Waksmunski, Andrea R., Grunin, Michelle ORCID: 0000-0002-3155-2858, Kinzy, Tyler G., Igo, Robert P., Jr., Haines, Jonathan L., Bailey, Jessica N. Cooke, Fritsche, Lars G., Igl, Wilmar, 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, Gabrielle 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, von Strachwitz, Claudia N., 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 A., Mohand-Said, Saddek, Sahel, Jose-Alain, Audo, Isabelle, Benchaboune, Mustapha, Cree, Angela J., Rennie, Christina A., Goverdhan, Srinivas, V, Hagbi-Levi, Shira, Campochiaro, Peter, Katsanis, Nicholas, Holz, Frank G., Blond, Frederic, Blanche, Helene, Deleuze, Jean-Francois, 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, Tan, Ava G., Gopinath, Bamini, Merriam, John C., Smith, R. Theodore, Khan, Jane C., Shahid, Humma, Moore, Anthony T., McGrath, J. Allie, Laux, Renee, Brantley, Milam A., Jr., Agarwal, Anita, Ersoy, Lebriz, Caramoy, Albert, Langmann, Thomas, Saksens, Nicole T. M., de Jong, Eiko K., Hoyng, Carel B., Cain, Melinda S., Richardson, Andrea J., Martin, Tammy M., Blangero, John, Weeks, Daniel E., Dhillon, Bal, van Duijn, Cornelia M., Doheny, Kimberly F., Romm, Jane, Klaver, Caroline C. W., Hayward, Caroline, Gorin, Michael B., Klein, Michael L., Baird, Paul N., den Hollander, Anneke, I, 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., Leveillard, Thierry ORCID: 0000-0001-5692-8770, Zhang, Kang, Brilliant, Murray H., Hewitt, Alex W., Swaroop, Anand, Chew, Emily Y., Pericak-Vance, Margaret A., DeAngelis, Margaret, Stambolian, Dwight, Iyengar, Sudha K., Weber, Bernhard H. F., 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. Invest. Ophthalmol. Vis. Sci., 60 (12). S. 4041 - 4052. ROCKVILLE: ASSOC RESEARCH VISION OPHTHALMOLOGY INC. ISSN 1552-5783

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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: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Waksmunski, Andrea R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grunin, MichelleUNSPECIFIEDorcid.org/0000-0002-3155-2858UNSPECIFIED
Kinzy, Tyler G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Igo, Robert P., Jr.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haines, Jonathan L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bailey, Jessica N. CookeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fritsche, Lars G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Igl, WilmarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grassmann, FelixUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sengupta, SebantiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bragg-Gresham, Jennifer L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Burdon, Kathryn P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hebbring, Scott J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wen, CindyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gorski, MathiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kim, Ivana K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cho, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zack, DonaldUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Souied, EricUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scholl, Hendrik P. N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bala, ElisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lee, Kristine E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hunter, David J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sardell, Rebecca J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mitchell, PaulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Merriam, Joanna E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cipriani, ValentinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoffman, Joshua D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schick, TinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lechanteur, Yara T. E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guymer, Robyn H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Johnson, Matthew P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jiang, YingdaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stanton, Chloe M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buitendijk, Gabrielle H. S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhan, XiaoweiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kwong, Alan M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boleda, AlexisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brooks, MatthewUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gieser, LinnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ratnapriya, RinkiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Branham, Kari E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Foerster, Johanna R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heckenlively, John R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Othman, Mohammad, IUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vote, Brendan J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liang, Helena HaiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Souzeau, EmmanuelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McAllister, Ian L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Isaacs, TimothyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hall, JanetteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lake, StewartUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mackey, David A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Constable, Ian J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Craig, Jamie E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kitchner, Terrie E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yang, ZhenglinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Su, ZhiguangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Luo, HongrongUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chen, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ouyang, HongUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Flagg, KenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lin, DanniUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mao, GuanpingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ferreyra, HenryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stark, KlausUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Strachwitz, Claudia N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolf, ArminUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brandl, CarolineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rudolph, GuentherUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Olden, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morrison, Margaux A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morgan, Denise J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schu, MatthewUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ahn, JeeyunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Silvestri, GiulianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tsironi, Evangelia E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Park, Kyu HyungUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Farrer, Lindsay A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Orlin, AntonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brucker, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, MingyaoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Curcio, Christine A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mohand-Said, SaddekUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sahel, Jose-AlainUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Audo, IsabelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Benchaboune, MustaphaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cree, Angela J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rennie, Christina A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goverdhan, Srinivas, VUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hagbi-Levi, ShiraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Campochiaro, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Katsanis, NicholasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Holz, Frank G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blond, FredericUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blanche, HeleneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deleuze, Jean-FrancoisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Truitt, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peachey, Neal S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meuer, Stacy M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Myers, Chelsea E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moore, Emily L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klein, RonaldUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hauser, Michael A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Postel, Eric A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Courtenay, Monique D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schwartz, Stephen G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kovach, Jaclyn L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scott, William K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liew, GeraldUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tan, Ava G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gopinath, BaminiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Merriam, John C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Smith, R. TheodoreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Khan, Jane C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shahid, HummaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moore, Anthony T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McGrath, J. AllieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Laux, ReneeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brantley, Milam A., Jr.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Agarwal, AnitaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ersoy, LebrizUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Caramoy, AlbertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Langmann, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saksens, Nicole T. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Jong, Eiko K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoyng, Carel B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cain, Melinda S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Richardson, Andrea J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Martin, Tammy M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blangero, JohnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weeks, Daniel E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dhillon, BalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Duijn, Cornelia M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Doheny, Kimberly F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Romm, JaneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klaver, Caroline C. W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hayward, CarolineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gorin, Michael B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klein, Michael L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baird, Paul N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
den Hollander, Anneke, IUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fauser, SaschaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yates, John R. W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Allikmets, RandoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, Jie JinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schaumberg, Debra A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klein, Barbara E. K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hagstrom, Stephanie A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chowers, ItayUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lotery, Andrew J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leveillard, ThierryUNSPECIFIEDorcid.org/0000-0001-5692-8770UNSPECIFIED
Zhang, KangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brilliant, Murray H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hewitt, Alex W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Swaroop, AnandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chew, Emily Y.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pericak-Vance, Margaret A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
DeAngelis, MargaretUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stambolian, DwightUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Iyengar, Sudha K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weber, Bernhard H. F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abecasis, Goncalo R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heid, Iris M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-142374
DOI: 10.1167/iovs.19-27827
Journal or Publication Title: Invest. Ophthalmol. Vis. Sci.
Volume: 60
Number: 12
Page Range: S. 4041 - 4052
Date: 2019
Publisher: ASSOC RESEARCH VISION OPHTHALMOLOGY INC
Place of Publication: ROCKVILLE
ISSN: 1552-5783
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GROWTH-FACTOR RECEPTOR; PHOSPHATIDYLINOSITOL 3-KINASE; CELL-SURVIVAL; ACTIVATION; ASSOCIATION; VARIANTS; NETWORKS; THERAPY; RAREMultiple languages
OphthalmologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/14237

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