Pathway Analysis Integrating Genome-Wide and Functional Data Identifies PLCG2 as a Candidate Gene for Age-Related Macular Degeneration
Open accessAbstract
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.
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A potential link between PLCG2 and macular degeneration has also been described.
“A potential link between PLCG2 and macular degeneration has also been described [116]”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [116]
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Cites
Gene Ontology: tool for the unification of biology
Ashburner, M., Ball, C. A., Blake, J. A., Botstein, D., Butler, H., Cherry, J. M., Davis, A. P., Dolinski, K., Dwight, S. S., Eppig, J. T., et al. (2000) · Nature Genetics · doi:10.1038/75556 · Cited by 43,206 · see citing works
KEGG: Kyoto Encyclopedia of Genes and Genomes
Kanehisa, M. (2000) · Nucleic Acids Research · doi:10.1093/nar/28.1.27 · Cited by 37,077 · see citing works
KEGG: Kyoto Encyclopedia of Genes and Genomes
Ogata, H., Goto, S., Sato, K., Fujibuchi, W., Bono, H., & Kanehisa, M. (1999) · Nucleic Acids Research · doi:10.1093/nar/27.1.29 · Cited by 31,232 · see citing works
MEME SUITE: tools for motif discovery and searching
Bailey, T. L., Boden, M., Buske, F. A., Frith, M., Grant, C. E., Clementi, L., Ren, J., Li, W. W., & Noble, W. S. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkp335 · Cited by 10,648 · see citing works
STRING v10: protein–protein interaction networks, integrated over the tree of life
Szklarczyk, D., Franceschini, A., Wyder, S., Forslund, K., Heller, D., Huerta-Cepas, J., Simonovic, M., Roth, A., Santos, A., Tsafou, K. P., et al. (2015) · Nucleic Acids Research · doi:10.1093/nar/gku1003 · Cited by 10,436 · see citing works
The UCSC Table Browser data retrieval tool
Karolchik, D. (2003) · Nucleic Acids Research · doi:10.1093/nar/gkh103 · Cited by 2,269 · see citing works
Integrated Systems Approach Identifies Genetic Nodes and Networks in Late-Onset Alzheimer’s Disease
Zhang, B., Gaiteri, C., Bodea, L.-G., Wang, Z., McElwee, J., Podtelezhnikov, A. A., Zhang, C., Xie, T., Tran, L., Dobrin, R., et al. (2013) · Cell · doi:10.1016/j.cell.2013.03.030 · Cited by 1,657 · see citing works
Fritsche, L. G., Igl, W., Bailey, J. N. C., Grassmann, F., Sengupta, S., Bragg-Gresham, J. L., Burdon, K. P., Hebbring, S. J., Wen, C., Gorski, M., et al. (2016) · Nature Genetics · doi:10.1038/ng.3448 · Cited by 1,544 · see citing works
Self-citationARUK Consortium, Sims, R., GERAD/PERADES, C., van der Lee, S. J., Naj, A. C., Bellenguez, C., Badarinarayan, N., Jakobsdottir, J., Kunkle, B. W., Boland, A., et al. (2017) · Nature Genetics · doi:10.1038/ng.3916 · Cited by 1,126 · see citing works
Mathelier, A., Fornes, O., Arenillas, D. J., Chen, C.-Y., Denay, G., Lee, J., Shi, W., Shyr, C., Tan, G., Worsley-Hunt, R., et al. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkv1176 · Cited by 937 · see citing works
Kulakovskiy, I. V., Vorontsov, I. E., Yevshin, I., Sharipov, R., Fedorova, A. D., Rumynskiy, E. I., Medvedeva, Y. A., Magana-Mora, A., Bajić, V. B., Papatsenko, D., et al. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx1106 · Cited by 921 · see citing works
Regulation of Phosphoinositide-specific Phospholipase C Isozymes
Rhee, S. G., & Bae, Y. S. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.24.15045 · Cited by 876 · see citing works
Xia, P., Aiello, L. P., Ishii, H., Jiang, Z. Y., Park, D. J., Robinson, G. S., Takagi, H., Newsome, W. P., Jirousek, M. R., & King, G. L. (1996) · Journal of Clinical Investigation · doi:10.1172/jci119006 · Cited by 566 · see citing works
NetPath: a public resource of curated signal transduction pathways
Kandasamy, K., Mohan, S. S., Raju, R., Keerthikumar, S., Kumar, G. S. S., Venugopal, A. K., Telikicherla, D., Navarro, J. D., Mathivanan, S., Pecquet, C., et al. (2010) · Genome biology · doi:10.1186/gb-2010-11-1-r3 · Cited by 499 · see citing works
Guo, D., Jia, Q., Song, H.-Y., Warren, R. S., & Donner, D. B. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.12.6729 · Cited by 482 · see citing works
Seddon, J. M. (2005) · Archives of Ophthalmology · doi:10.1001/archopht.123.3.321 · Cited by 446 · cited 1× · see citing works
“Although both genetic and environmental factors shape AMD susceptibility, between 46% and 71% of the phenotypic variance of the disease is attributable to genetic factors.(4) To understand the genetic architecture of AMD, the International Age-Related Macular Degeneration Genomics Consortium (IAMDGC) performed a large…”
BackgroundCold Urticaria, Immunodeficiency, and Autoimmunity Related to <i>PLCG2</i> Deletions
Ombrello, M. J., Remmers, E. F., Sun, G., Freeman, A. F., Datta, S., Torabi-Parizi, P., Subramanian, N., Bunney, T. D., Baxendale, R. W., Martins, M. S., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1102140 · Cited by 425 · see citing works
Regulation of Blood and Lymphatic Vascular Separation by Signaling Proteins SLP-76 and Syk
Abtahian, F., Guerriero, A., Sebzda, E., Lu, M., Zhou, R., Mócsai, A., Meyers, E. E., Huang, B., Jackson, D. G., Ferrari, V. A., et al. (2003) · Science · doi:10.1126/science.1079477 · Cited by 421 · see citing works
Utility Values and Age-related Macular Degeneration
Brown, G. C. (2000) · Archives of Ophthalmology · doi:10.1001/archopht.118.1.47 · Cited by 262 · see citing works
Yu, Y., Bhangale, T. R., Fagerness, J., Ripke, S., Thorleifsson, G., Tan, P. L., Souied, E. H., Richardson, A. J., Merriam, J. E., Buitendijk, G. H. S., et al. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr270 · Cited by 254 · see citing works
Inoue, O., Suzuki‐Inoue, K., Dean, W. L., Frampton, J., & Watson, S. P. (2003) · The Journal of Cell Biology · doi:10.1083/jcb.200208043 · Cited by 246 · see citing works
Public Attitudes About Eye and Vision Health
Scott, A. W., Bressler, N. M., Ffolkes, S., Wittenborn, J. S., & Jorkasky, J. F. (2016) · JAMA Ophthalmology · doi:10.1001/jamaophthalmol.2016.2627 · Cited by 232 · see citing works
Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph
Magno, L., Lessard, C. B., Martins, M., Lang, V., Cruz, P., Asi, Y., Katan, M., Bilsland, J., Lashley, T., Chakrabarty, P., et al. (2019) · Alzheimer's Research & Therapy · doi:10.1186/s13195-019-0469-0 · Cited by 143 · cited 2× · see citing works
“Heterozygous gain-of-function mutations in PLCG2 result in constitutive phospholipase activity and PLCG2-associated antibody deficiency and immune dysregulation, which is characterized by immunodeficiency and autoimmunity.39 This gene was recently identified as a candidate gene for rheumatoid arthritis (RA) due to its…”
Background(2000) · Immunological Reviews · doi:10.1034/j.1600-065x.2000.00611.x · Cited by 138 · see citing works
A Critical Role for Phospholipase Cγ2 in αIIbβ3-mediated Platelet Spreading
Wonerow, P., Pearce, A. C., Vaux, D. J., & Watson, S. P. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m305077200 · Cited by 135 · see citing works
Homma, Y., Takenawa, T., Emori, Y., Sorimachi, H., & Suzuki, K. (1989) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(89)91734-8 · Cited by 114 · see citing works
Conway, O. J., Carrasquillo, M. M., Wang, X., Bredenberg, J. M., Reddy, J. S., Strickland, S. L., Younkin, C. S., Burgess, J. D., Allen, M., Lincoln, S. J., et al. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0289-x · Cited by 112 · see citing works
Xu, K., & Yu, F. X. (2007) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.06-0560 · Cited by 91 · see citing works
The outcomes of pathway database computations depend on pathway ontology
Green, M. L. (2006) · Nucleic Acids Research · doi:10.1093/nar/gkl438 · Cited by 85 · see citing works
Manne, B. K., Badolia, R., Dangelmaier, C., Eble, J. A., Ellmeier, W., Kahn, M. L., & Kunapuli, S. P. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.629527 · Cited by 82 · see citing works
Genetic pleiotropy between age-related macular degeneration and 16 complex diseases and traits
Graßmann, F., Kiel, C., Zimmermann, M. E., Gorski, M., Grassmann, V., Stark, K. J., Heid, I. M., & Weber, B. H. F. (2017) · Genome Medicine · doi:10.1186/s13073-017-0418-0 · Cited by 61 · see citing works
Epidermal Growth Factor Receptor in Cultured Human Retinal Pigment Epithelial Cells
Yan, F., Hui, Y.-N., Li, Y., Guo, C., & Meng, H. (2007) · Ophthalmologica · doi:10.1159/000101926 · Cited by 56 · see citing works
Genetic analysis of biological pathway data through genomic randomization
Yaspan, B. L., Bush, W. S., Torstenson, E. S., Ma, D., Pericak-Vance, M. A., Ritchie, M. D., Sutcliffe, J. S., & Haines, J. L. (2011) · Human Genetics · doi:10.1007/s00439-011-0956-2 · Cited by 54 · see citing works
Self-citationAge-related macular degeneration
Ayoub, T., & Patel, N. (2009) · Journal of the Royal Society of Medicine · doi:10.1258/jrsm.2009.080298 · Cited by 52 · see citing works
Afroz, S., Giddaluru, J., Vishwakarma, S., Naz, S., Khan, A. A., & Khan, N. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00074 · Cited by 50 · see citing works
Defoe, D. M., & Grindstaff, R. D. (2004) · Experimental Eye Research · doi:10.1016/j.exer.2004.02.017 · Cited by 49 · see citing works
Deciphering Combinations of PI3K/AKT/mTOR Pathway Drugs Augmenting Anti-Angiogenic Efficacy In Vivo
Sasore, T., & Kennedy, B. N. (2014) · PLoS ONE · doi:10.1371/journal.pone.0105280 · Cited by 39 · see citing works
Haw, R., Croft, D. W., Yung, C. K., Ndegwa, N., D’Eustachio, P., Hermjakob, H., & Stein, L. D. (2011) · Database · doi:10.1093/database/bar031 · Cited by 37 · see citing works
Strategies for Pathway Analysis Using GWAS and WGS Data
White, M. J., Yaspan, B. L., Veatch, O. J., Goddard, P. C., Risse-Adams, O. S., & Contreras, M. G. (2018) · Current Protocols in Human Genetics · doi:10.1002/cphg.79 · Cited by 36 · see citing works
Ohmori, T., Yatomi, Y., Wu, Y., Osada, M., Satoh, K., & Ozaki, Y. (2001) · Biochemistry · doi:10.1021/bi0109459 · Cited by 33 · see citing works
Rudolph, A., Hein, R., Lindström, S., Beckmann, L., Behrens, S., Liu, J., Aschard, H., Bolla, M. K., Wang, J., Truong, T., et al. (2013) · Endocrine-Related Cancer · doi:10.1530/erc-13-0349 · Cited by 28 · see citing works
Winkler, T. W., Brandl, C., Graßmann, F., Gorski, M., Stark, K. J., Loss, J., Weber, B. H. F., & Heid, I. M. (2018) · PLoS ONE · doi:10.1371/journal.pone.0194321 · Cited by 26 · see citing works
Strategies for Pathway Analysis from GWAS Data
Yaspan, B. L., & Veatch, O. J. (2011) · Current Protocols in Human Genetics · doi:10.1002/0471142905.hg0120s71 · Cited by 25 · see citing works
Uckun, F. M., Özer, Z., & Vassilev, A. O. (2007) · British Journal of Haematology · doi:10.1111/j.1365-2141.2006.06468.x · Cited by 24 · see citing works
Chen, X.-D., Su, M., Chen, T., Hong, H., Han, A., & Li, W. (2017) · International Journal of Ophthalmology · doi:10.18240/ijo.2017.04.02 · Cited by 24 · see citing works
Rudolph, A., Fasching, P. A., Behrens, S., Eilber, U., Bolla, M. K., Wang, Q., Thompson, D., Czene, K., Brand, J. S., Li, J., et al. (2015) · Breast Cancer Research · doi:10.1186/s13058-015-0625-9 · Cited by 24 · see citing works
ASSOCIATIONS BETWEEN AGE-RELATED MACULAR DEGENERATION, OSTEOARTHRITIS AND RHEUMATOID ARTHRITIS
Keenan, T. D. L., Goldacre, R., & Goldacre, M. J. (2015) · Retina · doi:10.1097/iae.0000000000000651 · Cited by 22 · see citing works
Role of BLNK in Oxidative Stress Signaling in B Cells
Han, W., Takano, T., He, J., Ding, J., Gao, S., Noda, C., Yanagi, S., & Yamamura, H. (2001) · Antioxidants and Redox Signaling · doi:10.1089/152308601317203576 · Cited by 14 · see citing works
Pathway analysis by randomization incorporating structure—PARIS: an update
Butkiewicz, M., Bailey, J. N. C., Frase, A., DUDEK, S. M., Yaspan, B. L., Ritchie, M. D., Pendergrass, S. A., & Haines, J. L. (2016) · Bioinformatics · doi:10.1093/bioinformatics/btw130 · Cited by 9 · see citing works
Self-citationCourtenay, M. D., Cade, W. H., Schwartz, S. G., Kovach, J. L., Agarwal, A., Wang, G., Haines, J. L., Pericak‐Vance, M. A., & Scott, W. K. (2014) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.14-14494 · Cited by 8 · see citing works
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Magno, L., Bunney, T. D., Mead, E., Svensson, F., & Bictash, M. N. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00436-5 · Cited by 64 · see citing works
Baysac, K., Sun, G., Nakano, H., Schmitz, E. G., Cruz, A. C., Fisher, C., Bailey, A. C., Abbott, J. K., Aldave Becerra, J. C., Allenspach, E. J., et al. (2024) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2023.08.036 · Cited by 63 · see citing works
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Laíns, I., Zhu, S., Han, X., Chung, W., Yuan, Q., Kelly, R. S., Gil, J., Katz, R., Nigalye, A. K., Kim, I. K., et al. (2021) · Ophthalmology Science · doi:10.1016/j.xops.2021.100017 · Cited by 15 · see citing works
Ma, K., Nakajima, H., Basak, N., Barman, A., & Ratnapriya, R. (2025) · npj Genomic Medicine · doi:10.1038/s41525-025-00507-2 · Cited by 8 · see citing works
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Self-citationQiu, Y., Sun, T., Xu, F., Gao, P., Tang, G., & Peng, Q. (2021) · Europe PMC (PubMed Central) · Cited by 3 · see citing works
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- Authors
- Waksmunski, A. R., Grunin, M., Kinzy, T. G., Igo, R. P., Haines, J. L., Cooke Bailey, J. N., & for the International Age-Related Macular Degeneration Genomics Consortium
- Affiliations
- Case Western Reserve University (US)
- Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, Ohio, United States
- Venue
- Investigative Opthalmology & Visual Science
- Published
- 2019-09-23
- Volume
- 60
- Issue
- 12
- Pages
- 4041
- ISSN
- 0146-0404 (ISSN-L)
- 1552-5783
- PMC
- PMC6779289
- OpenAlex
- W2976419434
- Cited by
- 14
- References
- 50
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 7 · 2020: 1
- FWCI
- 2.70
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Investigative Ophthalmology & Visual Science (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- HAL (submittedVersion, cc-by-nc-nd)
- Minerva Access (University of Melbourne) (submittedVersion, other-oa)
- UWA Profiles and Research Repository (UWA) (submittedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- University of Regensburg Publication Server (University of Regensburg) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- RePub (Erasmus University Rotterdam) (submittedVersion)
- Funders
- Case Western Reserve University
- National Institutes of Health (KL2TR000440, 1X01HG006934-01)
- Medical Research Council (MC_UU_00007/10)
- National Eye Institute (R01EY022310, T32EY007157)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Keywords
- age-related macular degeneration, PLCγ2, candidate genes, pathway analysis, genetic burden, protein-protein interaction network, motif analysis, genetic architecture, PPARα, RAD51B, Notch4, mica, hepatic lipase
- MeSH terms
- Aged, Female, Genotype, Humans, Macular Degeneration, Male, Case-Control Studies, Databases, Factual, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Phospholipase C gamma, Protein Interaction Domains and Motifs, Genome-Wide Association Study
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