Genome-Wide Association and Functional Follow-Up Reveals New Loci for Kidney Function

Cristian Pattaro; Anna Köttgen; Alexander Teumer; Maija Garnaas; Carsten A. Böger; Christian Fuchsberger; Matthias Olden; Ming-Huei Chen; Adrienne Tin; Daniel Taliun; Man Li; Xiaoyi Gao; Mathias Gorski; Qiong Yang; Claudia Hundertmark; Meredith C. Foster; Conall M. O'Seaghdha; Nicole Glazer; Aaron Isaacs; Ching-Ti Liu; Albert V. Smith; Jeffrey R. O'Connell; Maksim Struchalin; Toshiko Tanaka; Guo Li; Andrew D. Johnson; Hinco J. Gierman; Mary Feitosa; Shih-Jen Hwang; Elizabeth J. Atkinson; Kurt Lohman; Marilyn C. Cornelis; Åsa Johansson; Anke Tönjes; Abbas Dehghan; Vincent Chouraki; Elizabeth G. Holliday; Rossella Sorice; Zoltan Kutalik; Terho Lehtimäki; Tõnu Esko; Harshal Deshmukh; Sheila Ulivi; Audrey Y. Chu; Federico Murgia; Stella Trompet; Medea Imboden; Barbara Kollerits; Giorgio Pistis; Tamara B. Harris; Lenore J. Launer; Thor Aspelund; Gudny Eiriksdottir; Braxton D. Mitchell; Eric Boerwinkle; Helena Schmidt; Margherita Cavalieri; Madhumathi Rao; Frank B. Hu; Ayse Demirkan; Ben A. Oostra; Mariza de Andrade; Stephen T. Turner; Jingzhong Ding; Jeanette S. Andrews; Barry I. Freedman; Wolfgang Koenig; Thomas Illig; Angela Döring; H.-Erich Wichmann; Ivana Kolcic; Tatijana Zemunik; Mladen Boban; Cosetta Minelli; Heather E. Wheeler; Wilmar Igl; Ghazal Zaboli; Sarah H. Wild; Alan F. Wright; Harry Campbell; David Ellinghaus; Ute Nöthlings; Gunnar Jacobs; Reiner Biffar; Karlhans Endlich; Florian Ernst; Georg Homuth; Heyo K. Kroemer; Matthias Nauck; Sylvia Stracke; Uwe Völker; Henry Völzke; CARDIoGRAM Consortium; Peter Kovacs; Michael Stumvoll; Inga Prokopenko; Reedik Mägi; Albert Hofman

doi:10.1371/journal.pgen.1002584

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Genome-Wide Association and Functional Follow-Up Reveals New Loci for Kidney Function

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Genome-Wide Association and Functional Follow-Up Reveals New Loci for Kidney Function

Cristian Pattaro, Anna Köttgen, Alexander Teumer, Maija Garnaas, Carsten A. Böger, Christian Fuchsberger, Matthias Olden, Ming-Huei Chen, Adrienne Tin, Daniel Taliun, …

PLoS genetics, Vol.8(3), p.e1002584

01/03/2012

DOI: https://doi.org/10.1371/journal.pgen.1002584

PMID: 22479191

Abstract

Biology

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2 , DDX1 , SLC47A1 , CDK12 , CASP9 , and INO80 . Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD. Chronic kidney disease (CKD) is an important public health problem with a hereditary component. We performed a new genome-wide association study in up to 130,600 European ancestry individuals to identify genes that may influence kidney function, specifically genes that may influence kidney function differently depending on sex, age, hypertension, and diabetes status of individuals. We uncovered 6 new loci associated with estimated glomerular filtration rate (eGFR), the primary measure of renal function, in or near MPPED2 , DDX1 , SLC47A1 , CDK12 , CASP9 , and INO80 . CDK12 effect was stronger in younger and absent in older individuals. MPPED2 , DDX1 , SLC47A1 , and CDK12 loci were associated with eGFR in African ancestry samples as well, highlighting the cross-ethnicity validity of our findings. Using the zebrafish model, we performed morpholino knockdown of mpped2 and casp9 in zebrafish embryos and revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. These results further our understanding of the pathogenesis of CKD and provide insights into potential novel mechanisms of disease.

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Title: Genome-Wide Association and Functional Follow-Up Reveals New Loci for Kidney Function
Creators: Cristian Pattaro - Eurac Research
Anna Köttgen - University Medical Center Freiburg
Alexander Teumer - Universität Greifswald
Maija Garnaas - Brigham and Women's Hospital
Carsten A. Böger - Georgia Institute of Technology
Christian Fuchsberger - University of Michigan–Ann Arbor
Matthias Olden - University Hospital Regensburg
Ming-Huei Chen - Georgia Institute of Technology
Adrienne Tin - Johns Hopkins University
Daniel Taliun - Eurac Research
Man Li - Johns Hopkins University
Xiaoyi Gao - Washington University in St. Louis
Mathias Gorski - University Hospital Regensburg
Qiong Yang - Boston University
Claudia Hundertmark - University Medical Center Freiburg
Meredith C. Foster - Framingham Heart Study
Conall M. O'Seaghdha - Georgia Institute of Technology
Nicole Glazer - Boston University
Aaron Isaacs - Erasmus MC
Ching-Ti Liu - Georgia Institute of Technology
Albert V. Smith - Icelandic Heart Association
Jeffrey R. O'Connell - Georgia Institute of Technology
Maksim Struchalin - Georgia Institute of Technology
Toshiko Tanaka - Georgia Institute of Technology
Guo Li - Georgia Institute of Technology
Andrew D. Johnson - Framingham Heart Study
Hinco J. Gierman - Stanford University
Mary Feitosa - Washington University in St. Louis
Shih-Jen Hwang - Georgia Institute of Technology
Elizabeth J. Atkinson - Mayo Clinic
Kurt Lohman - Wake Forest University
Marilyn C. Cornelis - Harvard University
Åsa Johansson - Uppsala University
Anke Tönjes - IFB Adiposity Diseases
Abbas Dehghan - Erasmus MC
Vincent Chouraki - Institut Pasteur de Lille
Elizabeth G. Holliday - Hunter Medical Research Institute
Rossella Sorice - Institute of Genetics and Biophysics
Zoltan Kutalik - University of Lausanne
Terho Lehtimäki - Tampere University
Tõnu Esko - University of Tartu
Harshal Deshmukh - University of Dundee
Sheila Ulivi - IRCCS Materno Infantile Burlo Garofolo
Audrey Y. Chu - Brigham and Women's Hospital
Federico Murgia - Georgia Institute of Technology
Stella Trompet - Leiden University Medical Center
Medea Imboden - Swiss Tropical and Public Health Institute
Barbara Kollerits - Innsbruck Medical University
Giorgio Pistis - Georgia Institute of Technology
Tamara B. Harris - Georgia Institute of Technology
Lenore J. Launer - Georgia Institute of Technology
Thor Aspelund - University of Iceland
Gudny Eiriksdottir - Georgia Institute of Technology
Braxton D. Mitchell - University of Maryland, Baltimore
Eric Boerwinkle - The University of Texas Health Science Center at Houston
Helena Schmidt - Medical University of Graz
Margherita Cavalieri - Georgia Institute of Technology
Madhumathi Rao - Tufts Medical Center
Frank B. Hu - Harvard University
Ayse Demirkan - Erasmus MC
Ben A. Oostra - Erasmus MC
Mariza de Andrade - Mayo Clinic
Stephen T. Turner - Mayo Clinic
Jingzhong Ding - Wake Forest University
Jeanette S. Andrews - Wake Forest University
Barry I. Freedman - Wake Forest University
Wolfgang Koenig - University Hospital Ulm
Thomas Illig - Helmholtz Zentrum München
Angela Döring - Helmholtz Zentrum München
H.-Erich Wichmann - Georgia Institute of Technology
Ivana Kolcic - University of Split
Tatijana Zemunik - University of Split
Mladen Boban - University of Split
Cosetta Minelli - Eurac Research
Heather E. Wheeler - Stanford University
Wilmar Igl - Uppsala University
Ghazal Zaboli - Uppsala University
Sarah H. Wild - University of Edinburgh
Alan F. Wright - MRC Institute of Genetics and Molecular Medicine
Harry Campbell - University of Edinburgh
David Ellinghaus - Kiel University
Ute Nöthlings - Kiel University
Gunnar Jacobs - University of Lübeck
Reiner Biffar - Universität Greifswald
Karlhans Endlich - Universität Greifswald
Florian Ernst - Universität Greifswald
Georg Homuth - Universität Greifswald
Heyo K. Kroemer - Universität Greifswald
Matthias Nauck - Universität Greifswald
Sylvia Stracke - Universitätsmedizin Greifswald
Uwe Völker - Universität Greifswald
Henry Völzke - Universitätsmedizin Greifswald
CARDIoGRAM Consortium
Peter Kovacs - Leipzig University
Michael Stumvoll - Leipzig University
Inga Prokopenko - School of Biosciences
Reedik Mägi - University of Tartu
Albert Hofman - Erasmus MC
Publication Details: PLoS genetics, Vol.8(3), p.e1002584
Publisher: Public Library of Science
Publication Date: 01/03/2012
Identifiers: 99928861702346; WOS:000302254800059
Academic Unit: School of Biosciences; Institute for Sustainability; Surrey Institute for People-Centred AI
Language: English
Resource Type: Journal article

Genome-Wide Association and Functional Follow-Up Reveals New Loci for Kidney Function

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