Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function

Daniel I. Chasman; Christian Fuchsberger; Cristian Pattaro; Alexander Teumer; Carsten A. Boeger; Karlhans Endlich; 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 F. Feitosa; Shih-Jen Hwang; Elizabeth J. Atkinson; Kurt Lohman; Marilyn C. Cornelis; Asa Johansson; Anke Toenjes; Abbas Dehghan; Jean-Charles Lambert; Elizabeth G. Holliday; Rossella Sorice; Zoltan Kutalik; Terho Lehtimaeki; Tonu Esko; Harshal Deshmukh; Sheila Ulivi; Audrey Y. Chu; Federico Murgia; Stella Trompet; Medea Imboden; Stefan Coassin; Giorgio Pistis; Tamara B. Harris; Lenore J. Launer; Thor Aspelund; Gudny Eiriksdottir; Braxton D. Mitchell; Eric Boerwinkle; Helena Schmidt; Margherita Cavalieri; Madhumathi Rao; Frank Hu; Ayse Demirkan; Ben A. Oostra; Mariza de Andrade; Stephen T. Turner; Jingzhong Ding; Jeanette S. Andrews; Barry I. Freedman; Franco Giulianini; Wolfgang Koenig; Thomas Illig; Christa Meisinger; Christian Gieger; Lina Zgaga; Tatijana Zemunik; Mladen Boban; Cosetta Minelli; Heather E. Wheeler; Wilmar Igl; Ghazal Zaboli; Sarah H. Wild; Alan F. Wright; Harry Campbell; David Ellinghaus; Ute Noethlings; Gunnar Jacobs; Reiner Biffar; Florian Ernst; Georg Homuth; Heyo K. Kroemer; Matthias Nauck; Sylvia Stracke; Uwe Voelker; Henry Voelzke; Peter Kovacs; Michael Stumvoll; Reedik Maegi; Albert Hofman; Andre G. Uitterlinden; Fernando Rivadeneira; Yurii S. Aulchenko; Ozren Polasek; CARDIoGRAM Consortium; Inga Prokopenko

doi:10.1093/hmg/dds369

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Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function

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Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function

Daniel I. Chasman, Christian Fuchsberger, Cristian Pattaro, Alexander Teumer, Carsten A. Boeger, Karlhans Endlich, Matthias Olden, Ming-Huei Chen, Adrienne Tin, Daniel Taliun, …

Human molecular genetics, Vol.21(24), pp.5329-5343

15/12/2012

DOI: https://doi.org/10.1093/hmg/dds369

PMID: 22962313

Abstract

Biochemistry & Molecular Biology

Genetics & Heredity

Life Sciences & Biomedicine

Science & Technology

In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P 5.6 10(9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 10(4)2.2 10(7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.

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Title: Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function
Creators: Daniel I. Chasman - Brigham and Women's Hospital
Christian Fuchsberger - University of Michigan–Ann Arbor
Cristian Pattaro - Eurac Research
Alexander Teumer - Universität Greifswald
Carsten A. Boeger - College Station Medical Center
Karlhans Endlich - Universität Greifswald
Matthias Olden - University Hospital Regensburg
Ming-Huei Chen - Boston University
Adrienne Tin - Johns Hopkins University
Daniel Taliun - Eurac Research
Man Li - Johns Hopkins University
Xiaoyi Gao - Supreme Council Of Health
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 - Harvard University
Nicole Glazer - Boston University
Aaron Isaacs - Centre for Medical Systems Biology
Ching-Ti Liu - Boston University
Albert V. Smith - Icelandic Heart Association
Jeffrey R. O'Connell - Supreme Council Of Health
Maksim Struchalin - Rotterdam University of Applied Sciences
Toshiko Tanaka - National Institute on Aging
Guo Li - University of Washington
Andrew D. Johnson - Framingham Heart Study
Hinco J. Gierman - Stanford University
Mary F. Feitosa - Supreme Council Of Health
Shih-Jen Hwang - Framingham Heart Study
Elizabeth J. Atkinson - Mayo Clinic
Kurt Lohman - Faculty of Public Health
Marilyn C. Cornelis - Harvard University
Asa Johansson - Uppsala University
Anke Toenjes - Institute of Inland Fisheries in Potsdam-Sacrow
Abbas Dehghan - Erasmus MC
Jean-Charles Lambert - Inserm
Elizabeth G. Holliday - Hunter Medical Research Institute
Rossella Sorice - Institute of Genetics and Biophysics
Zoltan Kutalik - University of Lausanne
Terho Lehtimaeki - University of Tampere
Tonu 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 - CNR Traversa La Crucca, Inst Populat Genet, I-07040 Sassari, Italy
Stella Trompet - Leiden University Medical Center
Medea Imboden - University of Basel
Stefan Coassin - Innsbruck Medical University
Giorgio Pistis - San Raffaele University of Rome
Tamara B. Harris - National Institutes of Health
Lenore J. Launer - National Institutes of Health
Thor Aspelund - University of Iceland
Gudny Eiriksdottir - Iceland Heart Assoc, Res Inst, IS-201 Kopavogur, Iceland
Braxton D. Mitchell - Supreme Council Of Health
Eric Boerwinkle - The University of Texas Health Science Center at Houston
Helena Schmidt - Medical University of Graz
Margherita Cavalieri - Medical University of Graz
Madhumathi Rao - Tufts Medical Center
Frank Hu - Harvard University
Ayse Demirkan - Leiden University
Ben A. Oostra - Centre for Medical Systems Biology
Mariza de Andrade - Mayo Clinic
Stephen T. Turner - Mayo Clinic
Jingzhong Ding - Supreme Council Of Health
Jeanette S. Andrews - Wake Forest University
Barry I. Freedman - Supreme Council Of Health
Franco Giulianini - Brigham and Women's Hospital
Wolfgang Koenig - University Hospital Ulm
Thomas Illig - Ludwig-Maximilians-Universität München
Christa Meisinger - Helmholtz Zentrum München
Christian Gieger - Helmholtz Zentrum München
Lina Zgaga - University of Edinburgh
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 - Univ Kiel, Inst Clin Mol Biol, D-24105 Kiel, Germany
Ute Noethlings - College Station Medical Center
Gunnar Jacobs - University of Lübeck
Reiner Biffar - Universität Greifswald
Florian Ernst - Innsbruck Medical University
Georg Homuth - Universität Greifswald
Heyo K. Kroemer - Universität Greifswald
Matthias Nauck - Universitätsmedizin Greifswald
Sylvia Stracke - Universitätsmedizin Greifswald
Uwe Voelker - Universität Greifswald
Henry Voelzke - Universität Greifswald
Peter Kovacs - IFB Adiposity Diseases
Michael Stumvoll - IFB Adiposity Diseases
Reedik Maegi - University of Tartu
Albert Hofman - Erasmus MC
Andre G. Uitterlinden - Erasmus MC
Fernando Rivadeneira - Erasmus MC
Yurii S. Aulchenko - Erasmus MC
Ozren Polasek - University of Split
CARDIoGRAM Consortium
Inga Prokopenko - School of Biosciences
Publication Details: Human molecular genetics, Vol.21(24), pp.5329-5343
Publisher: Oxford Univ Press
Number of pages: 15
Date published: 15/12/2012
Grant note: P 20545 / Austrian Science Fund (FWF) MC_PC_U127561128 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) R01AG025941 / NATIONAL INSTITUTE ON AGING; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA) CZB/4/710 / Chief Scientist Office N01HC025195 / DIVISION OF EPIDEMIOLOGY AND CLINICAL APPLICATIONS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Eye Institute (NEI) MC_U127561128 / Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC); European Commission P30DK079637 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) R01CA047988 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) R01HL043851 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI)
Identifiers: 99928750402346
Academic Unit: School of Biosciences; Institute for Sustainability; Surrey Institute for People-Centred AI
Language: English
Resource Type: Journal article

Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function

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