A transcriptome-wide association study based on 27 tissues identifies 106 genes potentially relevant for disease pathology in age-related macular degeneration
Authors: Strunz Tobias , Lauwen Susette , Kiel Christina ,   International AMD Genomics Consortium (IAMDGC), Fritsche Lars G. , Igl Wilmar , Bailey Jessica N. Cooke , Grassmann Felix , Sengupta Sebanti , Bragg-Gresham Jennifer L. , Burdon Kathryn P. , Hebbring Scott J. , Wen Cindy , Gorski Mathias , Kim Ivana K. , Cho David , Zack Donald , Souied Eric , Scholl Hendrik P. N. , Bala Elisa , Lee Kristine E. , Hunter David J. , Sardell Rebecca J. , Mitchell Paul , Merriam Joanna E. , Cipriani Valentina , Hoffman Joshua D. , Schick Tina , Lechanteur Yara T. E. , Guymer Robyn H. , Johnson Matthew P. , Jiang Yingda , Stanton Chloe M. , Buitendijk Gabriëlle H. S. , Zhan Xiaowei , Kwong Alan M. , Boleda Alexis , Brooks Matthew , Gieser Linn , Ratnapriya Rinki , Branham Kari E. , Foerster Johanna R. , Heckenlively John R. , Othman Mohammad I. , Vote Brendan J. , Liang Helena Hai , Souzeau Emmanuelle , McAllister Ian L. , Isaacs Timothy , Hall Janette , Lake Stewart , Mackey David A. , Constable Ian J. , Craig Jamie E. , Kitchner Terrie E. , Yang Zhenglin , Su Zhiguang , Luo Hongrong , Chen Daniel , Ouyang Hong , Flagg Ken , Lin Danni , Mao Guanping , Ferreyra Henry , Stark Klaus , Strachwitz Claudia N. von , Wolf Armin , Brandl Caroline , Rudolph Guenther , Olden Matthias , Morrison Margaux A. , Morgan Denise J. , Schu Matthew , Ahn Jeeyun , Silvestri Giuliana , Tsironi Evangelia E. , Park Kyu Hyung , Farrer Lindsay A. , Orlin Anton , Brucker Alexander , Li Mingyao , Curcio Christine , Mohand-Saïd Saddek , Sahel José-Alain , Audo Isabelle , Benchaboune Mustapha , Cree Angela J. , Rennie Christina A. , Goverdhan Srinivas V. , Grunin Michelle , Hagbi-Levi Shira , Campochiaro Peter , Katsanis Nicholas , Holz Frank G. , Blond Frédéric , Blanché Hélène , Deleuze Jean-François , Igo Robert P. , Truitt Barbara , Peachey Neal S. , Meuer Stacy M. , Myers Chelsea E. , Moore Emily L. , Klein Ronald , Hauser Michael A. , Postel Eric A. , Courtenay Monique D. , Schwartz Stephen G. , Kovach Jaclyn L. , Scott William K. , Liew Gerald , Tfan Ava G. , Gopinath Bamini , Merriam John C. , Smith R. Theodore , Khan Jane C. , Shahid Humma , Moore Anthony T. , McGrath J. Allie , Laux Reneé , Brantley Milam A. , Agarwal Anita , Ersoy Lebriz , Caramoy Albert , Langmann Thomas , Saksens Nicole T. M. , Jong Eiko K. de , Hoyng Carel B. , Cain Melinda S. , Richardson Andrea J. , Martin Tammy M. , Blangero John , Weeks Daniel E. , Dhillon Bal , Duijn Cornelia M. van , Doheny Kimberly F. , Romm Jane , Klaver Caroline C. W. , Hayward Caroline , Gorin Michael B. , Klein Michael L. , Baird Paul N. , Hollander Anneke I. den , Fauser Sascha , Yates John R. W. , Allikmets Rando , Wang Jie Jin , Schaumberg Debra A. , Klein Barbara E. K. , Hagstrom Stephanie A. , Chowers Itay , Lotery Andrew J. , Léveillard Thierry , Zhang Kang , Brilliant Murray H. , Hewitt Alex W. , Swaroop Anand , Chew Emily Y. , Pericak-Vance Margaret A. , DeAngelis Margaret , Stambolian Dwight , Haines Jonathan L. , Iyengar Sudha K. , Weber Bernhard H. F. , Abecasis Gonçalo R. , Heid Iris M. , Hollander Anneke den , Weber Bernhard H. F. 
Published: January 2020

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.