A transcriptome-wide association study based on 27 tissues identifies 106 genes potentially relevant for disease pathology in age-related macular degeneration
Tobias Strunz(University of Regensburg), Susette Lauwen(Radboud University Nijmegen), Christina Kiel(University of Regensburg), Lars G. Fritsche(University of Michigan), Wilmar Igl(University of Regensburg), Jessica N. Cooke Bailey(Cornell University), Felix Graßmann(University of Regensburg), Sebanti Sengupta(University of Michigan), Jennifer L. Bragg‐Gresham(University of Michigan), Kathryn P. Burdon(University of Tasmania), Scott J. Hebbring(Marshfield Clinic), Cindy Wen(UC San Diego Health System), Mathias Gorski(University of Regensburg), Ivana K. Kim(Massachusetts Eye and Ear Infirmary), David Cho(University of Pennsylvania), Donald J. Zack(Institut de la Vision), Eric H. Souied(Université Paris-Est Créteil), Hendrik P. N. Scholl(University of Bonn), Elisa Bala(Louis Stokes Cleveland VA Medical Center), Kristine E. Lee(University of Wisconsin–Madison), David J. Hunter(Harvard University), Rebecca J. Sardell(University of Miami), Paul Mitchell(The University of Sydney), Joanna E. Merriam(Columbia University), Valentina Cipriani(Moorfields Eye Hospital), Joshua Hoffman(Center for Human Genetics), Tina Schick(University Hospital Cologne), Yara Lechanteur(Radboud University Nijmegen), Robyn H. Guymer(The University of Melbourne), Matthew P. Johnson(The University of Texas Rio Grande Valley), Yingda Jiang(University of Pittsburgh), Chloë M. Stanton(Institute of Genetics and Cancer), Gabriëlle H.S. Buitendijk(Erasmus MC), Xiaowei Zhan(University of Michigan), Alan Kwong(University of Michigan), Alexis Boleda(National Institutes of Health), Matthew Brooks(University of Michigan), Linn Gieser(National Institutes of Health), Rinki Ratnapriya(National Institutes of Health), Kari Branham(University of Michigan), Johanna R. Foerster(University of Michigan), John R. Heckenlively(University of Michigan), Mohammad Othman(University of Michigan), Brendan J. Vote(University of Tasmania), Helena H. Liang(The University of Melbourne), Emmanuelle Souzeau(Flinders University), Ian L. McAllister(Lions Eye Institute), Timothy Isaacs(Lions Eye Institute), Janette M. Hall(Flinders University), Stewart Lake(Flinders University), David A. Mackey(Lions Eye Institute), Ian J. Constable(Lions Eye Institute), Jamie E. Craig(Flinders University), Terrie Kitchner(Marshfield Clinic), Zhenglin Yang(University of Electronic Science and Technology of China), Zhiguang Su(Sichuan University), Hongrong Luo(Sichuan University), Daniel Chen(UC San Diego Health System), Hong Ouyang(UC San Diego Health System), Ken Flagg(UC San Diego Health System), Danni Lin(UC San Diego Health System), Guanping Mao(UC San Diego Health System), Henry Ferreyra(UC San Diego Health System), Klaus Stark(University of Regensburg), Claudia N. von Strachwitz, Armin Wolf(Ludwig-Maximilians-Universität München), Caroline Brandl(University Hospital Regensburg), Guenther Rudolph(Ludwig-Maximilians-Universität München), Matthias Olden(University of Regensburg), Margaux A. Morrison(University of Utah), Denise J. Morgan(University of Utah), Matthew Schu(Boston University), Jeeyun Ahn(Seoul National University), Giuliana Silvestri(Queen's University Belfast), Evangelia E. Tsironi(University of Thessaly), Kyu Hyung Park(Seoul National University Bundang Hospital), Lindsay A. Farrer(Boston University), Anton Orlin(Cornell University), Alexander J. Brucker(Penn Presbyterian Medical Center), Mingyao Li(University of Pennsylvania), Christine A. Curcio(University of Alabama at Birmingham), Saddek Mohand‐Saïd(Centre National de la Recherche Scientifique), José‐Alain Sahel(Centre National de la Recherche Scientifique), Isabelle Audo(Centre National de la Recherche Scientifique), Mustapha Benchaboune(Inserm), Angela J. Cree(University of Southampton), Christina Rennie(University Hospital Southampton NHS Foundation Trust), Srinivas Goverdhan(University of Southampton), Michelle Grunin(Hadassah Medical Center), Shira Hagbi-Levi(Hadassah Medical Center), Peter A. Campochiaro(Johns Hopkins University), Nicholas Katsanis(Duke University), Frank G. Holz(University of Bonn), Frédéric Blond(Centre National de la Recherche Scientifique), Hélène Blanché(Fondation Jean Dausset-CEPH), Jean‐François Deleuze(Commissariat à l'Énergie Atomique et aux Énergies Alternatives), Robert P. Igo(Cornell University), Barbara Truitt(Cornell University), Neal S. Peachey(Cleveland Clinic), Stacy M. Meuer(University of Wisconsin–Madison), Chelsea E. Myers(University of Wisconsin–Madison), Emily Moore(University of Wisconsin–Madison), Ronald Klein(University of Wisconsin–Madison), Michael A. Hauser(Duke Medical Center), Eric A. Postel(Duke Medical Center), Monique D. Courtenay(University of Miami), Stephen G. Schwartz(University of Miami), Jaclyn L. Kovach(University of Miami), William K. Scott(University of Miami), Gerald Liew(The University of Sydney), Ava G. Tfan(The University of Sydney), Bamini Gopinath(The University of Sydney), John C. Merriam(Columbia University), R. Theodore Smith(New York University), Jane C. Khan(Lions Eye Institute), Humma Shahid(University of Cambridge), Anthony T. Moore(University of California San Francisco Medical Center), J. Allie McGrath(Center for Human Genetics), Reneé A. Laux(Cornell University), Milam A. Brantley(Vanderbilt University), Anita Agarwal(Vanderbilt University), Lebriz Ersoy(University Hospital Cologne), Albert Caramoy(University Hospital Cologne), Thomas Langmann(University Hospital Cologne), Nicole T.M. Saksens(Radboud University Nijmegen), Eiko K. de Jong(Radboud University Nijmegen), Carel B. Hoyng(Radboud University Nijmegen), Melinda Cain(The University of Melbourne), Andrea J. Richardson(The University of Melbourne), Tammy M. Martin(Oregon Health & Science University), John Blangero(The University of Texas Rio Grande Valley), Daniel E. Weeks(University of Pittsburgh), Bal Dhillon(University of Edinburgh), Cornelia M. van Duijn(Erasmus MC), Kimberly F. Doheny(Johns Hopkins University), Jane Romm(Johns Hopkins University), Caroline C. W. Klaver(Erasmus MC), Caroline Hayward(Institute of Genetics and Cancer), Michael B. Gorin(University of California, Los Angeles), Michael L. Klein(Oregon Health & Science University), Paul N. Baird(The University of Melbourne), Anneke I. den Hollander(Radboud University Nijmegen), Sascha Fauser(University Hospital Cologne), John R.W. Yates(University of Cambridge), Rando Allikmets(Columbia University), Jie Jin Wang(The University of Sydney), Debra A. Schaumberg(Brigham and Women's Hospital), Ronald Klein(University of Wisconsin–Madison), Stephanie A. Hagstrom(Cleveland Clinic), Itay Chowers(Hadassah Medical Center), Andrew Lotery(University of Southampton), Thierry Léveillard(Centre National de la Recherche Scientifique), Kang Zhang(Sichuan University), Murray H. Brilliant(Marshfield Clinic), Alex W. Hewitt(Lions Eye Institute), Anand Swaroop(National Institutes of Health), Emily Y. Chew(National Institutes of Health), Margaret A. Pericak‐Vance(University of Miami), Margaret M. DeAngelis(University of Utah), Dwight Stambolian(University of Pennsylvania), Jonathan L. Haines(Cornell University), Sudha K. Iyengar(Cornell University), Bernhard H. F. Weber(University of Regensburg), Gonçalo R. Abecasis(University of Michigan), Iris M. Heid(University of Regensburg), Anneke Den Hollander(Radboud University Nijmegen), Bernhard H. F. Weber(University of Regensburg)
Cited by 63Open Access
Abstract
Genome-wide association studies (GWAS) for late stage age-related macular degeneration (AMD) have identified 52 independent genetic variants with genome-wide significance at 34 genomic loci. Typically, such an approach rarely results in the identification of functional variants implicating a defined gene in the disease process. We now performed a transcriptome-wide association study (TWAS) allowing the prediction of effects of AMD-associated genetic variants on gene expression. The TWAS was based on the genotypes of 16,144 late-stage AMD cases and 17,832 healthy controls, and gene expression was imputed for 27 different human tissues which were obtained from 134 to 421 individuals. A linear regression model including each individuals imputed gene expression data and the respective AMD status identified 106 genes significantly associated to AMD variants in at least one tissue (Q-value < 0.001). Gene enrichment analysis highlighted rather systemic than tissue- or cell-specific processes. Remarkably, 31 of the 106 genes overlapped with significant GWAS signals of other complex traits and diseases, such as neurological or autoimmune conditions. Taken together, our study highlights the fact that expression of genes associated with AMD is not restricted to retinal tissue as could be expected for an eye disease of the posterior pole, but instead is rather ubiquitous suggesting processes underlying AMD pathology to be of systemic nature.
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