TABLE 2.
Gene associations for adult-onset glaucoma
| Disease | Study designa | # Cases/controls | Ethnic population | Gene | Chromosomal location | Gene function | References |
|---|---|---|---|---|---|---|---|
| Primary open-angle glaucoma | Genetic Linkage Analysis | 330/471 | European-derived | MYOC | 1q24.3 | Extracellular matrix protein in trabecular meshwork; mutant protein aggregates intracellularly | 58 |
| GWAS | 1263/34877 | Icelandic | CAV1/CAV2 | 7q31 | Mechanosensation and IOP regulation; nitric oxide signalling | 69 | |
| GWAS | 615/3956 | Australian | CDKN2B-AS | 9p21 | Long non-coding RNA; regulates expression of CDKN2B, CDKN2A and other target genes | 70 | |
| TMCO1 | 1q24.1 | Transmembrane protein | |||||
| GWAS | 2170/2347 | European-derived | SIX6 | 14q23.1 | Eye development | 71 | |
| GWAS Meta-Analysis | 1432/8102 | European and Australian | GAS7 | 17p13.1 | Neuronal development | 72 | |
| GWAS | 1155/1992 | Australian | ABCA1 | 9q31.1 | Cholesterol efflux pump | 73 | |
| AFAP1 | 4p16.1 | Modulates actin filament integrity | |||||
| GMDS | 6p25.3 | Fructose and mannose metabolism | |||||
| GWAS | 1007/1009 | Chinese, Singaporean Chinese | PMM2 | 16p13.2 | Glycosylation | 74 | |
| GWAS | 3504/9746 | Multi-ethnic (European, Asian and African descent) | TGFBR3 | 1p22.1 | TGF-beta receptor | 75 | |
| GWAS | 1225/4117 | European | ARHGEF12 | 11q23.3 | Rho kinase signalling | 76 | |
| GWAS | 3853/33480 | European-derived | TXNRD2 | 22q11.21 | Thioredoxin reductase | 77 | |
| ATXN2 | 12q24.12 | Formation of p-bodies and stress granules | |||||
| FOXC1 | 6p25.3 | Transcription factor; early ocular and systemic organogenesis | |||||
| GWAS | 3071/6750 | Australian | MYOF | 10q23 | Endothelial cell repair after mechanical stress | 78 | |
| CYP26A1 | Drug metabolism, lipid biosynthesis | ||||||
| LINC02052 | 3q27.3 | long non-coding RNA | |||||
| CRYGS | Gamma crystallin; cataract formation | ||||||
| LMX1B | 9q33.3 | Trabecular meshwork development | |||||
| LMO7 | 13q22.2 | Protein–protein interaction | |||||
| GWAS | 7378/36385 | Japanese | FNDC3B | 3q26.31 | Adipogenesis, ECM remodelling | 79 | |
| ANKRD55 | 5q11.2 | Unknown | |||||
| MAP3K1 | Ocular development | ||||||
| LHPP | 10q26.13 | Unknown | |||||
| HMGA2 | 12q14.3 | Ocular development | |||||
| MEIS2 | 15q14 | Interacts with FOXC1, expressed in trabecular meshwork | |||||
| LOXL1 | 15q24.1 | Crosslinks collagen and elastin | |||||
| GWAS meta-analysis | 11 018/126069 | European/Australian | CADM2 | 3p12.1 | Synapse organisation | 80 | |
| THSD7A | 7p21.3 | Cytoskeletal organisation | |||||
| ANGPT1 | 8q23.1 | TEK ligand; outflow pathway development | |||||
| ANKH | 5p15.2 | Regulates pyrophosphate levels | |||||
| LOC101929614 | 6q27 | Unknown | |||||
| EXOC2 | 6p25.3 | Remodelling of actin cytoskeleton | |||||
| BICC1 | 10q21.1 | RNA binding protein; negative regulator of Wnt signalling | |||||
| MECOM | 3q26.2 | Haematopoiesis, apoptosis, cell differentiation | |||||
| CTTNBP2 | 7q31 | Actin cytoskeletal assembly | |||||
| CFTR | Chloride channel | ||||||
| ETS1 | 11q24.3 | Transcription factor | |||||
| LOC107986141 | 3q25.1 | Unknown | |||||
| GWAS | 1113/1826 | African and African American | EXOC4 | 7q33 | Vesicle transport | 81 | |
| GWAS | 4986/58426 | Multi-ethnic (European, Hispanic/Latino, Asian, African American) | FMNL2 | 2q23.3 | Effector for Rho GTPases | 82 | |
| PDE7B | 6q23.3 | cAMP signalling | |||||
| near ELN | 7q11 | Tropoelastin; extracellular matrix constituent | |||||
| near TCF12 | 15q21.3 | Wnt signalling | |||||
| near IKZF2 | 2q34 | Haematopoiesis | |||||
| near DGKG | 3q27 | Lipid metabolism | |||||
| 3853/33480 | European | RSPO1 | 1p34.3 | Wnt/ß-catenin signalling | 83 | ||
| GWAS Meta-Analysis | DGKG | 3q27 | Lipid metabolism | ||||
| PKHD1 | 6p12 | Transmembrane protein | |||||
| CTTNBP2 | 7q31 | Actin cytoskeletal assembly | |||||
| CDH11 | 16q21 | Cell adhesion | |||||
| GWAS | 2320/2121 | African | APBB2 | 4p14–13 | Binds to amyloid precursor protein | 84 | |
| Rare variant analysis | 10 775/421022 | European | ANGPTL7 (protective variants) | 1p36.22 | Extracellular matrix organisation; activated in response to dexamethasone and TGF-beta | 85 | |
| GWAS | 7947/119318 | European/Australian | COL8A2 | 1p34.3 | Collagen type 8 alpha-2 chain | 86 | |
| BRE | 2p23.2 | Stress response | |||||
| THADA | 2p21 | Apoptosis | |||||
| PNPT1 | 2p16.1 | RNA processing and degradation | |||||
| ANTXR1 | 2p13.3 | Transmembrane protein | |||||
| PARD3B | 2q33.3 | Formation of tight junctions | |||||
| MIR4776–1 | 2q34 | microRNA | |||||
| KBTBD8 | 3p14.1 | Innate immunity, neural crest specification | |||||
| TSC22D2 | 3q25.1 | Transcription factor binding | |||||
| LPP | 3q27–28 | Cell adhesion | |||||
| POU6F2 | 7p14.1 | Early differentiation of ganglion cells | |||||
| SEMA3C | 7q21.11 | Axon growth | |||||
| TES | 7q31.2 | Cell adhesion, reorganisation of actin cytoskeleton | |||||
| PRKAG2 | 7q36.1 | Regulates energy metabolism; inhibits lipid biosynthesis | |||||
| FBXO32 | 8q24.13 | Component of ubiquitin-ligase complex | |||||
| PCSK5 | 9q21.3 | Post-transcriptional processing | |||||
| RALGPS1 | 9q33.3 | Cytoskeleton remodelling | |||||
| PLCE1 | 10q23.33 | Lipid metabolism | |||||
| PTPRJ | 11p11.2 | Cell adhesion, vascular development | |||||
| ME3 | 11q14.2 | Mitochondrial function | |||||
| TMTC2 | 12q21.31 | Calcium homeostasis | |||||
| SH2B3 | 12q24.12 | Negative regulator of TNF signalling pathway | |||||
| KLF5 | 13q22.1 | Transcription activator | |||||
| COL4A1 | 13q34 | Collagen type 4 alpha 1 chain | |||||
| NPC2 | 14q24.3 | Regulates cholesterol transport | |||||
| ZNF280D | 15q21.3 | Transcription factor | |||||
| VPS13C | 15q22.2 | Maintains mitochondrial transmembrane potential | |||||
| ADAMTS18 | 16q23.1 | ECM homeostasis | |||||
| BCAS3 | 17q23.2 | Angiogenesis, autophagy | |||||
| CASC20 | 20p12.3 | long non-coding RNA | |||||
| PTPN1 | 20q13.13 | Negative regulator of insulin signalling pathway | |||||
| EMID1 | 22q12.2 | Unknown | |||||
| TRIOBP | 22q13.1 | Neural tissue development, actin cytoskeleton organisation | |||||
| GWAS Meta-Analysis | 34 179/349321 | Multi-ethnic (European, Asian, African) | RERE | 1p36.23 | Ocular development | 87 | |
| GLIS1 | 1p32.3 | Transcription factor | |||||
| ELOCP18/RPE65 | 1p31.3 | Visual cycle function | |||||
| GPR88 | 1p21.2 | G-protein coupled receptor | |||||
| DDR2 | 1q23.3 | Cell adhesion, extracellular matrix remodelling | |||||
| TRIB2 | 2p24.3 | Immune function | |||||
| ZNF638 | 2p13.2 | Regulates adipogenesis | |||||
| THRB | 3p24.2 | Mediates biological activities of thyroid hormone | |||||
| ARHGEF3 | 3p14.3 | Activates RhoA GTPase | |||||
| ALCAM | 3q13.11 | Cell adhesion | |||||
| SCFD2 | 4q12 | Protein transport | |||||
| FAM13A | 4q22.1 | Adipocyte differentiation | |||||
| PITX2 | 4q25 | Transcription factor; early ocular and systemic organogenesis | |||||
| STOX2 | 4q35.1 | Transcription factor | |||||
| HLA-G | 6p22.1 | Human leukocyte antigen (HLA) gene | |||||
| CLIC5 | 6p21.1 | Chloride ion channel | |||||
| GJA1/HSF2 | 6q22.31 | Gap junction component/heat shock response | |||||
| SLC2A12 | 6q23.2 | Catalyses glucose uptake | |||||
| CREB5 | 7p15–14 | Inflammatory response | |||||
| SEPT7 | 7p14.2 | Cytokinesis | |||||
| PCLO | 7q21.11 | Synaptic vesicle trafficking | |||||
| SEMA3E | Mediates reorganisation of Actin cytoskeleton | ||||||
| ANGPT2/MCPH1 | 8p23.1 | TEK ligand; outflow pathway development | |||||
| GTF2E2 | 8p12 | Transcription initiation | |||||
| SVEP1 | 9q31.3 | Cell attachment, calcium ion binding | |||||
| CELF2 | 10p14 | mRNA processing | |||||
| MIR4483 | 10q25.3 | microRNA | |||||
| PLEKHS1 | Unknown | ||||||
| YAP1 | 11q22.1 | Transcriptional regulator | |||||
| CADM1 | 11q23.3 | Cell adhesion | |||||
| PTHL | 12p11.22 | Regulates epithelial/mesenchymal transition | |||||
| CCDC91 | Membrane trafficking | ||||||
| TTLL5 | 14q24.3 | Coregulator of glucocorticoid mediated gene expression | |||||
| SYNE3 | 14q32.13 | Acting binding protein | |||||
| SNHG10 | Non-coding RNA | ||||||
| SMAD6 | 15q22.31 | Negative regulator of TGF beta and BMP signalling | |||||
| SLCO3A1 | 15q26.1 | Activates NFkB | |||||
| SV2B | Vesicle trafficking and exocytosis | ||||||
| MAPT | 17q21.31 | Tau protein; microtubule assembly | |||||
| NPEPPS | 17q21.32 | Neuroprotection | |||||
| EYA2 | 20q13.12 | Ocular development | |||||
| GABPA | 21q21.3 | Transcriptional regulation of mitochondrial enzymes | |||||
| APP | Amyloid precursor protein | ||||||
| PSMG1 | 21q22.2 | Proteasome assembly | |||||
| LOC107985484 | non-coding RNA | ||||||
| MXRA5 | Xp22.33 | TGFß1 target; cell adhesion and extracellular matrix remodelling | |||||
| PRKX | Macrophage development | ||||||
| GPM6B | Xp22.2 | Membrane trafficking | |||||
| NDP | Xp11.3 | Activates Wnt/beta-catenin pathway | |||||
| EFHC2 | Calcium binding | ||||||
| TDGF1P3 | Xq23 | Unknown | |||||
| CHRDL1 | Ocular development, angiogenesis | ||||||
| Normal-tension glaucoma | Genetic Linkage Analysis | 131 families | European-derived | WDR36 | 5q22.1 | Cell cycle progression, signal transduction, apoptosis, gene regulation | 88 |
| Genetic Linkage Analysis | 54 families | European-derived | OPTN | 10p13 | Apoptosis, inflammation, vasoconstriction | 89 | |
| Genetic Linkage Analysis | 1 pedigree (Replicated in 2 additional patients) | African American | TBK1 | 12q14 | Innate immunity, autophagy | 90 | |
| GWAS | 720/3443 | European-derived | CDKN2B-AS | 9p21 | Long non-coding RNA; regulates expression of CDKN2B, CDKN2A and other target genes | 71 | |
| 8q22 locus | 8q22 | Unknown; region is highly active in choroid plexus and non-pigmented ciliary epithelial cells | |||||
| GWAS meta-analysis | 3247/47997 | Multi-ethnic (European, Asian and African descent) | LOC100147773 | 1q24.1 | Unknown | 87 | |
| FLNB | 3p14.1 | Actin cross-linking | |||||
| GMDS | 6p25.3 | Fructose and mannose metabolism | |||||
| ABCA1 | 9q31.1 | Cholesterol efflux pump | |||||
| SLC44A1 | Glucose transport | ||||||
| C14orf39 | 14q23.1 | Unknown | |||||
| Pseudoexfoliation glaucoma | GWAS | 274/14672 | Swedish and Icelandic | LOXL1 | 15q24.1 | Crosslinks collagen and elastin; pseudoexfoliation material constituent | 91 |
| GWAS | 1484/1188 | Japanese | CACNA1A | 19p13.13 | Calcium ion channel | 92 | |
| GWAS | 13 838/110275 | Multi-ethnic (24 countries, 6 continents) | POMP | 13q12 | Proteasome maturation protein | 93 | |
| TMEM136 | 11q23.3 | Transmembrane protein | |||||
| AGPAT1 | 6p21 | Role in lipid biosynthesis | |||||
| RBMS3 | 3p24 | RNA binding protein | |||||
| SEMA6A | 5q23 | Transmembrane protein expressed in developing neural tissue | |||||
| Primary angle closure glaucoma | GWAS | 1854/9608 | Chinese, Malay, Indian, Vietnamese | PLEKHA7 | 11p15.2–15.1 | Maintenance of adherens junctions, organisation of Actin cytoskeleton | 94 |
| COL11A1 | 1p21.1 | Collagen type 11 alpha subunit | |||||
| PCMTD1 | 8q11.23 | Unknown | |||||
| ST18 | Mediator of apoptosis and inflammation | ||||||
| GWAS | 10 503/29567 | Multi-ethnic (24 countries, 5 continents) | EPDR1 | 7p14.1 | Cell adhesion | 95 | |
| CHAT | 10q11.23 | Acetylcholine synthesis (role in pupillary constriction) | |||||
| GLIS3 | 9p24.2 | Transcription factor with role in eye development | |||||
| FERMT2 | 14q22.1 | Extracellular matrix component, cell adhesion | |||||
| DPM2 | 9q34.11 | Glycosylation | |||||
| FAM102A | Unknown function; induced in response to oestrogen |
a
GWAS, genome-wide association study.