Waksmunski, Andrea R. and Grunin, Michelle and Kinzy, Tyler G. and Igo, Robert P. and Haines, Jonathan L. and Bailey, Jessica N. Cooke and Fritsche, Lars G. and Igl, Wilmar and Grassmann, Felix and Sengupta, Sebanti and Bragg-Gresham, Jennifer L. and Burdon, Kathryn P. and Hebbring, Scott J. and Wen, Cindy and Gorski, Mathias and Kim, Ivana K. and Cho, David and Zack, Donald and Souied, Eric and Scholl, Hendrik P. N. and Bala, Elisa and Lee, Kristine E. and Hunter, David J. and Sardell, Rebecca J. and Mitchell, Paul and Merriam, Joanna E. and Cipriani, Valentina and Hoffman, Joshua D. and Schick, Tina and Lechanteur, Yara T. E. and Guymer, Robyn H. and Johnson, Matthew P. and Jiang, Yingda and Stanton, Chloe M. and Buitendijk, Gabrielle H. S. and Zhan, Xiaowei and Kwong, Alan M. and Boleda, Alexis and Brooks, Matthew and Gieser, Linn and Ratnapriya, Rinki and Branham, Kari E. and Foerster, Johanna R. and Heckenlively, John R. and Othman, Mohammad and Vote, Brendan J. and Liang, Helena Hai and Souzeau, Emmanuelle and McAllister, Ian L. and Isaacs, Timothy and Hall, Janette and Lake, Stewart and Mackey, David A. and Constable, Ian J. and Craig, Jamie E. and Kitchner, Terrie E. and Yang, Zhenglin and Su, Zhiguang and Luo, Hongrong and Chen, Daniel and Ouyang, Hong and Flagg, Ken and Lin, Danni and Mao, Guanping and Ferreyra, Henry and Stark, Klaus and von Strachwitz, Claudia N. and Wolf, Armin and Brandl, Caroline and Rudolph, Guenther and Olden, Matthias and Morrison, Margaux A. and Morgan, Denise J. and Schu, Matthew and Ahn, Jeeyun and Silvestri, Giuliana and Tsironi, Evangelia E. and Park, Kyu Hyung and Farrer, Lindsay A. and Orlin, Anton and Brucker, Alexander and Li, Mingyao and Curcio, Christine A. and Mohand-Said, Saddek and Sahel, Jose-Alain and Audo, Isabelle and Benchaboune, Mustapha and Cree, Angela J. and Rennie, Christina A. and Goverdhan, Srinivas and Hagbi-Levi, Shira and Campochiaro, Peter and Katsanis, Nicholas and Holz, Frank G. and Blond, Frederic and Blanche, Helene and Deleuze, Jean-Francois and Truitt, Barbara and Peachey, Neal S. and Meuer, Stacy M. and Myers, Chelsea E. and Moore, Emily L. and Klein, Ronald and Hauser, Michael A. and Postel, Eric A. and Courtenay, Monique D. and Schwartz, Stephen G. and Kovach, Jaclyn L. and Scott, William K. and Liew, Gerald and Tan, Ava G. and Gopinath, Bamini and Merriam, John C. and Smith, R. Theodore and Khan, Jane C. and Shahid, Humma and Moore, Anthony T. and McGrath, J. Allie and Laux, Renee and Brantley, Milam A. and Agarwal, Anita and Ersoy, Lebriz and Caramoy, Albert and Langmann, Thomas and Saksens, Nicole T. M. and de Jong, Eiko K. and Hoyng, Carel B. and Cain, Melinda S. and Richardson, Andrea J. and Martin, Tammy M. and Blangero, John and Weeks, Daniel E. and Dhillon, Bal and van Duijn, Cornelia M. and Doheny, Kimberly F. and Romm, Jane and Klaver, Caroline C. W. and Hayward, Caroline and Gorin, Michael B. and Klein, Michael L. and Baird, Paul N. and den Hollander, Anneke and Fauser, Sascha and Yates, John R. W. and Allikmets, Rando and Wang, Jie Jin and Schaumberg, Debra A. and Klein, Barbara E. K. and Hagstrom, Stephanie A. and Chowers, Itay and Lotery, Andrew J. and Leveillard, Thierry and Zhang, Kang and Brilliant, Murray H. and Hewitt, Alex W. and Swaroop, Anand and Chew, Emily Y. and Pericak-Vance, Margaret A. and DeAngelis, Margaret and Stambolian, Dwight and Iyengar, Sudha K. and Weber, Bernhard H. F. and Abecasis, Goncalo R. and Heid, Iris M. (2019) Pathway Analysis Integrating Genome-Wide and Functional Data Identifies PLCG2 as a Candidate Gene for Age-Related Macular Degeneration. INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 60 (12). pp. 4041-4051. ISSN 0146-0404, 1552-5783
Full text not available from this repository. (Request a copy)Abstract
PURPOSE. Age-related macular degeneration (AMD) is the worldwide leading cause of blindness among the elderly. Although genome-wide association studies (GWAS) have identified AMD risk variants, their roles in disease etiology are not well-characterized, and they only explain a portion of AMD heritability. METHODS. We performed pathway analyses using summary statistics from the International AMD Genomics Consortium's 2016 GWAS and multiple pathway databases to identify biological pathways wherein genetic association signals for AMD may be aggregating. We determined which genes contributed most to significant pathway signals across the databases. We characterized these genes by constructing protein-protein interaction networks and performing motif analysis. RESULTS. We determined that eight genes (C2, C3, LIPC, MICA, NOTCH4, PLCG2, PPARA, and RAD51B) "drive'' the statistical signals observed across pathways curated in the Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome, and Gene Ontology (GO) databases. We further refined our definition of statistical driver gene to identify PLCG2 as a candidate gene for AMD due to its significant gene-level signals (P < 0.0001) across KEGG, Reactome, GO, and NetPath pathways. CONCLUSIONS. We performed pathway analyses on the largest available collection of advanced AMD cases and controls in the world. Eight genes strongly contributed to significant pathways from the three larger databases, and one gene (PLCG2) was central to significant pathways from all four databases. This is, to our knowledge, the first study to identify PLCG2 as a candidate gene for AMD based solely on genetic burden. Our findings reinforce the utility of integrating in silico genetic and biological pathway data to investigate the genetic architecture of AMD.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | GROWTH-FACTOR RECEPTOR; PHOSPHATIDYLINOSITOL 3-KINASE; CELL-SURVIVAL; ACTIVATION; ASSOCIATION; VARIANTS; NETWORKS; THERAPY; RARE; age-related macular degeneration; pathway analysis; genome-wide association study; database; phospholipase C gamma 2 |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Augenheilkunde Medicine > Lehrstuhl für Humangenetik Medicine > Institut für Epidemiologie und Präventivmedizin > Lehrstuhl für Genetische Epidemiologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 06 Apr 2020 10:06 |
| Last Modified: | 06 Apr 2020 10:06 |
| URI: | https://pred.uni-regensburg.de/id/eprint/26299 |
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