilt University

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: Abstract Chronic kidney disease (CKD), defined by low estimated glomerular filtration rate (eGFR), contributes to global morbidity and mortality. Here we conduct a transethnic Genome-Wide Association Study of eGFR in 280,722 participants of the Million Veteran Program (MVP), with replication in 765,289 participants from the Chronic Kidney Disease Genetics (CKDGen) Consortium. We identify 82 previously unreported variants, confirm 54 loci, and report interesting findings including association of the sickle cell allele of betaglobin among non-Hispanic blacks. Our transcriptome-wide association study of kidney function in healthy kidney tissue identifies 36 previously unreported and nine known genes, and maps gene expression to renal cell types. In a Phenome-Wide Association Study in 192,868 MVP participants using a weighted genetic score we detect associations with CKD stages and complications and kidney stones. This investigation reinterprets the genetic architecture of kidney function to identify the gene, tissue, and anatomical context of renal homeostasis and the clinical consequences of dysregulation.

Date: 2019
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DOI: 10.1038/s41467-019-11704-w

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