Genetics of primary open-angle glaucoma

C H A P T E R

11 Genetics of primary open-angle glaucoma Hannah Youngblooda, Yutao Liua,b,c a

Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA, United States b James and Jean Culver Vision Discovery Institute, Medical College of Georgia, Augusta University, Augusta, GA, United States cCenter for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA, United States

Introduction Primary open-angle glaucoma Glaucoma describes a set of optic neuropathies that are characterized by retinal ganglion cell (RGC) death, optic nerve atrophy, and subsequent peripheral to central vision loss [1]. As the number one cause of irreversible blindness globally, glaucoma is expected to impact about 80 million individuals by 2020 [2, 3]. Primary open-angle glaucoma (POAG), the most prevalent type of glaucoma, is characterized by common glaucoma symptoms lacking an attributable cause and will account for roughly three-fourths of these cases [1–3]. Advanced age, positive family history, and elevated intraocular pressure (IOP) are risk factors for POAG [1]. Approximately 4%–16% of POAG patients have an immediate family member affected by POAG [4]. Individuals with African or Hispanic ancestry evidence higher rates of the disease [1].

Symptoms and diagnosis Because POAG is generally asymptomatic (i.e., no pain), individuals often do not consult an ophthalmologist until there is already significant vision loss [1]. Therefore, many POAG patients are not aware of their disease status. POAG is defined as having a diagnosis after age 40 while glaucoma diagnosed prior to 40 is called juvenile open-angle glaucoma (JOAG). The primary and only modifiable risk factor for POAG, high IOP (22 mmHg), may not be present in all cases [1]. POAG with untreated high IOP is called high-tension glaucoma while

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glaucoma occuring at a normal IOP level (21 mmHg) is called normal-tension glaucoma (NTG). Both HTG and NTG evidence a loss of RGCs and a large cup-to-disk ratio (CDR) despite differences in IOP levels [1].

Therapies The only effective treatment for POAG is to reduce the IOP levels both in patients with HTG and NTG. Most management strategies seek to lower IOP through either medications or, in unresolved cases, laser treatment or surgery in order to lower risk and delay progression [1]. Even when the IOP is able to be managed, however, glaucoma may still continue to progress [1]. This is especially true in cases of NTG where IOP is already at moderate levels. Furthermore, IOP is not standard across individuals; POAG may develop in individuals with low IOP while individuals with high IOP may never experience glaucomatous loss of vision [1].

POAG genetics A variety of different genetic approaches, including genome-wide linkage analyses and genome-wide association studies (GWAS), have been used to discover genes and chromosomal loci contributing to POAG. These studies have identified many genes and variants associated not only with POAG as a whole, but also with its subtypes (i.e., HTG, NTG, and advanced POAG) and representative phenotypes. Conducting these studies in a variety of populations has also aided our understanding of how identified variants contribute similarly and differently to POAG in diverse populations.

Linkage analyses Genetic linkage analyses are used to determine chromosomal regions associated with a phenotype by examining recombination frequencies in the genetic profiles of families that evidence Mendelian inheritance of the phenotype [1]. Sixteen chromosomal loci linked with POAG (GLC1A through GLC1P) have been identified in this manner (Table 1). Eight of these loci have been refined to specific genes, each of which are examined in the following. MYOC, ASB10, and EFEMP1 Myocilin (MYOC), ankyrin repeat and SOCS box containing 10 (ASB10), and EGFcontaining fibulin extracellular matrix protein 1 (EFEMP1) are three candidate genes identified through linkage analyses that may contribute to POAG by reducing aqueous humor (AH) flow through protein accumulation. The causal role of MYOC mutations in POAG was first established with linkage analysis studies looking at families that evidenced highly penetrant autosomal dominant inheritance of JOAG [4]. The gene was found to be located at the GLC1A locus on chromosome 1q24 [5]. Composed of three exons, the MYOC gene encodes a 504 amino acid protein that is expressed in multiple tissues with unknown function [37, 38]. Most mutations are localized in the olfactomedin domain in the C-terminal region and often result in a truncated protein product

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TABLE 1

Chromosomal loci determined by genome-wide linkage analysis.

Candidate gene

Gene locus

Chromosomal location

Open angle glaucoma phenotype

MYOC

GLC1A

1q24.3

Unidentified

GLC1B

IL20RB

Possible mechanisms

References

POAG, JOAG

Intercellular accumulation and AH flow reduction

[4, 5]

2cen-q13

POAG

Unknown

[6–8]

GLC1C

3q21-24

POAG

Inflammation resulting in retinal axon damage

[9–12]

Unidentified

GLC1D

8q23

POAG

Unknown

[13]

OPTN

GLC1E

10p13

POAG, NTG

Faulty autophagy

[14, 15]

ASB10

GLC1F

7q36.1

POAG

Faulty protein degradation and AH flow reduction

[16, 17]

WDR36

GLC1G

5q22.1

POAG

Cellular stress and apoptosis

[18]

EFEMP1

GLC1H

2p16.3-p15

POAG, JOAG

Protein aggregation and small optic nerve disc area

[19–21]

Unidentified

GLC1I

15q11-q13

POAG

Unknown

[22–25]

Unidentified

GLC1J

9q22

JOAG

Unknown

[26]

Unidentified

GLC1K

20p12

JOAG

Unknown

[26]

Unidentified

GLC1L

3p22-21

POAG

Unknown

[27]

Unidentified

GLC1M

5q22.1-q32

JOAG

Unknown

[28, 29]

Unidentified

GLC1N

15q22-q24

JOAG

Unknown

[30]

NTF4

GLC1O

19q13.33

POAG

Reduced tyrosine kinase receptor B activity

[31–33]

TBK1

GLC1P

12q14

POAG, NTG

Faulty autophagy

[34–36]

[1, 37, 39]. MYOC mutations account for the majority of familial POAG cases and 2%–4% sporadic POAG [39]. The POAG patients with MYOC mutations are often characterized with early onset and very high IOP [37, 39]. MYOC can be found in the AH of healthy individuals, but it seems to not have a necessary function there as increased or decreased levels of expression do not affect normal eye function including aqueous outflow and IOP level [40–45]. Therefore, POAG does not appear to result from a loss of function in mutated MYOC, but rather a gain of function [1]. It has been shown that mutated MYOC accumulates intracellularly rather than entering the AH normally [43, 46–49]. This intracellular accumulation induces ER stress and may obstruct normal cell processes such as endocytosis and apoptosis necessary to keep the trabecular meshwork (TM) clear for AH flow [1]. Therefore, AH flow through the TM and out of the anterior chamber would be reduced, ultimately resulting in elevated IOP [1]. A linkage analysis study in a large multi-generation family with POAG has identified mutations in the ASB10 gene located in chromosome 7q36 GLC1F locus [17, 50]. ASB10 is known to be expressed in the TM where its involvement in proteasomal degradation may

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contribute to AH outflow by keeping the outflow path clear of accumulated proteins [17, 51]. This possible function is supported by studies that have shown that AH outflow is reduced by 50% when ASB10 is knocked down [17]. However, it still needs to be replicated in other POAG datasets. POAG was first linked to the chromosome 2p16 GLC1H locus containing the EFEMP1 gene in a linkage study of an African American family with autosomal dominant inheritance of POAG [1, 21]. Mutations in EFEMP1 may lead to protein aggregation [21]. In this way, expression of this mutated protein in the ciliary body, TM, and cornea may impact the AH and its outflow [1, 52]. The involvement of this gene in POAG pathogenesis is further supported by the fact that POAG-associated cytokine TGF-β2 can modulate EFEMP1 expression in the TM [52]. However, because the protein is also expressed in the retina and has been linked to other retinal problems (i.e., Malattia Leventinese, Doyne honeycomb retinal dystrophy, and decreased optic nerve disc area), its association with POAG may be due to its function in the retina which is largely unknown [1, 53–57]. The increased expression of EFEMP1 in response to optic nerve crush injury further supports a retinal role of EFEMP1 in POAG pathology [58]. Interleukin 20 receptor subunit β Another candidate gene identified through linkage analysis in a large POAG family is interleukin 20 receptor subunit β (IL20RB), a gene within the chromosomal 3q21 GLC1C locus [59]. This study linked POAG incidence to a specific T104M mutation occurring in an interleukin-binding domain which allows interleukins 19, 20, and 24 to bind and regulate IL-20 [60]. IL-20 regulation has been demonstrated in TM cell culture [1]. The retinal expression of one of these regulatory cytokines, IL-24, has been shown to increase upon optic nerve damage [61]. However, the mutation in the interleukin-binding domain was not present in all the affected subjects in the family of interest, meaning there are phenocopies without the same mutation. Additional research is necessary to further validate the role of IL20RB in the pathogenesis of POAG. Optineurin and TANK-binding kinase 1 Linkage analyses have identified mutations in the optineurin (OPTN) gene and the TANKbinding kinase 1 (TBK1) gene to contribute to POAG pathogenesis, especially NTG. Since OPTN and TBK1 participate in similar pathways and interact with each other, it is thought that mutations in these two genes may cause POAG through a shared mechanism [62–64]. Interestingly, mutations of these two genes have also been identified to cause amyotrophic lateral sclerosis (ALS), further suggesting their important role in neuronal function [65–69]. Positioned in the chromosome 10p13 GLC1E locus, specific mutations of OPTN cause NTG [1]. Some of the normal functions of OPTN include regulation of apoptosis, autophagy, pathogen defense, protein trafficking, cell division, and TNFα-induced inflammation [63, 64, 70–79]. The POAG-causal mutation in this gene is the E50K mutation that results in severe, early-onset POAG [80]. A transgenic mouse has been developed to model the effects of this mutation in NTG pathogenesis and has evidenced RGC loss and decreased acuity [81]. Located on chromosome 12q14 in the GLC1P locus, TBK1 codes for TBK1 that shares many of the same functions as OPTN [1]. This serine/threonine kinase has been shown to regulate inflammation, mitophagy, and autophagy. The most prominent mutation in TBK1 for POAG

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is a duplication of the gene [35, 36, 82–86]. Genomic duplications of TBK1 have been shown to induce abnormal autophagy in several cell-based studies including a study using NTG patient iPSC-derived RGCs [35, 76, 87–90]. A TBK1 mouse model for NTG has been developed based on this duplication to further study its role in glaucoma pathogenesis [91]. In summary, OPTN and TBK1 are both related to inflammation and autophagy. Although abnormal autophagy has been observed in POAG RGCs, it remains unclear how faulty autophagy contributes to retinal damage and glaucoma progression. The animal models based on glaucoma-specific mutations in these genes will help elucidate the mechanism behind this pathogenesis. WD repeat domain 36 WDR36, located at chromosome 5q22 locus GLC1G, is another POAG candidate gene identified through linkage analysis [1]. This gene codes for the nucleolar protein WD repeat domain 36, which plays a role in the formation of 18S rRNA [1]. WDR36 variants have been associated with decreased levels of mature 18S rRNA [92, 93]. The effects on 18S rRNA in turn result in stress and apoptotic response [92, 93]. While these cellular events have been demonstrated in zebrafish and human TM cells, the actual effects on eye health remain controversial [92, 93]. While some studies have shown abnormalities in ocular development and damage to RGC axons in response to WDR36 mutations, other studies have not shown these changes [92–94]. In all cases, however, there seems to be no effect on IOP [93, 94]. The inconsistent genetic findings in POAG patients and functional studies have raised many questions regarding the actual role of WDR36 mutations in POAG pathogenesis [93, 95–107]. Neurotrophin 4 Another POAG candidate gene, neurotrophin 4 (NTF4), was not actually identified via linkage analysis, but rather was found as a candidate gene in a POAG case-control dataset [31]. Seven coding variants were identified in the GLC10 locus containing this gene on chromosome 19q13.33 [31]. Other than a proposed effect on tyrosine kinase receptor B activity, the contribution of NTF4 variants to POAG remains unclear and has been refuted by several other groups [31, 32, 108–110].

Genome-wide association studies GWAS identify genetic variants that are associated with a specific trait/phenotype/ disorder. GWAS use high-throughput genome-wide DNA genotyping of large sample sets to identify common genetic variants [i.e., single nucleotide polymorphisms (SNPs) with minor allele frequency 0.05] that correlate with the phenotype of interest [1]. Case-controlbased GWAS have successfully identified approximately 40 SNPs associated with POAG (Table 2). Most of these POAG-associated variants have been replicated in at least two or more independent studies. Until recently, one limitation of GWAS was that the majority of these studies were conducted in European and Asian populations. POAG, however, shows a higher prevalence in populations with African/Hispanic ancestry and therefore the SNPs identified in European and Asian populations may not be representative of African/Hispanic POAG cases [1]. Recent and ongoing studies on multiethnic populations have confirmed many of

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TABLE 2 Genomic regions associated with POAG as determined by genome-wide association studies (GWAS). Gene closest to SNP

Open-angle glaucoma phenotype

Ethnicity

References

PLXDC2

POAG

Japanese

[116]

TMTC2

POAG

Japanese

[116]

ZP4

POAG

Japanese

[116]

SRBD1

NTG

Japanese

[117]

ELOVL5

NTG

Japanese

[117]

CAV1/ CAV2

POAG

Icelandic, Multiethnic, African Ancestry

[118–120]

TMCO1

Advanced POAG, POAG, HTG

Australian, Multiethnic, European American, African Ancestry

[119–122]

CDKN2B-AS1

Advanced POAG, POAG, NTG

Australian, European American, Multiethnic, African Ancestry

[119, 121–124]

SIX1/SIX6

POAG, HTG

European American, African Ancestry, Multiethnic

[114, 119, 122, 125]

LRP12/ZFPM2

NTG

European American

[122, 125]

ABCA1

Advanced POAG, POAG, HTG, NTG

European Ancestry, Multiethnic, Chinese, African Ancestry

[119, 120, 126, 127]

GMDS

Advanced POAG, POAG

European Ancestry, African Ancestry

[119, 126]

AFAP1

Advanced POAG, POAG

European Ancestry, African Ancestry, Multiethnic

[114, 119, 126]

GAS7

POAG, Advanced POAG

Multiethnic, African Ancestry

[115, 119, 120]

PMM2

POAG, HTG, NTG, Advanced, POAG

Chinese, African Ancestry

[115, 119, 127]

ARHGEF12

POAG, HTG

European Ancestry, African Ancestry

[119, 128]

CDC7-TGFBR3

POAG

Multiethnic, African Ancestry

[119, 124]

TXNRD2

POAG

European American, African Ancestry, Multiethnic

[114, 119, 122]

ATXN2

POAG

European American, African Ancestry

[119, 122]

FOXC1

NTG, HTG, POAG

European American, African Ancestry

[119, 122]

C120RF23

NTG

European American

[122]

IKZF2

POAG

Multiethnic

[114]

PDE7B

POAG

Multiethnic

[114]

ANKH

POAG

Multiethnic

[114]

DGKG

POAG

Multiethnic

[114]

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TABLE 2 Genomic regions associated with POAG as determined by genome-wide association studies (GWAS).—cont’d Gene closest to SNP

Open-angle glaucoma phenotype

Ethnicity

References

PLCE1

POAG

Multiethnic

[114]

THSD7A

POAG

Multiethnic

[114]

FMNL2

POAG

Multiethnic

[114]

TMTC2

POAG

Multiethnic

[114]

CDKN1A

POAG

Multiethnic

[114]

TCF12

POAG

Multiethnic

[114]

EXOC2

POAG

Multiethnic

[114]

LMX1B

POAG

Multiethnic

[114]

ANGPT1

POAG

Multiethnic

[114]

ELN

POAG

Multiethnic

[114]

CADM2

POAG

Multiethnic

[114]

TMEM136

POAG

Multiethnic

[114]

DST

POAG

African Ancestry

[119]

MNS1

POAG

African Ancestry

[119]

EXOC4

POAG

African Ancestry

[119]

ENO4

Advanced POAG

African American

[115]

TGFBR3

POAG

African American

[115]

MYOC

POAG

African American

[115]

CYP1B1

POAG

African American

[115]

FNDC3B

POAG

African American

[115]

ABO

POAG

African American

[115]

the SNPs found in European and Asian populations as well as some novel variants [111–115]. Some of the most significant genetic variants identified by GWAS are discussed below. Caveolins 1 and 2 Several genome-wide analyses have identified variants located on chromosome 7q31 in between the caveolin genes CAV1 and CAV2 as being associated with POAG [118–120, 129–134]. The caveolins are expressed throughout ocular tissue where they function in a variety of pathways including transport, proliferation, endocytosis, and cell signaling [135–139]. The identified genetic variants are more significantly associated with females [131, 134].

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These CAV1/2 variants may contribute to POAG pathogenesis by regulating AH outflow and thereby affecting IOP [1]. Studies have shown that CAV1 and CAV2 evidence differential expression in primary human Schlemm’s canal (SC) endothelial cells of POAG compared to control SC cells [140, 141]. In addition, TM cells also evidence CAV1 and CAV2 expression [137]. Dexamethasone has been shown to increase CAV1 expression in TM cells while POAG-associated TGF-β2 has been shown to reduce its expression [137]. Furthermore, knocking down these genes is known to result in impaired AH outflow and subsequent elevated IOPs in mouse models [12, 135, 142, 143]. Transmembrane and coiled-coil domain 1 Sequence variants in the transmembrane and coiled-coil domain 1 (TMCO1) gene have been associated with POAG, HTG, advanced POAG, and IOP [119–122, 132, 144–148]. The risk for developing POAG has been shown to be 12% higher in non-Hispanic whites having one of these TMCO1 variants [147]. Furthermore, several TMCO1 variants have been associated with earlier onset of POAG [149]. There has been some controversy, however, over whether TMCO1 variants are associated with POAG in populations with African ancestry. Several recent large-scale studies have replicated the association of TMCO1 variants with POAG in African and multiethnic populations [119, 120, 150]. TMCO1 codes for the ER TMCO1 protein which functions as a calcium channel that opens in response to changes in ER calcium levels [151, 152]. Although the role of TMCO1 in POAG pathogenesis and IOP regulation remains unclear, its strong expression in the TM suggests that its association with IOP fluctuation may be due to its effects on AH outflow [149]. CDKN2B antisense RNA 1 Sequence variants in the CDKN2B antisense RNA 1 (CDKN2B-AS1) gene have been highly associated with POAG and vertical CDR [119, 121–125, 144, 153–161]. These variants are more strongly associated with POAG in females and NTG populations [122, 125, 144, 162–165]. Similarly to TMCO1, the association between CDKN2B-AS1 variants and POAG in populations with African ancestry has been replicated recently in African and multiethnic populations [119, 120, 150]. CDKN2B-AS1 is located on chromosome 9p21 as a long noncoding RNA (lncRNA) [1]. The retina, optic nerve, and ciliary body all express this antisense lncRNA which negatively regulates local genes through its association with polycomb repressive complexes 1 and 2 (PRC1/PRC2) [1, 121]. The CDKN2B protein is also expressed in the retina, the cornea, and TM [166]. Studies have shown that deletion of both alleles for the CDKN2B-AS1 homologous region in mice results in increased IOP and RGC damage after 1 year, while the deletion of only one allele shows no effect [167, 168]. However, it is noted that CDKN2B-AS1 in the human genome does not have an equivalent lncRNA in the mouse genome. SIX homeobox 6 Variants located on chromosome 14q23 in the SIX1-SIX6 locus have been associated with POAG and vertical CDR [114, 119, 122, 125, 144, 154, 158–160, 169–171]. Further genetic mapping has narrowed the association to the SIX6 gene. The SIX6 gene encodes for the SIX homeobox 6 protein involved in ocular development. This protein is expressed throughout developing eyes and mutations within its sequence can result in developmental defects such

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as those seen in anopthalmia [172–174]. The variants most strongly associated with POAG and changes in vertical CDR are rs33912345 (H141N) and rs146737847 (Q129K) [1, 175, 176]. The H141N variant associated with POAG has been associated with a decreased retinal nerve fiber layer (RNFL) thickness [175, 177, 178]. RNFL thickness is even further decreased for individuals homozygous for the risk allele [177, 178]. In addition to decreased RNFL thickness, the H141N variant has also been associated with RGC senescence [179]. Furthermore, this SIX6 variant has been shown to upregulate the previously discussed POAG-associated lncRNA CDKN2B-AS1 [1]. Despite its strong association with POAG, the N141 variant has been difficult to study because it is the only allele present in animal models and also the only allele present in certain human populations (i.e., West and South African populations) [1, 156, 180]. The monomorphic nature of this SIX6 allele may in part explain the high prevalence of POAG in populations of African ancestry. ATP-binding cassette subfamily A member 1 Several studies have shown association of ATP-binding cassette subfamily A member 1 (ABCA1) with POAG and its subtypes (i.e., NTG, HTG, and advanced POAG) [119, 120, 126, 127]. This gene encodes a membrane-bound cholesterol transporter that is expressed throughout the eye including RGCs [126, 181, 182]. It has been suggested that ABCA1 variants might contribute to retinal inflammation and loss of RGCs [1]. GDP-mannose 4,6-dehydratase and forkhead box C1 GDP-mannose 4,6-dehydratase (GMDS) and forkhead box C1 (FOXC1) are two neighboring genes on chromosome 6 [1]. Variants within the GMDS/FOXC1 region have been associated with POAG in populations with European ancestry and African ancestry [119, 122, 126]. While variants in the GMDS gene show significant association with both early and advanced stages of POAG, variants in the FOXC1 gene have been associated with both NTG and HTG. Interestingly, mutations in the FOXC1 gene may lead to anterior segment developmental defects and glaucoma [40, 119, 122, 126, 183–185]. Despite their genomic proximity, variants in these two genes appear to contribute to POAG independently [122]. Actin filament-associated protein 1 Actin filament associated protein 1 (AFAP1) gene encodes actin filament-associated protein 1. Several GWAS have shown that variants in the AFAP1 gene are associated with POAG, including advanced POAG [114, 119, 126]. Its association has been replicated in multiethnic populations as well as populations with either European or African ancestry. Expressed in both ocular and nonocular tissues, AFAP1 transduces mechanical stretch signals to activate c-Src protein tyrosine kinase [126, 186]. However, it remains unclear how AFAP1 contributes to the pathogenesis of POAG. Thioredoxin reductase 2 Thioredoxin reductase 2 (TXNRD2) is a mitochondrial protein encoded by the TXNRD2 gene on chromosome 22. Variants in the TXNRD2 gene have been associated with POAG in several populations [114, 119, 122, 187]. TXNRD2 is expressed in the retina and optic nerve head and may decrease oxidative stress in POAG by removing reactive oxygen species [122, 188]. Studies have shown that TXNRD2 can serve as a protective agent for RGCs under

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oxidative stress [189]. It will be necessary to study how TXNRD2 contributes to the increased risk of glaucoma. Ataxin 2 Sequence variants in the Ataxin 2 (ATXN2) gene have been identified to be associated with POAG in populations with European or African ancestry [119, 122]. This chromosome 12 gene is expressed in both anterior (i.e., TM, cornea, and ciliary body) and posterior (i.e., retina and optic nerve) ocular tissues. It functions as an ER and plasma membrane protein involved in mTOR signaling and phagocytosis [122]. In addition to its association with POAG, certain sequence repeat variants in this gene have been identified in human patients with ALS or spinocerebellar ataxia 2, suggesting an overlapping pathogenesis between POAG and neurodegenerative disorders [1, 190].

Endophenotypes Endophenotypes refer to inherited traits that exist in a disease-independent manner although they may be associated with the disease [191]. They usually can be measured quantitatively [1]. Because the traits expressed in POAG can vary widely, endophenotype analysis can identify many genetic variants that contribute to specific POAG traits rather than to POAG as a combined disease status. The most commonly studied POAG endophenotypes are IOP, central corneal thickness (CCT), vertical CDR, and RNFL thickness, which are addressed in the following. Intraocular pressure IOP, the pressure exerted by intraocular fluids on the wall of the eye and measured at the surface of the cornea, is the most prominent risk factor for POAG. As described previously, lowering IOP is the primary target of glaucoma management [1]. Family-based linkage analyses have identified several chromosomal loci (chr5q22, 14q22, and 10q22) that are associated with IOP level [192–194]. Additionally, GWAS have identified many sequence variants associated with IOP, which include variants near or within TMCO1, GAS7, CAV1/CAV2, GLCC11/ ICA1, MVB12B/FAM125B, ARHGEF12, FNDC3B, ABCA1, ABO, ADAMTS8, and chr11p11.2 [1, 57, 120, 144, 146, 195, 196]. Variants in all but ABO and ADAMTS8 genes are also associated with POAG [1]. These identified loci, however, explain only 1.2%–1.5% of heritable IOP variation [120]. Recently, more large-scale GWAS have identified over 120 sequence variants that are associated with IOP, many of which are also associated with POAG [114, 197–199]. It remains unclear how these large number of variants contribute to IOP regulation. As the only glaucoma risk factor able to be treated, IOP and its source of variation warrants more attention. Central cornea thickness Abnormal central cornea thickness (CCT) is another risk factor for POAG that evidences familial inheritance [200–203]. While ocular hypertension may occur in patients with a thicker central cornea, a thinner central cornea has been often associated with risk for POAG in different ethnic populations [204–207]. In addition to being a risk factor for POAG, a thick

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or thin central cornea can skew tonometer readings resulting in underestimated IOP and undiagnosed or misdiagnosed glaucoma. CCT varies with different ethnicity; for example, individuals with African ancestry are more likely to have a thinner central cornea [208, 209]. Many genomic loci containing sequence variants associated with CCT have been identified through GWAS and include ZNF69-BANP, FOXO1, COL5A1, RXRA-COL5A1, AVFR8, AKAP13, COL8A2, WNT7B, WNT10A-USP37, NR3C2, GPR15, TIPARP, LCN12-PTGDS, CWC27-ADAMTS6, GLT8D2, SMAD3, VKORC1L1, COL4A3, FAM46A-IBTK, LPAR1, ARID5B, TBL1XR1-KCNMB2, ARHGAP20-POU2AF1, C7ORF42, MPDZ-NF1B, FGF9-SGCG, TJP1, LRRK1, CHSY1, HS3ST3B1-PMP22, and FNDC3B [210–217]. Additionally, genes related to collagen organization and myosin activity were found by pathway analysis [214]. Similarly to the IOP loci, these loci explain a very small portion of heritable CCT variation [201–203, 214]. There are many questions about the mechanistic relationship between the disease and this risk factor [214]. In addition to associations with loss of visual field and changes in optic nerve topography, thinner CCT has also been correlated with reduced oxygen supply to the anterior chamber angle region [218–227]. This lowered oxygen level could result in damaging oxidative stress to the anterior chamber angle, leading to reduced AH outflow and increased IOP [1, 228]. The theory that CCT contributes to POAG by affecting IOP might also be supported by the fact that the only locus that correlates with both CCT and POAG (FNDC3B) is also associated with IOP. Vertical CDR Another glaucoma related endophenotype is vertical CDR, a diagnostic measurement used to determine the amount of RGC loss by measuring the amount of optic nerve head cupping [1, 229]. Many chromosomal loci have been associated with variation in vertical CDR and its contributing factors, cup area and optic disk area [1]. Of these loci, CDKN2B-AS1, SIX6, ATOH7, CDC7-TGFBR3, and CDKN1A correlate with both vertical CDR factors and POAG [124, 125, 156, 160, 175, 176, 179, 196]. In addition, two lncRNAs known to contribute to retinal degeneration, NEAT1 and MALAT1, are located between two of the identified loci, FRMD8 and SCYL1 [141, 230–232]. However, their association with POAG has not currently been verified. RNFL thickness Closely related to vertical CDR, RNFL thickness is another POAG indicator. Two loci associated with RNFL thickness, DCLK3 and SIX6, have been identified by linkage analysis [233]. Variants in the SIX6 gene have been associated with both RNFL and POAG [1, 177, 178].

POAG pathways Several studies have examined molecular pathways contributing to POAG pathology including those with POAG-associated genes. Some of these pathways relate to cellular stress response such as ER stress response, autophagy, and mitochondrial function [1]. Others relate to metabolism, including the metabolism of lipids, carbohydrates, gamma-aminobutyric acid (GABA), acetyl-CoA, and estrogen [234–237]. Vascular tone pathways have also been

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implicated [238]. Furthermore, identified POAG genes may be involved in multiple pathways or may interact with other POAG genes [101]. Studies have shown that MYOC and CYP1B1, OPTN and TBK1, and SIX6 and CDKN23 interact with one another [62, 63, 76, 77, 86, 179, 239–242]. In addition, several SNPs also evidence interactions: ANF385B and ELMO1, ALX4 and RBFOX1, OPCML and RYR3, ROBO1 and HTR2A, and CTNND2 and NRG3 [243]. All of these relationships between the many genes associated with POAG confer added complexity to this already complex ocular disease.

Conclusion In conclusion, POAG is a complex inherited optic neuropathy leading to irreversible blindness. Although age and high IOP are considered risks for the disease, POAG can also occur at all ages and in individuals with relatively normal or low IOP. Even though POAG develops in individuals from all ethnic populations, certain ethnic populations have a higher propensity for POAG. A multitude of genetic studies have been conducted to identify contributing genetic elements to the disease. These studies have identified many genes and genomic loci associated with POAG, as well as those associated with POAG subtypes and endophenotypes in different populations. Despite this great progress, there is still much to be learned about this complex ocular disease. Improved genetic tools, better animal models, and increased access to human glaucomatous samples will hopefully aid in our understanding of the genetic contributions to POAG.

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