A catalog of genetic loci associated with kidney function from analyses of a million individuals

Matthias Wuttke; Yong Li; Man Li; Karsten B Sieber; Mary F Feitosa; Mathias Gorski; Adrienne Tin; Lihua Wang; Audrey Y Chu; Anselm Hoppmann; Holger Kirsten; Ayush Giri; Jin-Fang Chai; Gardar Sveinbjornsson; Bamidele O Tayo; Teresa Nutile; Christian Fuchsberger; Jonathan Marten; Massimiliano Cocca; Sahar Ghasemi; Yizhe Xu; Katrin Horn; Damia Noce; Peter J van der Most; Sanaz Sedaghat; Zhi Yu; Masato Akiyama; Saima Afaq; Tarunveer S Ahluwalia; Peter Almgren; Najaf Amin; Johan Ärnlöv; Stephan J L Bakker; Nisha Bansal; Daniela Baptista; Sven Bergmann; Mary L Biggs; Ginevra Biino; Michael Boehnke; Eric Boerwinkle; Mathilde Boissel; Erwin P Bottinger; Thibaud S Boutin; Hermann Brenner; Marco Brumat; Ralph Burkhardt; Adam S Butterworth; Eric Campana; Archie Campbell; Harry Campbell; Mickaël Canouil; Robert J Carroll; Eulalia Catamo; John C Chambers; Miao-Ling Chee; Miao-Li Chee; Xu Chen; Ching-Yu Cheng; Yurong Cheng; Kaare Christensen; Renata Cifkova; Marina Ciullo; Maria Pina Concas; James P Cook; Josef Coresh; Tanguy Corre; Cinzia Felicita Sala; Daniele Cusi; John Danesh; E Warwick Daw; Martin H de Borst; Alessandro De Grandi; Renée de Mutsert; Aiko P J de Vries; Frauke Degenhardt; Graciela Delgado; Ayse Demirkan; Emanuele Di Angelantonio; Katalin Dittrich; Jasmin Divers; Rajkumar Dorajoo; Kai-Uwe Eckardt; Georg Ehret; Paul Elliott; Karlhans Endlich; Michele K Evans; Janine F Felix; Valencia Hui Xian Foo; Oscar H Franco; Andre Franke; Barry I Freedman; Sandra Freitag-Wolf; Yechiel Friedlander; Philippe Froguel; Ron T Gansevoort; He Gao; Paolo Gasparini; J Michael Gaziano; Vilmantas Giedraitis; Christian Gieger; V. A. Million Veteran Program

doi:10.1038/s41588-019-0407-x

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A catalog of genetic loci associated with kidney function from analyses of a million individuals

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A catalog of genetic loci associated with kidney function from analyses of a million individuals

Matthias Wuttke, Yong Li, Man Li, Karsten B Sieber, Mary F Feitosa, Mathias Gorski, Adrienne Tin, Lihua Wang, Audrey Y Chu, Anselm Hoppmann, …

Nature genetics, Vol.51(6), pp.957-972

01/06/2019

DOI: https://doi.org/10.1038/s41588-019-0407-x

PMID: 31152163

Abstract

Chromosome Mapping

Genetic Association Studies - methods

Genetic Predisposition to Disease

Genome-Wide Association Study

Glomerular Filtration Rate

Humans

Inheritance Patterns

Kidney Function Tests

Phenotype

Polymorphism, Single Nucleotide

Quantitative Trait Loci

Quantitative Trait, Heritable

Renal Insufficiency, Chronic - genetics

Renal Insufficiency, Chronic - physiopathology

Renal Insufficiency, Chronic - urine

Uromodulin - urine

White People

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.

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Title: A catalog of genetic loci associated with kidney function from analyses of a million individuals
Creators: Matthias Wuttke - University of Freiburg
Yong Li - University Medical Center Freiburg
Man Li - University of Utah
Karsten B Sieber - Target
Mary F Feitosa - Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA
Mathias Gorski - University Hospital Regensburg
Adrienne Tin - Johns Hopkins University
Lihua Wang - Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA
Audrey Y Chu - MSD
Anselm Hoppmann - University Medical Center Freiburg
Holger Kirsten - Leipzig University
Ayush Giri - Vanderbilt University Medical Center
Jin-Fang Chai - National University Health System
Gardar Sveinbjornsson - deCODE Genetics/Amgen, Inc., Reykjavik, Iceland
Bamidele O Tayo - Loyola University Chicago
Teresa Nutile - Institute of Genetics and Biophysics
Christian Fuchsberger - Eurac Research
Jonathan Marten - MRC Institute of Genetics and Molecular Medicine
Massimiliano Cocca - IRCCS Materno Infantile Burlo Garofolo
Sahar Ghasemi - Universitätsmedizin Greifswald
Yizhe Xu - University of Utah
Katrin Horn - Leipzig University
Damia Noce - Eurac Research
Peter J van der Most - University Medical Center Groningen
Sanaz Sedaghat - Erasmus MC
Zhi Yu - Johns Hopkins University
Masato Akiyama - RIKEN Center for Integrative Medical Sciences
Saima Afaq - Imperial College London
Tarunveer S Ahluwalia - Steno Diabetes Center
Peter Almgren - Malmö University
Najaf Amin - Erasmus MC
Johan Ärnlöv - Karolinska Institutet
Stephan J L Bakker - University Medical Center Groningen
Nisha Bansal - University of Washington
Daniela Baptista - University Hospital of Geneva
Sven Bergmann - University of Lausanne
Mary L Biggs - University of Washington
Ginevra Biino - National Research Council
Michael Boehnke - Statistical Research
Eric Boerwinkle - The University of Texas Health Science Center at Houston
Mathilde Boissel - Institut Pasteur de Lille
Erwin P Bottinger - Icahn School of Medicine at Mount Sinai
Thibaud S Boutin - MRC Institute of Genetics and Molecular Medicine
Hermann Brenner - German Cancer Research Center
Marco Brumat - University of Trieste
Ralph Burkhardt - University Hospital Regensburg
Adam S Butterworth - University of Cambridge
Eric Campana - University of Trieste
Archie Campbell - University of Edinburgh
Harry Campbell - University of Edinburgh
Mickaël Canouil - European Genomic Institute for Diabetes
Robert J Carroll - Vanderbilt University Medical Center
Eulalia Catamo - IRCCS Materno Infantile Burlo Garofolo
John C Chambers - Imperial College London
Miao-Ling Chee - Singapore National Eye Center
Miao-Li Chee - Singapore National Eye Center
Xu Chen - Karolinska Institutet
Ching-Yu Cheng - Duke-NUS Medical School
Yurong Cheng - University Medical Center Freiburg
Kaare Christensen - University of Southern Denmark
Renata Cifkova - Charles University
Marina Ciullo - Institute of Genetics and Biophysics
Maria Pina Concas - IRCCS Materno Infantile Burlo Garofolo
James P Cook - University of Liverpool
Josef Coresh - Johns Hopkins University
Tanguy Corre - University of Lausanne
Cinzia Felicita Sala - San Raffaele University of Rome
Daniele Cusi - National Research Council
John Danesh - University of Cambridge
E Warwick Daw - Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA
Martin H de Borst - University Medical Center Groningen
Alessandro De Grandi - Institute for Biomedicine
Renée de Mutsert - Leiden University Medical Center
Aiko P J de Vries - Leiden University Medical Center
Frauke Degenhardt - Kiel University
Graciela Delgado - Heidelberg University
Ayse Demirkan - Erasmus MC
Emanuele Di Angelantonio - University of Cambridge
Katalin Dittrich - Center for Pediatric Research, University of Leipzig, Leipzig, Germany
Jasmin Divers - Wake Forest University
Rajkumar Dorajoo - Agency for Science, Technology and Research
Kai-Uwe Eckardt - Department of Nephrology and Hypertension, Friedrich Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
Georg Ehret - University Hospital of Geneva
Paul Elliott - Imperial College London
Karlhans Endlich - German Centre for Cardiovascular Research
Michele K Evans - National Institutes of Health
Janine F Felix - Erasmus MC
Valencia Hui Xian Foo - Singapore National Eye Center
Oscar H Franco - Erasmus MC
Andre Franke - Kiel University
Barry I Freedman - Wake Forest University
Sandra Freitag-Wolf - University Hospital Schleswig-Holstein
Yechiel Friedlander - Hebrew University of Jerusalem
Philippe Froguel - European Genomic Institute for Diabetes
Ron T Gansevoort - University Medical Center Groningen
He Gao - Imperial College London
Paolo Gasparini - IRCCS Materno Infantile Burlo Garofolo
J Michael Gaziano - VA Boston Healthcare System
Vilmantas Giedraitis - Uppsala University
Christian Gieger - Helmholtz Zentrum München
V. A. Million Veteran Program
Publication Details: Nature genetics, Vol.51(6), pp.957-972
Date published: 01/06/2019
Grant note: U01 HL130114 / NHLBI NIH HHS R01 DK062370 / NIDDK NIH HHS MC_UU_00007/10 / Medical Research Council R01 HL120393 / NHLBI NIH HHS P30 DK116074 / NIDDK NIH HHS S10 OD023680 / NIH HHS Z01 AG000513-08 / Intramural NIH HHS R01 DK072193 / NIDDK NIH HHS R01 DK093757 / NIDDK NIH HHS RG/13/13/30194 / British Heart Foundation
Identifiers: 99928818802346
Academic Unit: Institute for Sustainability; Surrey Institute for People-Centred AI; School of Biosciences
Language: English
Resource Type: Journal article

A catalog of genetic loci associated with kidney function from analyses of a million individuals

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