The genetics of glaucoma: Disease associations, personalised risk assessment and therapeutic opportunities-A review

Abstract

Glaucoma refers to a heterogenous group of disorders characterised by progressive loss of retinal ganglion cells and associated visual field loss. Both early-onset and adult-onset forms of the disease have a strong genetic component. Here, we summarise the known genetic associations for various forms of glaucoma and the possible functional roles for these genes in disease pathogenesis. We also discuss efforts to translate genetic knowledge into clinical practice, including gene-based tests for disease diagnosis and risk-stratification as well as gene-based therapies.

1 |. INTRODUCTION

Glaucoma is the leading cause of irreversible blindness in the world and the prevalence is continuing to rise as the global population ages.¹ The term glaucoma refers to a heterogenous group of diseases that all share the characteristics of progressive optic neuropathy and distinctive patterns of visual field loss.² ‘Early-onset’ glaucoma presents in childhood and early adulthood, whereas ‘adult-onset’ forms of disease present after age 40.³ Currently, medical and surgical treatments for various forms of glaucoma focus on lowering intraocular pressure (IOP), which is a strong risk factor but not the root cause for disease development. Addressing the underlying molecular mechanisms that cause various forms of glaucoma may help reduce the global burden of blindness.

Twin and population-based studies have long identified family history as a strong risk factor for glaucoma, supporting the hypothesis that genetic factors play a critical role in disease pathogenesis.^4–9 In recent years, studies have significantly advanced understanding of the genetic basis of various forms of glaucoma. Genes associated with early-onset and syndromic forms of glaucoma typically exhibit a Mendelian inheritance pattern (autosomal dominant or autosomal recessive). These genes have been identified through linkage-based analyses of pedigrees of affected families and, in more recent years, through whole exome sequencing.¹⁰ Early-onset glaucoma genes may show incomplete penetrance (probability of a disease-causing mutation being phenotypically expressed) or variable expressivity (different phenotypes in individuals carrying the same disease-causing mutation). Adult-onset forms of glaucoma, on the other hand, are complex-inherited diseases, where a single gene mutation is not sufficient to cause disease; the disease phenotype is a result of the interactions of multiple genetic factors, as well as gene–environment interactions.¹⁰ The genes associated with adult-onset forms of glaucoma have largely been identified through genome-wide association studies (GWAS) performed in large populations of cases and matched controls.

Here, we summarise the genetic associations for various forms of early-onset and adult-onset glaucoma and discuss possible functional mechanisms whereby these genes contribute to disease development. We also discuss efforts to translate this knowledge into clinical practice, including the development of gene panels and polygenic risk scores for disease diagnosis and risk stratification, as well as opportunities for gene-based therapy.

2 |. GENE ASSOCIATIONS FOR EARLY-ONSET GLAUCOMA

Early-onset forms of glaucoma include primary congenital glaucoma, developmental glaucomas (including Axenfeld-Rieger syndrome and aniridia), juvenile open-angle glaucoma, and pigmentary glaucoma. The genes associated with each form of early-onset glaucoma and their known functions are listed in Table 1.

TABLE 1.

Early-onset glaucoma genes

Disease	Study design	Gene	Chromosomal location	Inheritance pattern	Gene function	References
Primary congenital glaucoma	Genetic Linkage Analysis	CYP1B1	2p22.2	Autosomal recessive, sporadic	Steroid metabolism, anterior segment development	11–15
	Genetic Linkage Analysis	LTBP2	14q24.3	Autosomal recessive	Extracecullar matrix protein involved in cell adhesion, elastic fibre assembly and microfibril structure	16–18
	Whole exome sequencing	TEK/TIE2	9p21.2	Autosomal dominant	Receptor tyrosine kinase; development of aqueous outflow pathway	19
	Whole exome sequencing	ANGPT1	8q23.1	Autosomal dominant	Ligand for TEK; development of aqueous outflow pathway	20
Axenfeld-Rieger syndrome	Genetic Linkage Analysis	PITX2	4q25	Autosomal dominant	Transcription factor; early ocular and systemic organogenesis	21–24
	Genetic Linkage Analysis	FOXC1	6p25.3	Autosomal dominant	Transcription factor; early ocular and systemic organogenesis	25–28
Aniridia	Genetic linkage analysis	PAX6	11p13	Autosomal dominant	Transcription factor; early ocular and systemic organogenesis	29–32
	Whole exome sequencing	ITPR1	3p26.1	Autosomal recessive (Gillespie syndrome)	Calcium ion channel	33
Juvenile open-angle glaucoma	Genetic Linkage Analysis	MYOC	1q24.3	Autosomal dominant	Extracellular matrix protein in trabecular meshwork; mutant protein aggregates intracellularly	34,35
Pigmentary glaucoma	Whole exome sequencing	PMEL	12q13.2	Autosomal dominant	Ocular pigmentation	36

2.1 |. Primary congenital glaucoma

Primary congenital glaucoma (PCG) presents in infancy with characteristic ocular findings, including buphthalmos, Haab’s striae, elevated IOP and optic nerve cupping.³⁷ Developmental abnormalities in the anterior segment and aqueous outflow pathway are thought to cause the IOP elevations observed in this disease. Most cases of PCG are sporadic, though 10%–40% are familial.³⁸ Of the familial cases, most have an autosomal recessive inheritance pattern with variable penetrance and expressivity.³⁹ Autosomal dominant inheritance has also been reported.⁴⁰

Linkage analyses using PCG-affected families have identified five distinct loci associated with PCG: GLC3A (chromosome 2p22-p21), GLC3B (1p36.2-p36.1), GLC3C (14q24.3), GLC3D (14q24.2-q24.3, but not overlapping with GLC3C), and GLC3E (9p21).^19,41–44

The causal gene in the GLC3A locus is CYP1B1, which was the first PCG gene to be identified.¹¹ This gene belongs to the cytochrome P450 family of enzymes that are involved in the metabolism of medications, vitamins, steroids, fatty acids and other chemicals.¹² CYP1B1 mutations have been identified in multiple ethnic populations, causing autosomal recessive PCG with variable expressivity.¹³ Cyp1b1 knockout mice have abnormalities in the trabecular meshwork, Schlemm’s canal, cornea and iris, though these mice do not exhibit elevations in IOP.¹⁴ In a zebrafish model, Cyp1b1 is expressed in the ocular fissures of developing zebrafish retina; decreased Cyp1b1 levels result in premature breakdown of the ventral fissure, leading to altered neural crest migration into the anterior segment.¹⁵

The causal gene in the GLC3D locus is latent transforming growth factor beta (TGF-β) binding protein 2 (LTBP2), which causes autosomal recessive PCG.¹⁶ LTBP2 belongs to the latent TGF-β binding protein family, which are multi-domain extracecullar matrix proteins that play roles in cell adhesion, elastic fibre assembly and microfibril structure.¹⁷ This gene is expressed in the anterior segment of the eye, particularly in the ciliary processes.¹⁶ Ltpb2-knockout mice do not survive beyond embryonic day 6.5, suggesting a critical role in early development.¹⁸ The precise mechanism whereby mutations in the LTBP2 gene functionally contribute to PCG development remains poorly characterised.

Tunica interna endothelial cell kinase (TEK, also known as TIE2) is the causal gene in the GLC3E locus.¹⁹ Rare variants in this gene were found in 10 of 189 unrelated PCG families using whole exome sequencing and exhibit an autosomal dominant inheritance pattern with variable expressivity. Each mutation was shown to result in protein haploinsufficiency due to loss of function. This receptor tyrosine kinase is a part of the TEK/Angiopoietin signalling pathway, serving as a receptor for the ligands Angiopoietin-1 (ANGPT1), Angiopoietin-2 (ANGPT2) and Angiopoietin-4 (ANGPT4). In a mouse model, hemizygosity for Tek results in hypomorphic Schlemm’s canal and trabecular meshwork tissue as well as elevated IOP, suggesting a critical role for this gene in development of the aqueous outflow pathway.¹⁹ Rare mutations have also been identified in the TEK ligand ANGPT1 in 3 patients in an international cohort of 284 PCG patients using whole exome sequencing, further supporting a role for this pathway in PCG pathogenesis.²⁰ Angpt1-knockout mice also exhibit a severely hypomorphic Schlemm’s canal and elevated IOP.²⁰

2.2 |. Axenfeld-Rieger syndrome

Axenfeld-Rieger syndrome (ARS) is characterised by anterior segment dysgenesis (posterior embyrotoxon and iris abnormalities) as well as associated systemic features (facial dysmorphism, dental anomalies, redundant periumbilical skin, cardiac defects and growth retardation).⁴⁵ Most cases have autosomal dominant inheritance, but sporadic cases have also been reported; variable penetrance and expressivity is also noted.⁴⁶ Up to 50% of patients will develop secondary glaucoma due to incomplete development of the aqueous outflow pathway. The associated glaucoma may present in infancy or in early adulthood.⁴⁵

Genetic linkage studies have identified two genes associated with ARS: pituitary homeobox 2 (PITX2) on chromosome 4q25^21,22 and forkhead box C1 (FOXC1) on chromosome 6p25.^25,26 Both of these genes encode transcription factors that activate genes responsible for early ocular and systemic organ development. Pitx2 and Foxc1 knockout mice each recapitulate the features of ARS but do not survive past the embryonal or neonatal period, respectively.^23,27 Disruption of Pitx2 or Foxc1 in zebrafish also recapitulates the ocular and systemic features of ARS.^24,28

2.3 |. Aniridia

Aniridia is characterised by bilateral, partial or complete iris and foveal hypoplasia, resulting in decreased visual acuity and nystagmus.⁴⁷ Around 50% will develop glaucoma in childhood or early adulthood due to anterior rotation of a rudimentary iris stump and chronic angle closure.⁴⁸ Two-thirds of aniridia cases have autosomal dominant inheritance and do not have any associated systemic features; there is complete penetrance but variable expressivity in these patients.⁴⁹ One-third of cases are sporadic, of which a subset have a syndromic form known as WAGR syndrome (Wilms tumour, Aniridia, Genitourinary abnormalities and mental Retardation).⁵⁰ 2% of aniridia cases have an autosomal recessive inheritance pattern and have associated systemic features of cerebellar ataxia and mental retardation (Gillespie syndrome).⁵⁰

Linkage analyses have demonstrated that autosomal dominant cases are caused by mutations in paired box gene-6 (PAX6) on chromosome 11p13.^29,30 90% of all aniridia cases are caused by PAX6 mutations, including sporadic cases.³¹ Individuals with WAGR syndrome also have a deletion of the neighbouring Wilms Tumour 1 (WT1) gene in addition to PAX6.^29,51 The PAX6 gene encodes a transcription factor that plays a critical role in activating genes involved in eye, nose, central nervous system and pancreatic development in the embryonal period.³² Heterozygous mouse models demonstrate aniridia-like iris abnormalities.³² The neighbouring WT1 gene is a transcription factor and tumour suppressor gene that plays a critical role in normal genitourinary development.⁵²

PAX6 mutations have been reported in two patients with the autosomal recessive Gillespie syndrome, though these patients also had atypical findings such as corectopia and ptosis.⁵³ Whole exome sequencing of five families affected with Gillespie syndrome also identified truncating mutations in the inositol 1,4,5-triphosphate receptor type 1 gene (ITPR1).³³ This gene encodes calcium release channels in the endoplasmic reticulum; the truncating mutations identified in this study result in non-functional calcium channel formation.³³

2.4 |. Juvenile open-angle glaucoma

Juvenile open-angle glaucoma (JOAG) is an early-onset form of open-angle glaucoma that presents between the ages of 3 and 40.⁵⁴ Compared to adult-onset primary open-angle glaucoma, JOAG typically has higher IOP, is more rapidly progressive, and less responsive to topical medical therapy.^55,56 JOAG has an autosomal dominant inheritance pattern with high penetrance.⁵⁴ A genetic linkage analysis in affected families identified the GLC1A locus (chromosome 1q21–31) to be associated with JOAG risk.⁵⁷ The myocilin (MYOC) gene, previously known as trabecular meshwork glucocorticoid response gene (TIGR), was later identified as the causal gene in this locus.⁵⁸

Between 8% and 63% of JOAG cases are caused by MYOC mutations.^59,60 A small proportion of adult-onset primary open-angle glaucoma cases (3%–4%) are also caused by MYOC mutations.⁶¹ Several MYOC mutations have been identified, which have variable phenotypes. Pro370Leu, Tyr437Ile, Ile477Asn are all associated with early onset disease, whereas Gln368STOP is associated with late onset disease and an overall milder phenotype.⁶¹ Pedigree-based studies have also demonstrated that compared to the more common Gln368STOP mutation, the Thr377Met mutation is associated with younger age of onset, higher peak IOP and increased likelihood of undergoing incisional glaucoma surgery.⁶²

Myocilin protein is normally highly expressed in the trabecular meshwork extracellular matrix. A study in primary cultures of human trabecular meshwork cells demonstrated that disease-associated myocilin mutations cause protein misfolding, intracellular protein aggregation in the endoplasmic reticulum (ER), and lack of secretion into the extracellular matrix.³⁴ This results in increased ER stress, deformation of trabecular meshwork cells, and diminished cell proliferation.³⁵ This is hypothesised to lead to trabecular meshwork dysfunction and increased outflow resistance, leading to elevations in IOP.

2.5 |. Pigmentary glaucoma

Pigment dispersion syndrome (PDS) is characterised by bilateral pigment deposition on the posterior central cornea (Krukenberg spindle), mid-peripheral iris transillumination defects and dense trabecular meshwork pigmentation.⁶³ Between 35–50% of individuals with PDS will develop pigmentary glaucoma (PG) due to obstruction of aqueous outflow and IOP elevation.⁶⁴ The disease typically presents in the third and fourth decades of life, but onset has been reported as early as age 11.⁶⁵ While rates of PDS are comparable among genders, PG is much more common in men and also has an earlier age of onset in males.⁶⁶ Myopia and vigorous exercise are also important risk factors for disease development.⁶⁶

Between 26% and 48% of PG patients report a positive family history, suggesting that genetic factors play a role in disease pathogenesis.⁶⁷ Pedigrees of affected families have identified an autosomal dominant inheritance pattern with incomplete penetrance, though PDS/PG is likely genetically heterogenous and also influenced by environmental factors.³⁶ A genetic linkage analysis of four families with autosomal dominant PDS/PG previously mapped a disease-associated locus at chromosome 7q35–36, though the causal gene has not yet been identified.⁶⁸ A more recent whole-exome sequencing study of two pedigrees identified two variants in the premelanosome protein (PMEL) gene associated with PDS/PG.³⁶ An additional seven PMEL variants were found through targeted screening of three independent cohorts (n = 394 individuals).³⁶ The PMEL gene encodes a melanosome component, which is involved in melanin synthesis, storage and transport. Five of the nine variants identified in this study showed defective PMEL protein processing and altered amyloid fibril formation in HeLa cells.³⁶ Knockdown of the zebrafish homologous gene was shown to result in pigmentation defects and an enlarged ocular anterior segment, further supporting a functional role for PMEL in PDS/PG pathogenesis.³⁶

3 |. GENE ASSOCIATIONS FOR ADULT-ONSET GLAUCOMA

Adult-onset forms of glaucoma include primary open-angle glaucoma (including the normal-tension glaucoma subtype), pseudoexfoliation glaucoma and primary angle-closure glaucoma. The genes associated with each form of adult-onset glaucoma and their known functions are listed in Table 2. The genes listed represent the gene closed to the lead SNP for each GWAS loci which may not always be the ‘causative’ gene for each locus. Additionally, there may be multiple genes at each locus that can contribute to disease. Without additional fine-mapping studies the gene defined by proximity to the lead SNP has traditionally been considered relevant to disease.

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

^aGWAS, genome-wide association study.

3.1 |. Primary open-angle glaucoma

Primary open-angle glaucoma (POAG) presents after age 40 and is characterised by progressive optic neuropathy in the setting of an unobstructed iridocorneal angle and no identifiable secondary causes.⁹⁶ IOP is often elevated, but approximately one third of patients will never have documented IOP above 21 mmHg, a subtype defined as ‘normal-tension glaucoma’ (NTG).

Early studies for POAG causal genes were conducted using linkage-analyses in affected families. This led to identification of the myocilin (MYOC) gene associated with autosomal dominantly inherited POAG as well as JOAG, as discussed previously.⁵⁸ Additional linkage analyses identified autosomal dominant inherited mutations in the optineurin (OPTN), WD Repeat Domain 36 (WDR36), and TANK Binding Kinase 1 (TBK1) genes, primarily in individuals with the NTG subtype.^88–90 OPTN is believed to play a neuroprotective role which may be affected by disease-associated mutations. The TBK1 gene encodes a kinase that regulates genes in the NF-kB signalling pathway and also interacts with OPTN; the functional mechanism whereby TBK1 mutations cause glaucoma remains poorly characterised, however. Little is known about the function of WDR36 or how mutations in this gene cause glaucoma. While these autosomal dominant inherited mutations for POAG have high penetrance, collectively they only account for approximately 5% of all cases of adult-onset POAG.³

More commonly, POAG is a complex-inherited trait, where multiple genes with small effect sizes and possible environmental influences are necessary for disease development. Most POAG associated genes have been identified through large-scale genome wide association studies (GWAS), where common single nucleotide polymorphisms (SNPs) across the genome (coding and non-coding) are investigated in disease cases and matched controls. Multiple GWASs and GWAS meta-analyses have been performed for POAG, as summarised in Table 2. Collectively, these GWASs have identified 127 loci associated with POAG risk that have consistent effects across individuals of European, east Asian and African ancestries.⁸⁷ Few GWASs have investigated POAG causal genes in other ethnic groups and this remains an important area of future research.

Interestingly, many of the POAG-associated loci function in early ocular development or have been identified as causal genes for early-onset glaucomas (SIX6, LMX1B, FOXC1, PITX2, ANGPT1, ANGPT2, RERE, ADAMTS18, MEIS2). This suggests that common variants in these genes are insufficient to produce an early-onset phenotype but could lead to POAG in later life, potentially due to the impact of additional genetic modifiers or environmental risk factors.

Pathway analyses for POAG-associated risk loci have identified important possible pathogenic mechanisms for POAG development.^87,97 These include endoplasmic reticulum stress response (MYOC), extracellular matrix and cell adhesion (MYOC, FNDC3B, AFAP1, COL4A1, COL8A2, THSD7A, EXOC2, ANGPTL7), TGF beta signalling (CDKN2B-AS, TGFBR3, SMAD6, MXRA5), TNF alpha signalling (OPTN, TBK1), vascular development (ANGPT1, ANGPT2), regulation of autophagy (OPTN, TBK1, BCAS3), lipid metabolism (ABCA1, DGKG, NPC2), eNOS signalling (CAV1/CAV2) and mitochondrial function (TXNRD2, ME3, VPS13C).

Interestingly, at least 16 loci associated with POAG risk are targeted by existing drugs, suggesting that these drugs could potentially be repurposed for targeted, personalised POAG treatment options.⁸⁷

3.2 |. Pseudoexfoliation Glaucoma

Pseudoexfoliation syndrome (XFS) is an age-related systemic disorder characterised by deposition of extracellular fibrillar material throughout the body.⁹⁸ Nearly half of all individuals with PXF will develop pseudoexfoliation glaucoma (XFG), the most common secondary form of open-angle glaucoma worldwide. Compared to POAG, XFG is associated with greater mean IOP, more advanced visual field loss at diagnosis and worse treatment response.⁹⁹ XFS is also associated with elevated risk for several nonocular disorders, including cardiovascular disease, cerebrovascular disease, Alzheimer’s like dementia, sensorineural hearing loss and pelvic organ prolapse.⁹⁸

GWASs have identified a total of seven loci strongly associated with risk for developing XFS/XFG. The lysyl oxidase-like 1 (LOXL1) gene on chromosome 15 was the first gene to be associated with XFG risk and to date remains the strongest known genetic contributor for this disease (OR 2.46–20.10 for the 3 SNPs in initial GWAS, p < 1.0 × 10⁻²¹).⁹¹ LOXL1 polymorphisms are strongly associated with disease risk in all ethnic populations studied to date, though the risk alleles for all known coding and non-coding variants are flipped in one or more ethnic population.¹⁰⁰ This suggests that these variants are either not functional or have different effects based on the genetic background of a given population. Notably, the allele that is more common in a population is always the risk allele suggesting that homozygosity is associated with risk and heterozygosity (the minor allele) is protective. Heterozgyous variants may be less likely to be associated with protein aggregation especially involving the intrinsic disordered domains.

The LOXL1 gene encodes an enzyme that crosslinks collagen and elastin in the extracellular matrix.¹⁰¹ Moreover, LOXL1 is a constituent of the pseudoexfoliation material that deposits in ocular and systemic tissues in this disease.¹⁰² LOXL1 expression levels are also altered in tissues from patients with XFS/XFG, with elevated levels noted in early disease and reduced levels in later stages of disease.^103,104 LOXL1 knockout mice have an altered blood–brain barrier, lens abnormalities and elevations in IOP, but no deposition of pseudoexfoliation material is noted.^105,106

The functional mechanism whereby LOXL1 gene variants functionally contribute to disease pathogenesis remains poorly characterised. Coding variants in LOXL1 have no effect on protein enzymatic activity.¹⁰⁷ Non-coding variants in intron 1 of LOXL1 were shown to modulate promoter activity of the LOXL1-AS1 long non-coding RNA, which in turn regulates expression of other extracellular matrix genes and pseudoexfoliation material constituents.^108,109 However, the risk alleles for all investigated SNPs are flipped in other ethnic populations. An additional group of non-coding variants spanning intron 1 and 2 of LOXL1 were found to alter binding of the transcription factor retinoid X receptor alpha and modulate alternative splicing of LOXL1 pre-mRNA, though the risk alleles for these variants were also flipped in other ethnic populations.¹¹⁰ Current work suggests that risk alleles are located in regions of intrinsic disorders domains that can promote protein aggregation.^111,112 This result as well as the observation that variant heterozygosity is associated with protective effects may suggest that disruption of protein aggregates by heterozygote effects is protective.¹¹²

More recent GWASs have identified additional genes associated with XFS/XFG risk, though the effect sizes for all of these genes are much lower than for LOXL1. In a Japanese dataset, a SNP in the calcium voltage-gated channel subunit alpha1A (CACNA1A) gene was significantly associated with XFS risk (OR 1.16, p = 3.36 × 10⁻¹¹), a finding that was confirmed in individuals from 17 additional countries across 6 continents.⁹² The CACNA1A gene encodes a subunit of a transmembrane voltage-gated calcium ion channel. Given that calcium is present in XFS fibrils,¹¹³ it is hypothesised that altered calcium ion channel function may promote the aggregation of XFS material. To date, no studies have investigated the functional mechanism for CACNA1A variants in XFS/XFG pathogenesis.

A larger GWAS including cases and controls from 24 countries across 6 continents identified five new loci associated with XFS: proteasome maturation protein (POMP; OR 1.17, 95% CI 1.11–1.22, p = 2.97 × 10⁻¹⁰); transmembrane protein 136 (TMEM136; OR 1.10, 95% CI 1.05–1.16, p = 1.0 × 10⁻⁴); 1-acylglycerol-3-phosphate O-acyltransferase 1 (AGPAT1; OR 1.19, 95% CI 1.11–1.27, p = 1.29 × 10⁻⁶); RNA binding motif single stranded interacting protein 3 (RBMS3; OR 1.15, 95% CI 1.09–1.22, p = 4.9 × 10⁻⁷); and semaphorin 6A (SEMA6A; OR 0.89, 95% CI 0.85–0.94, p = 2.3 × 10⁻⁵).⁹³ Expression levels of POMP and TMEM136 protein were investigated in this study and both were reduced in ocular tissue samples from PXF patients compared to controls. The POMP gene encodes a proteasome maturation protein, which may functionally contribute to disease pathogenesis given that the related autophagy pathway has also been implicated in XFS.¹¹⁴ Little is known about the biological roles of the other four genes or how disease-associated variants contribute to XFS development.

3.3 |. Steroid-induced Glaucoma

Topical and intravitreal corticosteroids are a common treatment for various uveitic and vitreoretinal diseases, which has led to a rising incidence of steroid-induced ocular hypertension and glaucoma.¹¹⁵ Steroid-induced glaucoma is a form of secondary open-angle glaucoma caused by increased resistance to outflow at the level of the trabecular meshwork. An estimated one-third of the population is moderately steroid responsive (rise of IOP 6–15 mmHg from baseline with steroid treatment), while 4–6% of the population is highly steroid responsive (IOP increase of >15 mmHg from baseline or IOP over 31 mmHg after steroid exposure).¹¹⁶ Studies have found an increased risk of steroid-induced glaucoma among first-degree relatives of affected individuals, and in those with a personal or family history of POAG, suggesting that genetic factors may contribute to steroid response.¹¹⁶

At the time of this review, no genetic associations have been identified for steroid-induced glaucoma, though GWASs are currently underway and will likely identify genetic contributors for this form of glaucoma in the near future.

3.4 |. Primary angle-closure glaucoma

Pangle-closure glaucoma (PACG) is diagnosed based on the presence of an occludable anterior chamber angle, trabecular meshwork obstruction by peripheral iris, and evidence of glaucomatous optic neuropathy.⁹⁶ Pupillary block is the most common underlying aetiology. It is estimated that PACG will affect over 30 million people worldwide by 2040.¹¹⁷ Moreover, population based studies have shown that, compared to POAG, PACG carries a three-fold higher risk of severe, bilateral visual impairment.¹¹⁸ Hyperopia, advanced age and female gender are important risk factors for PACG.¹¹⁸ Studies have also demonstrated a higher prevalence in certain ethnic groups (East Asian and Inuit) and in first-degree relatives of affected individuals, supporting an underlying genetic basis for this common disease.^119,120

Two GWASs have identified eight loci strongly associated with risk for developing PACG. The first GWAS was performed in a case/control cohort from five Asian countries (Singapore, Hong Kong, Malaysia, India and Vietnam).⁹⁴ Three loci reached genome-wide significance levels in this study: pleckstrin homology domain–containing protein 7 (PLEKHA7; OR = 1.22, p = 5.33 × 10⁻¹²); collagen type 11 alpha-1 chain (COL11A1) (OR = 1.20, p = 9.22 × 10⁻¹⁰); and a SNP located between protein-L-isoaspartate o-methyltransferase domain containing 1 (PCMTD1) and ST18 C2H2C-type zinc finger transcription factor (ST18; OR = 1.50, p = 3.29 × 10⁻⁹).

The PLEKHA7 gene plays a critical role in maintenance and stability of adherens junctions. PLEKHA7 is expressed in PACG relevant ocular tissues and in tissues that maintain the blood-aqueous barrier.¹²¹ PLEKHA7 gene expression is downregulated in lens epithelial cells and iris tissue samples from PACG patients compared to controls, with a greater reduction seen in individuals who are carriers of the risk allele for the rs11024102 SNP in PLEKHA7.¹²² Knockdown of PLEKHA7 expression in non-pigmented ciliary epithelial cells leads to impaired actin cytoskeleton organisation and compromises para-cellular barriers between cells, providing a potential functional mechanism whereby altered PLEKHA7 levels affect aqueous outflow and blood aqueous barrier function.¹²⁰ The COL11A1 gene encodes the alpha chain of type XI collagen; it is hypothesised that variants in this gene may impact axial length, an important risk factor for developing PACG, though this has not yet been investigated with functional studies. Little is known about the functions of PCMTD1 and ST18, or which gene is the more likely candidate susceptibility gene in this locus.¹²²

A larger GWAS for PACG included samples from 24 countries across 5 continents.⁹⁵ Five additional loci reached genome-wide significance levels: ependymin-related 1 (EPDR1; OR = 1.24, p = 5.94 × 10⁻¹⁵), choline o-acetyltransferase (CHAT; OR = 1.22, p = 2.85 × 10⁻¹⁶), GLIS family zinc finger 3 (GLIS3; OR = 1.18, p = 1.43 × 10⁻¹⁴), FERM domain-containing kindlin 2 (FERMT2) (OR = 1.14, p = 3.43 × 10⁻¹¹), and a SNP located between dolichyl-phosphate mannosyltransferase-2 (DPM2) and early oestrogen-induced gene 1 (FAM102A; OR = 1.15, p = 8.32 × 10⁻¹²).

Similar to PLEKHA7, both EPDR1 and FERMT2 are also involved in cell-adhesion, further supporting a functional role for this pathway in PACG pathogenesis.⁹⁵ CHAT synthesises acetylcholine, which causes pupillary constriction; given that pupillary dilation can precipitate an angle closure attack, altered CHAT function could make functional sense in the context of this disease, though studies exploring the underlying mechanisms have not been performed. Little is known about the functions of GLIS3, DPM2 and FAM102A or how disease-associated SNPs in these loci contribute to PACG pathogenesis.

4 |. DIAGNOSTIC OPPORTUNITIES

Currently, gene-based diagnostic tests are available for early-onset forms of glaucoma, where a single gene mutation is sufficient to produce the disease phenotype. For adult-onset, complex-inherited forms of glaucoma, polygenic risk scores have been investigated as a potential tool for personalised risk stratification.

4.1 |. Gene-based testing

For Mendelian, early-onset forms of glaucoma, gene-based testing can help confirm a disease diagnosis. Moreover, screening of relatives can identify individuals who also have the causal mutation and warrant close follow-up to enable prompt diagnosis and treatment. In the future, identification of the genetic aetiology of disease may also inform treatment decisions as gene-based therapies become available.

Options for gene-based testing include the Genetic Eye Disease Panel for Optic Nerve Disease and Early Manifest Glaucoma (GEDi-O) panel available through the Ocular Genomics Institute at Massachusetts Eye and Ear. This panel uses a targeted enrichment and next generation sequencing approach and tests for mutations in 22 genes (ACO2, AFG3L2, AUH, C12orf65, CISD2, CYP1B1, FOXC1, FOXF2, LTBP2, MTPAP, MYOC, NDUFS1, NR2F1, OPA1, OPA3, OPTN, PAX6, PITX2, POLG, SPG7, TEK, and WFS1).¹²³ The sensitivity and specificity of the GEDi panels for inherited retinal degeneration and early-onset glaucoma were investigated and found to be 97.9% and 100%, respectively.¹²⁴ Notably, the sensitivity was substantially higher than that achieved with whole exome sequencing (88.3%) in this study.

4.2 |. Polygenic risk scores

A polygenic risk score (PRS) evaluates the cumulative effect of multiple SNPs in different genes on disease risk, which is useful in cases of complex-inherited disease where a single mutation is not sufficient for disease development. Several recent studies have investigated the utility of a PRS consisting of IOP-associated SNPs in predicting POAG phenotypes. In one study, an IOP-based PRS was applied to the UK Biobank dataset (n = 435 678 participants).¹²⁵ Compared to the bottom quintile, individuals in the top quintile were found to have 6.34 times higher likelihood of having POAG (95% CI 4.82–8.33, p = 2.1 × 10⁻⁵⁷). Another study applied an IOP-based PRS to 2154 POAG patients from the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG).¹²⁶ Compared with the lowest quintile, the highest quintile of PRS was found to have higher maximal IOP by 1.7 mmHg (Standard Deviation [SD] 0.62 mmHg, p < 0.01), younger age of diagnosis by 3.7 years (SD 1.0 years, p < 0.001), and a greater rate of incisional glaucoma surgery (OR 1.5, 95% CI 1.1–2.0, p < 0.01). An IOP-based PRS has also been found to be associated with higher early morning and mean IOP outside office hours in POAG patients, as measured with the iCare HOME tonometer (n = 239 Australian participants).¹²⁷ Compared to the lowest quintile, eyes in the highest PRS quintile had an early morning IOP increase of 4.3 mmHg (95% CI 1.4–7.3, p = 0.005) and a mean increase in IOP outside office hours of 2.7 mmHg (95% CI 0.61–4.7, p = 0.013).

A PRS consisting of IOP, vertical cup-to-disc ratio (VCDR) and POAG-associated SNPs has also been constructed and evaluated in the UK biobank (n = 67 040 participants).⁸⁶ Individuals in the top decile of PRS were found to reach an absolute risk of glaucoma 10 years earlier than the bottom decile and have 15-fold higher risk of developing advanced glaucoma compared to the remaining 90% (OR 3.43–5.17, p = 1.4 × 10⁻⁴²). The PRS was also shown to predict glaucoma progression in early manifest glaucoma cases (p = 0.004) and the need for surgical intervention in patients with advanced disease (p = 3.6 × 10⁻⁶).

The effects of polygenic risk on MYOC penetrance has also been examined.¹²⁸ This study investigated 200 individuals in the UK Biobank who carried the heterozygous phenotype for p.Gln368Ter, the most common MYOC variant associated with open-angle glaucoma risk. A genome-wide POAG PRS was constructed and the prevalence of disc-defined glaucoma was found to increase with each decile of POAG PRS. Overall, one in four individuals carrying the MYOC p.Gln368Ter variant had evidence of glaucoma, which is a significantly higher penetrance than previously reported.

In addition to POAG, a PRS has also been investigated in PACG. This PRS was constructed using eight disease associated SNPs in 844 PACG patients of Chinese ethnicity from Singapore.¹²⁹ Compared to individuals in the lowest quartile, those in the highest quartile of weighted PRS were more likely to have severe disease on visual field testing (OR = 3.11, 95% CI 1.95–4.96, p < 0.001).

The effects of an IOP-based PRS in modulating gene–environment interactions has also been investigated in the UK Biobank dataset (n = 121 374 participants).¹³⁰ Overall, there was no association between caffeine intake and POAG risk (p > 0.1). However, the IOP PRS modified this relationship, as those in the highest IOP PRS quintile who consumed ≥321 mg/day had a 3.9-fold higher glaucoma prevalence compared to those in the lowest PRS quintile who consumed no caffeine (p = 0.0003).

Efforts have also been made to integrate machine learning technologies for accurate cohort phenotyping for GWAS and PRS analyses. A machine learning model was developed to predict optic nerve head features from colour fundus photos, which was then used to assess VCDR in the UK Biobank dataset (n = 65, 680 participants).¹³¹ A subsequent GWAS of machine learning-based VCDR replicated 62 of 65 previously identified loci and also identified 95 novel loci for VCDR in the UK Biobank dataset. The machine learning-based GWAS results were also shown to improve polygenic prediction of VCDR and POAG in an independent EPIC-Norfolk cohort.

5 |. THERAPEUTIC OPPORTUNITIES

Current medical and surgical therapies for glaucoma primarily focus on lowering IOP, which is a key risk factor for disease development and progression but not the root cause of disease itself. An understanding of the genetic basis for various forms of glaucoma has provided opportunities for targeting specific gene defects or molecular pathways that contribute to disease pathogenesis.

For early-onset forms Mendelian of glaucoma, a mutation in a single gene is sufficient to produce the disease phenotype and, therefore, therapies that target this defect can potentially be curative. Technological advancements, especially discovery of the CRISPR/Cas9 system, have revolutionised genome-editing and accelerated the development of genetic therapies, with several CRISPR/Cas9-based clinical trials now underway.^132–134 A CRISPR/Cas9-based treatment for myocilin-associated glaucoma has been studied using in vitro human trabecular meshwork cell culture and in vivo mouse models.¹³⁵ Genome editing was used to knockdown expression of mutant MYOC, which led to reduced misfolded protein load and ER stress in human trabecular meshwork cells. In mice, CRISPR/Cas9 editing prevented IOP elevation and subsequent glaucoma development. Similarly, CRISPR/Cas9 editing of a PAX6 mutation was recently shown to rescue the eye phenotype in a mouse model of aniridia.¹³⁶ Human clinical trials have not yet been initiated for either MYOC or PAX6 treatments but may be in the near future. Genome editing technologies may also be applied to other early-onset glaucoma genes in the future, including CYP1B1, TEK, FOXC1 and PITX2.

For complex-inherited forms of glaucoma, multiple gene variants and environmental risk factors lead to the disease phenotype. It is also likely that defects in different molecular pathways lead to the same clinical endpoint. As prospective clinical studies and translational mechanistic studies better characterise the different pathways that play a causal role in adult-onset glaucoma it may be possible to recommend targeted treatment approaches for a given individual. For example, patients with gene variants in mitochondrial genes may benefit from anti-oxidant therapies, whereas patients with mutations in lipid metabolism genes may benefit from cholesterol-lowering medications.⁹⁷ Therapies may also be developed based on genes that protect against glaucoma development. For example, rare variants in the ANGPTL7 gene, including a protein-truncating variant, are associated with lower IOP levels in the UK biobank, suggesting that downregulation of ANGPTL7 could protect against POAG development or progression.⁸⁵

6 |. CONCLUSIONS AND FUTURE DIRECTIONS

Significant progress has been made in our understanding of the genetic basis of various forms of early-onset and adult-onset glaucoma in recent years. Moreover, this knowledge has already begun to impact clinical practice for early-onset forms of glaucoma through the availability of gene panels to confirm disease diagnosis and screen at-risk relatives. Polygenic risk scores are also being developed as a tool for personalised risk assessment in adult-onset forms of glaucoma, though these studies have largely been retrospective. In terms of treatment, pre-clinical studies suggest that gene-based therapies could potentially provide a curative option for early-onset Mendelian forms of disease. For adult-onset disease, it may be possible in the future to provide personalised therapeutic plans for a given patient based on knowledge of their specific gene mutations and the molecular pathways they impact.

Despite this progress, much still remains unknown about the genetics of glaucoma. The known genes for various forms of glaucoma only explain a portion of disease heritability; with larger, more ethnically diverse datasets and continued advancements in gene-discovery technologies, additional genes will likely be identified. The functional characterisation of genetic associations will also be critical for improving understanding of disease mechanisms and identifying novel therapeutic targets. As more genes are identified, refinement of gene panels and polygenic risk scores will be needed. Longitudinal, prospective studies in individuals with high polygenic risk are also critical for better understanding genotype–phenotype correlations and the role of environmental modifiers. Lastly, continued efforts to translate knowledge of the causal genes for glaucoma into more targeted therapeutic approaches may help greatly reduce the global burden of irreversible blindness.