Common and Rare Genetic Risk Factors for Glaucoma Ryan Wang and Janey L. Wiggs Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts 02114 Correspondence: [email protected]The characterization of genes responsible for glaucoma isthe critical first step toward the development of gene-based diagnostic and screening tests, which could identify individuals at risk for disease before irreversible optic nerve damage occurs. Early-onset forms of glau- coma affecting children and young adults are typically inherited as Mendelian autosomal dominant or recessive traits whereas glaucoma affecting older adults has complex inheri- tance. In this report, we present a comprehensive overview of the genes and genomic regions contributing to inherited glaucoma. RATIONALE FOR DISCOVERY OF GENES CONTRIBUTING TO GLAUCOMA T he characterization of genes responsible for glaucoma is the critical first step toward the development of gene-based diagnostic and screening tests, which could identify individuals at risk for disease before irreversible optic nerve damage occurs. Current glaucoma therapies are limited to reducing elevated intraocular pres- sure (IOP), a major risk factor for the disease. The discovery of disease-related genes could provide new insights into the underlying mo- lecular mechanisms responsible for glaucoma that could form the basis of novel gene-based therapies, including strategies for neuroprotec- tion. Understanding the role of the protein product in health and disease will also provide new insights into the underlying molecular mechanisms responsible for disease. Glaucoma can affect individuals of all ages. Early-onset forms of glaucoma affecting chil- dren and young adults are typically inherited as Mendelian autosomal dominant or recessive traits whereas glaucoma affecting older adults has complex inheritance. Early-onset forms of glaucoma are rare whereas adult-onset forms are more common. RARE VARIANTS CAUSING EARLY-ONSET GLAUCOMA WITH AUTOSOMAL DOMINANT OR AUTOSOMAL RECESSIVE INHERITANCE Compared with adult-onset glaucoma, early- onset forms of glaucoma are rare with incidence ranging from 1/2500 to 1/20,000, depending on the condition and the population (Stoilov et al. 1997; Beijani et al. 2000; Chakrabarti et al. 2010). Genetic variants causing early-onset Editors: Eric A. Pierce, Richard H. Masland, and Joan W. Miller Additional Perspectives on Retinal Disorders: Genetic Approachesto Diagnosis and Treatment available at www.perspectivesinmedicine.org Copyright # 2014 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 101101/cshperspect.a017244 Cite this article as Cold Spring Harb Perspect Med 2014;4:a017244 1 www.perspectivesinmedicine.org on July 4, 2020 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/ Downloaded from
Transcript
Common and Rare Genetic Risk Factorsfor Glaucoma
Ryan Wang and Janey L. Wiggs
Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary,Boston, Massachusetts 02114
The characterization of genes responsible for glaucoma is the critical first step toward thedevelopment of gene-based diagnostic and screening tests, which could identify individualsat risk for disease before irreversible optic nerve damage occurs. Early-onset forms of glau-coma affecting children and young adults are typically inherited as Mendelian autosomaldominant or recessive traits whereas glaucoma affecting older adults has complex inheri-tance. In this report, we present a comprehensive overview of the genes and genomic regionscontributing to inherited glaucoma.
RATIONALE FOR DISCOVERY OF GENESCONTRIBUTING TO GLAUCOMA
The characterization of genes responsiblefor glaucoma is the critical first step toward
the development of gene-based diagnostic andscreening tests, which could identify individualsat risk for disease before irreversible optic nervedamage occurs. Current glaucoma therapies arelimited to reducing elevated intraocular pres-sure (IOP), a major risk factor for the disease.The discovery of disease-related genes couldprovide new insights into the underlying mo-lecular mechanisms responsible for glaucomathat could form the basis of novel gene-basedtherapies, including strategies for neuroprotec-tion. Understanding the role of the proteinproduct in health and disease will also providenew insights into the underlying molecularmechanisms responsible for disease.
Glaucoma can affect individuals of all ages.Early-onset forms of glaucoma affecting chil-dren and young adults are typically inheritedas Mendelian autosomal dominant or recessivetraits whereas glaucoma affecting older adultshas complex inheritance. Early-onset forms ofglaucoma are rare whereas adult-onset formsare more common.
RARE VARIANTS CAUSING EARLY-ONSETGLAUCOMA WITH AUTOSOMALDOMINANT OR AUTOSOMAL RECESSIVEINHERITANCE
Compared with adult-onset glaucoma, early-onset forms of glaucoma are rare with incidenceranging from 1/2500 to 1/20,000, dependingon the condition and the population (Stoilovet al. 1997; Beijani et al. 2000; Chakrabarti etal. 2010). Genetic variants causing early-onset
Editors: Eric A. Pierce, Richard H. Masland, and Joan W. Miller
Additional Perspectives on Retinal Disorders: Genetic Approaches to Diagnosis and Treatment available at
www.perspectivesinmedicine.org
Copyright # 2014 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 101101/cshperspect.a017244
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glaucoma are highly penetrant, although var-iable expressivity may be observed. The genescurrently known to cause early-onset glaucomaare listed in Table 1. All of these genes wereinitially identified using genetic linkage analy-ses of large, multigenerational families. Thesegenes are responsible for congenital glaucoma(CYP1B1 and LTBP2), developmental glaucoma(PITX2, FOXC1, PAX6, and LMX1B), juvenile-onset primary open angle glaucoma (MYOC),and familial normal-tension glaucoma (OPTNand TBK1).
Congenital Glaucoma
Congenital glaucoma (or infantile glaucoma)typically develops before three years of age(Aponte et al. 2010). The condition is primari-ly inherited as an autosomal recessive trait, al-though autosomal dominant families have beendescribed (Sarfarazi et al. 2000). Genetic link-age studies have identified three loci likely tocontain genes contributing to congenital glau-coma: GLC3A (2p21), GLC3B (1p36), andGLC3C (14q22) (Safarazi et al. 1995; Akarsu etal. 1996; Stoilov and Sarfarazi 2002). Two geneshave been discovered: CYP1B1, encoding cyto-chrome P450 1B1 (GLC3A), and LTBP2 (latenttransforming growth factor binding protein 2)(Ali et al. 2009; Beijani et al. 2000). Mutationsin both CYP1B1 and LTBP2 cause autosomalrecessive disease.
CYP1B1 mutations are the most commoncause of congenital glaucoma worldwide (Stoi-
lov et al. 1997). Disease-causing mutations in-clude missense mutations, nonsense mutations,frameshifts, and large-gene deletions (Stoilovet al. 1997; Sarfarazi 2000; Michels-Rauten-strauss et al. 2001). Although these mutationsare highly penetrant, variable expressivity is awell-known feature of CYP1B1-related disease.Genotype–phenotype studies have suggestedthat mutations causing premature truncationof the protein (frameshifts, deletions, inser-tions, and nonsense mutations) cause more se-vere disease with earlier onset than diseasecaused by missense mutations. The gene prod-uct, cytochrome P450 1B1, metabolizes com-plex molecules such as polycyclic aromatic hy-drocarbons and 17b-estradiol (Tokizane et al.2005; Tsuchiya et al. 2005; Sowers et al. 2006).The role of the protein in congenital glaucomais not clear; however, it has been hypothesizedthat cytochrome P450 1B1 activity is responsi-ble for metabolism of compounds involved inocular development (Choudhary et al. 2008;Choudhary et al. 2009).
LTBP2 (Latent transforming growth factor,TGF, b-binding protein 2) was initially identi-fied as the causative gene in patients with early-onset glaucoma from Pakistan and in patients ofGypsy ethnicity (Ali et al. 2009; Narooie-Nejadet al. 2009). The gene is located 1.3 Mb from theGLC3C locus on 14q22; however, LTBP2 muta-tions have not been identified in the family ini-tially used to define the GLC3C locus, suggest-ing that a second congenital glaucoma gene islocated in this region (Sharafieh et al. 2013).
Table 1. Genes responsible for early-onset glaucoma
The LTBP2 protein is located in the extracellu-lar matrix, where it associates with micofibrilscontaining fibrillin-1 (Jelodari-Mamaghani etal. 2013). Interestingly, LTBP2 mutations havebeen associated with Weill-Marchesani andWeill-Marchesani-like syndrome, a conditioncharacterized by microspherophakia and ab-normal ocular anterior segment development(Haji-Seyed-Javadi et al. 2012). LTBP2 appearsto be a rare cause of congenital glaucoma inethnically diverse populations, such as in theUnited States (Lim et al. 2012).
Developmental Glaucoma
Abnormal development of the anterior seg-ment can lead to dysgenesis of critical ante-rior segment structures involved in glaucoma,including the trabecular outflow pathways andSchlemn’s canal. Developmental glaucoma maybe syndromic (Axenfeld-Rieger syndrome andaniridia) or limited to only ocular involvement.Some patients with anterior segment dysgenesisnever develop glaucoma, whereas others havevery severe disease evident at birth (Gould andJohn 2002). Four genes coding for proteins in-volved in regulation of gene expression can con-tribute to developmental glaucoma (PITX2,FOXC1, PAX6, and LMX1B). Mutations in thesegenes cause autosomal dominant disease withhigh penetrance but variable expressivity bothwithin and among affected families. The phe-notypic features of disease caused by thesegenes, as well as those caused by CYP1B1 andLTBP2, are similar, making it impossible to es-tablish the genetic diagnosis through clinicalexamination alone (Fig. 1). Genetic testing canestablish a molecular diagnosis as well as clarifythe inheritance information necessary for accu-rate genetic counseling.
PITX2 and LMX1B cause syndromic formsof developmental glaucoma (Rieger syndromeand Nail-Patella syndrome, respectively). Ap-proximately 50% of patients with PITX2 muta-tions develop glaucoma (Reis et al. 2012). Re-cently, mutations involving a genomic regiondistal to PITX2 have been identified as diseasecausing (Volkmann et al. 2011). Patients withLMX1B mutations are affected by Nail-Patella
syndrome, which can involve the eye, causing avariety of glaucoma-related features (Chen et al.1998; Dreyer et al. 1998; Mimiwati et al. 2006).Mutations in PAX6 cause abnormal develop-ment of stem cells in the iris and corneal limbus,resulting in a broad range of clinical features,from agenesis of the iris to corneal opacificationcaused by a deficiency of limbal stem cells (Hin-gorani et al. 2009). FOXC1 was initially iden-tified as a gene responsible for iris hypoplasia(Mears et al. 1998). Subsequent studies haveidentified cardiac abnormalities and possiblyother systemic features in patients with muta-tions in these genes (Gould et al. 1997; Swider-ski et al. 1999; Winnier et al. 1999).
Juvenile-Onset Primary Open-AngleGlaucoma
Patients affected by open-angle glaucoma havedisease despite normal anatomic structures.
Adult-onset primary open-angle glaucoma(POAG) develops after 50 years of age, whereasjuvenile-onset (orearly-onset) open-angle glau-
Figure 1. Anterior segment phenotypes in patientswith developmental glaucoma. Anterior segmentphotographs taken with a camera attached to a slit-lamp are shown for four patients with mutationsin genes associated with early-onset glaucoma. No-table features are peripheral corneal opacification(CYP1B1), irido-corneal adhesions (PITX2) andiris atrophy (FOXC1). In the patients with FOXC1mutations the atrophic iris makes it possible to seethe pupillary sphincter muscle, which is normally notvisible because of overlying iris stroma.
Common and Rare Genetic Risk Factors for Glaucoma
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coma affects children and young adults, withonset typically between the ages of 3 and 20. Ju-venile open-angle glaucoma is inherited asan autosomal dominant trait (Wiggs et al.1998) and is characterized by very high IOP(Wiggs et al. 1995; Johnson et al. 1996). Linkagestudies using large families have identified anumber of juvenile open-angle glaucoma loci:GLC1A (1q24.3-q25.2) (Sheffield et al. 1993),GLC1J (9q22) (Wiggs et al. 2004), GLC1K(20p12) (Wiggs et al. 2004), GLC1M (5q22.1-q32) (Wang et al. 2004; Pang et al. 2006; Fanet al. 2007), and GLC1N (15q22-q24) (Wanget al. 2006). Among these loci only one gene,MYOC, coding for myocilin, has been identi-fied (Kubota et al. 1997; Stone et al. 1997). Mis-sense changes in the protein account for 10% ofthe cases of juvenile open-angle glaucoma andalso 3%–5% of the cases of adult-onset POAG(Wiggs et al. 1998; Fingert et al. 1999). Disease-causing mutations are primarily located in theprotein’s olfactomedin domain (Fig. 2) (Adamet al. 1997; Stone et al. 1997; Fingert et al. 1999).Myocilin is an extracellular protein of unknown
function, and loss of the protein function doesnot result in glaucoma (Wiggs and Vollrath2001; Kim et al. 2001), suggesting that the un-derlying genetic mechanism is likely to be again-of-function or dominant-negative effect.Additionally, a common nonsense variant locat-ed in exon 1 (Fig. 2) is a benign polymorphismand does not cause glaucoma or any other phe-notype (Lam et al. 2000). Disease-causing mu-tations reduce the solubility of the protein, lead-ing to protein misfolding and subsequentprotein aggregation in the endoplasmic reticu-lum (Aroca-Aguilar et al. 2010). The misfoldedprotein response may lead to a loss of trabecularmeshwork cells, resulting in high IOP (Joe et al.2003). Interestingly, limiting protein aggrega-tion using the small molecule phenyl butyrate(PBA) causes reduction in IOP both in vitro andin vivo, possibly pointing to novel gene-basedtherapy for patients with myocilin mutations(Yam et al. 2007; Zode et al. 2011, 2012). Recent-ly, common variants in genes coding for multi-plexin collagens XVand XVIII have been shownto modify the severity of myocilin-related glau-
Lys423Glu
Val426Phe
Tyr437His
IIe477Asn
Asn480Lys
Ser502Pro
Pro370Leu
Gly364Val
Glu323Lys
Gly246Arg
Thr293Lys
GLN368X
Thr377Met
Ala445Val
2011 202 243 244 504Olf
LZ
Arg46X
Figure 2. MYOC mutations causing glaucoma. The gene location of selected MYOC mutations known to causeglaucoma are shown. Exon 1 extends from codon 1–201, exon 2 from codon 202–243, and exon 3 from codon244–504. Exon 1 contains a leucine zipper (LZ) and exon 3 contains the Olfactomedin domain (Olf ). Mutationscausing early-onset glaucoma are shown in blue, adult-onset glaucoma in red, and a nonsense mutation knownto be a benign polymorphism in green.
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coma, suggesting that myocilin may interactwith these protein in the extracellular matrixand/or in maintaining the integrity of the tra-becular outflow pathways (Liton et al. 2005;Wiggs et al. 2013b).
Familial Normal-Tension Glaucoma
Normal-tension glaucoma (NTG) is a type ofopen-angle glaucoma characterized by opticnerve degeneration despite normal IOP. MostNTG patients have adult-onset disease; how-ever, rarely, the disease can have early onsetwith autosomal dominant inheritance. Twogenes have been associated with familial NTG:OPTN and TBK1 (Rezaie et al. 2002; Mortonet al. 2008; Fingert et al. 2011).
Rare missense mutations in OPTN, whichencodes optineurin and particularly the E50Kmutation, cause a severe early-onset familialform of NTG. (Aung et al. 2005; Morton et al.2008). Optineurin is involved in basic cellularfunctions including protein trafficking, main-tenance of the Golgi apparatus, as well as theNF-kB pathway, antiviral responses, and anti-bacterial signaling (Ying 2012). Of interest, op-tineurin interacts with Tank1 (TBK1), whichhas also been implicated in familial NTG (Mor-ton et al. 2008). The optineurin E50K mutationcauses the protein to become inactive and/orinsoluble (Minegeshi et al. 2013). This muta-tion also enhances the interaction of optineurinwith Tank1 (Fingert et al. 2011).
COMMON VARIANTS CONTRIBUTINGTO ADULT-ONSET GLAUCOMA WITHCOMPLEX INHERITANCE
POAG, adult-onset NTG, pseudoexfoliationglaucoma, and primary angle-closure glaucomaare common traits with complex inheritance.Genetic variants contributing to these condi-tions have been identified using genome-wideassociation approaches (Thorleifsson et al.2007, 2010; Burdon et al. 2011; Vithana et al.2012; Wiggs et al. 2012, 2013a). Generally, vari-ants contributing to common complex traitssuch as adult-onset glaucoma have small indi-vidual effects on disease development. Aggregat-ed effects from multiple risk factors, includingenvironmental risk factors, can have a larger im-pact. Robust genetic associations have been ob-served for POAG (CDKN2BAS [Burdon et al.2011; Wiggs et al. 2012], SIX1/SIX6 [Wiggset al. 2012], CAV1/CAV2 [Thorliefsson et al.2010; Wiggs et al. 2011], TMCO1 [Burdonet al. 2011]), NTG (CDKN2BAS [Wiggs et al.2012] and a regulatory region on 8q22 [Wiggset al. 2012]), pseudoexfoliation (LOXL1 [Thor-leifsson et al. 2007]), and primary angle-closureglaucoma (PLEKHA7 and COL11A1 [Vithanaet al. 2012]) (Table 2). Additionally, genetic var-iants associated with quantitative ocular traitsthat are risk factors for common forms of glau-coma have also been identified. These includeIOP (van Koolwijk et al. 2012), central cornealthickness (CCT) (Vithana et al. 2011; Lu et al.2013), and optic nerve parameters including
Table 2. Genes/loci contributing to adult-onset glaucoma
Gene Disease Function Reference(s)
CDKN2BAS POAG, NTG Cell cycle regulation, TGF-b signaling Burdon et al. 2011;Wiggs et al. 2012
TMCO1 POAG Unknown Burdon et al. 2011SIX1/SIX6 POAG Optic nerve development Fan et al. 2011; Ramdas
et al. 20118q22
enhancerNTG Regulation of fluid production in
ciliary body and choroid plexusWiggs et al. 2012
CAV1/CAV2 POAG Endothelial membranes Thorleifsson et al. 2010LOXL1 Pseudoexfoliation Elastinogenesis and maintenance Thorleifsson et al. 2007PLEKHA7 Angle-closure glaucoma Adherens junction protein Vithana et al. 2012COL11A1 Angle-closure glaucoma Sclera development Vithana et al. 2012
Common and Rare Genetic Risk Factors for Glaucoma
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cup-to-disc ratio and optic nerve area (Ramdaset al. 2010; Macgregor et al. 2010; Axenovichet al. 2011) (Table 3).
The clinical features of POAG generally in-clude both elevated IOP and optic nerve degen-eration. Patients with optic nerve disease with-out elevation of IOP are referred to as the NTGsubgroup. Large genome-wide association stud-ies (GWAS) have been completed for POAGin the Icelandic population (Thorleifsson etal. 2010), Australian population (Burdon et al.2011), and in the United States (Wiggs et al.2012). The Icelandic study identified a signif-icant association between genetic variants lo-cated in the CAV1/CAV2 genomic region andPOAG. This finding has been replicated in acase-control sample from the US (Wiggs et al.2011) and recently, CAV1/CAV2 variants havebeen shown to be preferentially associated withpatients who have loss of the central visual fieldearly in the disease (Loomis et al. 2014). Both theAustralian and the US studies identified sig-nificant associations with CDKN2BAS, a longnoncoding antisense RNA that inhibits the ex-pression of CDKN2B, an inhibitor of CDK4, aprotein involved in promoting cell division(Burdon et al. 2011; Wiggs et al. 2012). The Aus-tralian study showed significant association withvariants in the TMCO1 genomic region, a genethat also appears to be associated with elevatedIOP (see below). The US study identified sig-nificant association with variants in the SIX1/SIX6 genomic region; these are also associatedwith the cup-to disc ratio, a quantitative opticnerve parameter (Ramdas et al. 2010; Wiggset al. 2012).
NTG
Optic nerve degeneration without IOP eleva-tion (,21 mmHg) is the defining clinical fea-ture of NTG. Identifying the genetic factorsthat contribute to this condition could provideimportant insights into neuroprotective ther-apies for glaucoma. An analysis of the NTGsubgroup in a large genome-wide associationstudy of POAG using a United States case-con-trol sample identified common variants in theCDKN2BAS region and a novel regulatory re-gion on chromosome 8q22 as significant riskfactors (Wiggs et al. 2012). The 8q22 region isa DNaseI hypersensitivity site that has high ac-tivity in the choroid plexus, which is responsiblefor the production of cerebrospinal fluid, andthe ciliary body, which is responsible for theproduction of aqueous humor. Interestingly, re-cent hypotheses suggest that the translaminarpressure across the lamina cribrosa may be arisk factor for optic nerve damage, and this pres-sure gradient is defined by the difference be-tween the IOP and cerebrospinal fluid pressure(Jonas and Wang 2013).
Pseudoexfoliation Syndrome
Pseudoexfoliation syndrome is a generalizeddisorder of extracellular matrix that results ina chronic deposition of fibrillar aggregatesthroughout the ocular anterior segment. Accu-mulation of the fibrillar material in the trabec-ular meshwork is thought to contribute to thedevelopment of glaucoma associated with thiscondition (Schlotzer-Schrehardt et al. 1995;
Table 3. Selected genes/loci contributing to quantitative ocular traits related to glaucoma
Gene Trait Function Reference(s)
CDKN2BAS Cup-to-disc-ratio Cell cyle regulation, TGF-b signaling Fan et al. 2011; Ramdas et al. 2011SIX1/SIX6 Cup-to-disc-ratio Developmental protein Fan et al. 2011ATOH7 Optic nerve area Developmental protein Macgregor et al. 2010TMCO1 IOP Unknown function van Koolwijk et al. 2012GAS7 IOP Unknown function van Koolwijk et al. 2012ZNF469 CCT Regulates expression of extracellular
matrix componentsAbu et al. 2008
COL5A1 CCT Extracellular matrix Lu et al. 2013COL8A2 CCT Extracellular matrix Vithana et al. 2011
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Naumann et al. 1998). A genome-wide associ-ation study conducted in the Icelandic popula-tion first identified common variants in theLOXL1 gene as significant risk factors (Thor-leifsson et al. 2007). Subsequently, associationbetween LOXL1 gene variants and pseudoex-foliation has been replicated in populationsworldwide (Fan et al. 2011). LOXL1 (lysyl-oxi-dale like 1) is necessary for formation and main-tenance of elastin. It is not yet known howLOXL1 variants influence development of pseu-doexfoliation; however, recent evidence sug-gests that the variants associated with diseasecause a decrease in gene expression, possiblyresulting in reduced enzyme activity (Schlot-zer-Schrehardt 2009). The LOXL1 risk allelesare very common in pseudoexfoliation cases(95%–99%) but are also common in the nor-mal population (60%–80%) suggesting thatthe gene variants are necessary but not sufficientfor disease development (Fan et al. 2011). Re-cently, residence in northern latitudes has beenidentified as an environmental risk factor forthis condition (Stein et al. 2011; Kang et al.2012).
Primary Angle-Closure Glaucoma
Primary angle-closure glaucoma is commonin Asian countries. A recent genome-wide as-sociation study using five independent Asiancase-control samples identified three genomicregions statistically associated with POAG:rs3753841 (COL11A1), rs1015213 (located be-tween PCMTD1 and ST18), and rs11024102(PLEKHA7) (Vithana et al. 2012). All of thesesingle-nucleotide polymorphisms were alsoreplicated in a combined Australian-Nepalesecase-control sample (Awadalla et al. 2013).COL11A1 is expressed in the sclera, and muta-tions in COL11A1 are known to cause Stickler’ssyndrome, a condition that includes myopia,among other ocular features (Richards et al.1996). As primary angle-closure glaucoma canbe related to hyperopia, the genome-wide as-sociation study results may point to a role forCOL111A1 in development of refractive errors,possibly because of abnormal scleral develop-ment.
Quantitative Ocular Traits that Are RiskFactors for Glaucoma
For traits with complex inheritance, it can beuseful to identify genetic factors influencingthe underlying individual traits, such as IOP,optic nerve parameters, and CCT, that contrib-ute to the overall disease (Charlesworth et al.2010). These traits are quantitative, highly her-itable, and show substantial variation in humanpopulations. IOP is the only modifiable riskfactor for glaucoma. Recent genome-wide anal-yses using normal populations have identifiedtwo genes significantly associated with IOP,GAS7 and TMCO1 (van Koolwijk et al. 2012).Similar analyses for optic nerve parameters as-sociated with glaucoma risk have identifiedCDKN2BAS and SIX1SIX6 as genetic risk fac-tors contributing to cup-to-disc-ratio (Ramdaset al. 2010; Fan et al. 2011) and ATOH7 as animportant determinant of optic nerve size(Macgregor et al. 2010). Populations fromaround the world have been used to identifygenetic factors contributing to CCT, one ofthe most heritable of the quantitative oculartraits (Toh et al. 2005). A recent study fromthe International Glaucoma Genetics Consor-tium (IGGC) identified 16 loci significantly as-sociated with CCT (Fig. 3) (Lu et al. 2013).Pathway analyses suggested that collagen andextracellular matrix pathways are importantregulators of CCT (Lu et al. 2013).
COMPLEX INTERACTIONS: GENE–ENVIRONMENT, GENE–GENEINTERACTIONS, AND EPIGENETICEFFECTS
Complex genetic and gene–environment inter-actions are expected to contribute to the geneticarchitecture of common adult-onset disorders.Nutritional factors, such as dietary fat, antiox-idant intake, and other lifestyle factors includ-ing smoking and postmenopausal hormone usemay influence the development of POAG (Pas-quale and Kang 2009). A gene–environmentinteraction involving hormone replacementtherapy and NOS3 (the gene coding for nitricoxide synthase 3) has been identified as a risk
Common and Rare Genetic Risk Factors for Glaucoma
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factor for POAG (Kang et al. 2010). The estro-gen metabolism pathway is also associated withPOAG in women (Pasquale et al. 2013). Gene–gene interactions contributing to POAG havebeen suggested for WDR36 and p53 (both influ-encing apoptosis) (Blanco-Marchite et al. 2011)and for genetic variants in ATOH7 and SIX1/SIX6 (Fan et al. 2011).
BIOLOGICAL PATHWAYS AND PROCESSESSUGGESTED BY GENETIC VARIANTSCONTRIBUTING TO GLAUCOMA
Genome-wide association studies have identi-fied multiple genes potentially involved in glau-coma pathogenesis; however, the stringent cor-rection for multiple testing and type I erroridentifies only variants with the largest maineffects as statistically significant (Manolio et al.
2008). Many biologically meaningful associa-tions of smaller effect size may go undetected;including variants with smaller effect size in sys-tematic groups could reveal novel biologicalpathways or systems underlying disease sus-ceptibility. Pathway-based analysis groups genevariants into biologically meaningful entities todistinguish the actual from the false-positiveassociations. In short, this type of analysis canbe used to uncoveradditional genotype–pheno-type associations that the single-allele genome-wide association analysis may have missed.Hypothesis-independent pathway analyses sug-gest that the underlying molecular pathogene-sis of POAG involves a broad range of biologi-cal processes, including cell adhesion, immuneresponsiveness, energy metabolism, and neuro-transmission (Cooke Bailey et al. 2013). Identi-fication of genes contributing to both early-on-
DCLK1
Optic nerveparameters
NTGPOAG
IOP
CCT
SKYL1/LTBP3
CDC7/TGFBR3
SIX1/SIX6
CAV1/CAV2
FNDC3B
COL8A2 CHSY1HS3ST3B1/PMP22
ZNF469RXRA/COL5A1
FGF9/SGCGLCN12/PTGDS
CWC27/ADAMTS6TGP1 GPR15 FOXO1LRRK1 USP37 AKAP13
TMCO1
GAS7
8q22CDKN2BAS
SALL1 CHEK2
ATOH7
Figure 3. Gene and genomic regions with common variants that contribute to glaucoma and glaucoma-relatedocular quantitative traits. Variants contributing to both primary open-angle glaucoma and normal tensionglaucoma as well as selected ocular quantitative traits (CCT, IOP, and optic nerve parameters) are shown. Genenames are presented in dark font. Genes contributing to POAG are contained in the orange ellipse, NTG in thepurple ellipse, CCT in the blue ellipse, IOP in the red ellipse, and optic nerve parameters in the green ellipse.Genes that contribute to more than one trait are indicated by their placement in the overlapping regions. Forexample, CDKN2BAS contributes to NTG, POAG, and to optic nerve parameters.
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set and adult-onset forms of glaucoma are alsohighlighting biological pathways and processesof importance to glaucoma pathogenesis. Sev-eral of these are discussed below.
Extracellular Matrix Metabolism
Maintenance of extracellular matrix is emergingas an important theme in glaucoma pathogen-esis (Acott et al. 2008; Crawford Downs et al.2011). Several of the genes contributing to ear-ly-onset glaucoma (MYOC, LTBP2, COL18A1)and adult-onset glaucoma (LOXL1) have im-portant roles in extracellular matrix (Ueda etal. 2002; Ali et al. 2009; Sethi et al. 2011; Wiggset al. 2013b), and three important genes relatedto CCT impact extracellular matrix (Lu et al.2013). Further investigation of genes shown tocontribute to extracellular processes in oculartissues relevant to glaucoma could be of interest.
Transforming Growth Factor b (TGF-b)Signaling
TGF-b I and TGF-b II appear to have importantroles in optic nerve degeneration (Zode et al.2009; Fuchshofer 2011) as well as trabecularmeshwork function (Sethi et al. 2011; Fuch-shofer 2012). LTPB2 (associated with congenitalglaucoma and anterior segment dysgenesis) andCDKN2BAS (associated with POAG, NTG) arepart of the overall TGF-b signaling pathway.Additionally, NTG pathway analysis showed sig-nificant association with the TGF-b signalingpathway overall (Wiggs et al. 2012).
Tumor Necrosis Factor a (TNF-a) Signaling
Both genes contributing to familial NTG(OPTN, TBK1) can impact TNF-a signaling(Fingert et al. 2011). Blocking of the TNF-areceptor in an animal model of glaucoma ap-pears to be neuroprotective (Roh et al. 2012).These results suggest that TNF-a signaling canhave an important role in ganglion cell apopto-sis in glaucoma. Higher levels of soluble TNF-ahave been identified in women before the devel-opment of NTG (Kang et al. 2013), a findingconsistent with this hypothesis.
Estrogen Metabolism
The hormone 17b-estradiol can regulate ex-pression of both CAV1 and NOS3 (both associ-ated with POAG), and loss of caveolin-1 func-tion can cause increased expression of NOS3(Zhou et al. 2009; Sud et al. 2010), suggestingan interaction between these proteins. Addi-tionally, P450 1B1 (CYP1B1, associated withcongenital glaucoma) is an important factorin estrogen metabolism (Hanna et al. 2000).Gender effects in glaucoma have also been sug-gested by studies showing that estrogen recep-tors are expressed on the retinal ganglion cells ofthe optic nerve (Munaut et al. 2001), and thatestrogen may have a neuroprotective effect inanimal models of glaucoma (Zhou et al. 2007;Russo et al. 2008). Further studies examininggender effects in POAG, and gender interactionswith genes contributing to this disorder will beof interest.
CONCLUDING REMARKS
Genes responsible for both early-onset andadult-onset glaucoma have been identified us-ing genetic and genomic technologies and ap-proaches. Family-based genetic linkage analyseshave yielded disease-causing genes for early-onset glaucoma, whereas genome-wide asso-ciation studies have identified genes and geno-mic regions contributing to adult-onset formsof the disease. Biological pathways contribut-ing to glaucoma and other complex interac-tions (gene–gene and gene–environment) areemerging. Future directions for new gene dis-covery include whole exome sequencing andother next generation sequencing technologies,genome-wide association studies using largernumbers of cases and controls and includingrare variant analyses, and further evaluation ofthe contributions of biological pathways, gene–gene and gene–environment interactions.
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Common and Rare Genetic Risk Factors for Glaucoma
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