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Developments in Ocular Genetics: 2013 Annual Review

Aboobakar, Inas F. BS, DUMSIII; Allingham, R. Rand MD

The Asia-Pacific Journal of Ophthalmology: May/June 2014 - Volume 3 - Issue 3 - p 181–193
doi: 10.1097/APO.0000000000000063
Annual Review
Editor's Choice

Purpose To highlight major advancements in ocular genetics from the year 2013.

Design Literature review.

Methods A literature search was conducted on PubMed to identify articles pertaining to genetic influences on human eye diseases. This review focuses on articles published in print or online in the English language between January 1, 2013, and December 31, 2013. A total of 120 articles from 2013 were included in this review.

Results Significant progress has been made in our understanding of the genetic basis of a broad group of ocular disorders, including glaucoma, age-related macular degeneration, cataract, diabetic retinopathy, keratoconus, Fuchs endothelial dystrophy, and refractive error.

Conclusions The latest next-generation sequencing technologies have become extremely effective tools for identifying gene mutations associated with ocular disease. These technological advancements have also paved the way for utilization of genetic information in clinical practice, including disease diagnosis, prediction of treatment response, and molecular interventions guided by gene-based knowledge.

From the Department of Ophthalmology, Duke University Medical Center, Durham, NC.

Received for publication April 28, 2014; accepted May 21, 2014.

The authors have no funding or conflicts of interest to declare.

Reprints: R. Rand Allingham, MD, Duke University Eye Center, 2351 Erwin Rd, Box 3802, Durham, NC 27710. E-mail:

Vision loss is an important health problem worldwide, affecting an estimated 285 million people.1 In the United States alone, a recent estimate of the direct and indirect costs associated with major adult visual disorders is $35.4 billion.2 Development of improved diagnostic and therapeutic measures is essential for reducing the burden of common, potentially blinding disorders that are increasing in prevalence as global populations age.

Genetic factors play a significant role in all common ocular diseases, including glaucoma, age-related macular degeneration (AMD), cataract, diabetic retinopathy (DR), and refractive error. In recent years, there has been a dramatic increase in gene discovery for ocular diseases, driven by large-scale genome-wide association studies (GWASs), powerful meta-analyses, and next-generation sequencing technologies (eg, whole-exome sequencing). Gene discovery has also fueled translational research geared toward development of gene-based screening tests and targeted gene therapies.

The speed and volume of information in the field of ocular genetics are so great that a full catalog is beyond the scope of this review. Rather, we have highlighted the discoveries with greatest potential for impact on the field. This review includes articles published in the English language between January 1, 2013, and December 31, 2013. The search was conducted on PubMed using the terms “eye” and “gene,” which returned approximately 2050 articles. Publications were considered if they described research on the role of genetic variation in human eye disease or traits. We have summarized the findings of approximately 120 of the articles that best represented areas of substantial progress in the field of ocular genetics. Several additional publications were included to provide context to current or recent discoveries. Publications have been grouped by disease for ease of reference (Tables 1 and 2).





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Overview of Current Genetic Technologies

Technological advancements have been crucial for the rapid progress made in the field of ocular genetics in the past several years. Important technologies that are heavily utilized include GWASs, whole-exome sequencing, and epigenetic studies.

Genome-wide association studies involve genotyping of common single-nucleotide polymorphisms (SNPs) in diseased individuals and control subjects. The allele frequencies for these SNPs are compared between the 2 groups to determine if a given SNP is strongly associated with the disease or trait of interest. An important limitation of GWASs is the fact that they can only identify common variants associated with disease risk, not rare variants.3 Moreover, GWASs provide only the genomic location of genetic variants and no information about disease mechanism. Elucidation of the functional effects of identified variants remains an important challenge.

Whole-exome sequencing uses next-generation sequencing technologies to identify variants in protein-coding regions, or exons, of known genes. It enables researchers to screen thousands of loci simultaneously and can be used for the study of both monogenic (Mendelian) diseases and complex inherited disorders.4 Moreover, it is suitable for identification of both rare and common variants.4 However, it cannot be used for the study of noncoding, intronic variants. As the cost of next-generation sequencing continues to decline, use of whole-genome sequencing may be a viable alternative and would enable identification of intronic variants.

Epigenetics is the study of heritable modifications in gene expression that do not involve changes in the underlying DNA sequence. These modifications include DNA methylation and histone modifications. Environmental exposures and diet can alter epigenetic imprinting, which offers a mechanistic link between environmental risk factors and disease development.5 Methods such as chromatin immunoprecipitation and treatment of genomic DNA with sodium bisulfite have enabled in vitro studies of epigenetic imprinting.

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Age-Related Cataract

Age-related cataract (ARC) results from clouding of the lens and remains the dominant cause of visual impairment and blindness in the world.6 It is a complex and multifactorial disorder, with both environmental and genetic components. Genetic factors account for approximately 50% of the variation in clinical severity for nuclear cataracts.7 Genes that have previously been implicated in the pathogenesis of ARC include PITX3, MAF, and KLC1.7

Given that DNA damage and oxidative stress play critical roles in the pathogenesis of ARC, variants in 4 DNA repair genes (BLM, WRN, ERCC6, and OGG1) were explored for possible association with ARC in the Han Chinese population.8 Single-nucleotide polymorphisms in the WRN gene were strongly associated with risk for cataract in this study. Polymorphisms in the glutathione-S-transferase omega 1 and 2 genes, which help protect lens cells from oxidative damage, were also examined for association with ARC.9 Single-nucleotide polymorphism rs156697 (Asn142Asp) in the GSTO2 gene increased risk for ARC in smokers and in individuals with work-related exposure to UV irradiation. A variant in an HSP70 gene (HSPA1B-1267 A/A polymorphism), which acts in cell stress responses, was recently shown to have a protective role against ARC development.10 The role of copy number variants (CNVs) of DNA repair genes has also been studied in the Han Chinese population.11 Copy number variants in heat shock factor protein 4 were significantly associated with ARC risk in this population.

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Age-Related Macular Degeneration

Age-related macular degeneration leads to loss of central vision as a result of photoreceptor cell death. It is the leading cause of vision loss among individuals older than 65 years in developed nations.12 There are 2 forms of the disease: (1) nonneovascular (NNVAMD), characterized by accumulation of drusen, thinning of the macula, and geographic atrophy, and (2) neovascular (NVAMD), characterized by abnormal choroidal blood vessel growth. Risk factors for AMD include age, white race, family history, female gender, smoking, and hypertension.13 Genes that are associated with AMD risk include CFH, C3, C2-CFB, CFI, HTRA1/LOC387715/ARMS2, CETP, TIMP3, LIPC, VEGFA, COL10A1, TNFRSF10A, and APOE.13 However, the functional role of genetic variants in disease pathogenesis remains poorly characterized.

Given that most SNPs associated with AMD risk are common variants, the role of rare variants in this disease was recently explored. One study identified rare missense variants in the CFI, C3, and C9 genes that were strongly associated with advanced AMD.14 The risk allele for the rare variant in C3 (Gln155) resulted in resistance to proteolytic inactivation by CFH and CFI, suggesting that this variant may have a functional role in excessive complement activation. A rare, highly penetrant missense variant (p.Gly119Arg) in the CFI gene may also play a functional role in AMD pathogenesis.15 Compared with the Gly119 wild-type protein, the Arg119 mutant protein is expressed and secreted at decreased levels. Moreover, the mutant protein is less effective at mediating degradation of C3b when compared with the wild-type protein. Functional studies in zebrafish found that the Arg119 mutant caused smaller average hyaloid vessel diameter compared with the wild type, confirming the functional nature of this gene variant.

Additional genetic loci associated with AMD have also been described. For instance, a GWAS in individuals of European and Asian ancestry identified 7 novel loci associated with advanced AMD (COL8A1-FILIP1L, IER3-DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9, and B3GALTL).12 These genes are involved in regulation of complement activity, lipid metabolism, extracellular matrix remodeling, and angiogenesis, all of which are believed to play a role in AMD pathogenesis.12

Interestingly, genetic variants affect AMD treatment response. For instance, variants in VEGFA, HTRA1, and LOC387715/ARMS2 were found to influence visual outcome in patients receiving anti–vascular endothelial growth factor (VEGF) injections for NVAMD.16–18 Moreover, CFH and ARMS2 variants influence response to zinc and antioxidant treatment for NNVAMD.19 Patients with ARMS2 risk alleles may benefit most from zinc-only supplementation, whereas patients with CFH risk alleles may benefit most from antioxidant-only supplementation. In another study, patients with risk alleles for both the CFH rs1061170 and ARMS2 rs10490924 polymorphisms were found to benefit from dietary antioxidant and fish consumption, whereas individuals who had low genetic risk (one or no risk alleles) did not benefit.20 The low-density lipoprotein cholesterol–lowering medication simvastatin has also been shown to slow progression of NNVAMD, especially in those homozygous for the risk allele (CC) for the CFH rs1061170 (Y402H) variant.21

Two studies recently examined the role of epigenetic factors in AMD pathogenesis and reported conflicting findings. In one study, decreased methylation of the IL17RC promoter was found in AMD patients, with accompanying elevation of IL17RC mRNA and protein levels in peripheral blood, retina, and choroid.22 However, a replication study found no evidence of IL17RC hypomethylation in AMD patients, highlighting the need for replication of epigenetic association studies prior to clinical application.23

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Central Corneal Thickness

There is strong evidence of a role for central corneal thickness (CCT) in ocular diseases. For instance, a thinner CCT is a risk factor for primary open angle glaucoma (POAG) and is also associated with keratoconus (KC) and brittle cornea syndrome.24 Increasingly powerful GWASs have identified multiple loci associated with CCT in both white and Asian populations. These include AKAP13, COL5A1, RXRA-COL5A1, COL8A2, FAM53B, FOXO1, IBTK, LRRK1, and ZNF469.24

Studies published this past year identified several additional loci associated with CCT. For instance, the RPN2 gene was found to be associated with CCT in a GWAS designed to identify novel loci for POAG and AMD.25 In addition, a meta-analysis of approximately 20,000 individuals of European and Asian descent identified 16 novel loci associated with CCT.26 Pathway analysis revealed that these CCT-associated loci cluster in collagen and extracellular matrix pathways. To determine whether these loci confer susceptibility to ocular diseases, 26 SNPs were tested in case-control data sets for glaucoma and KC.26 The FOXO1 and FNDC3B loci were both significantly associated with KC. The FNDC3B locus, which is involved in adipogenesis, was also associated with POAG.

To look for possible ethnic differences in genetic factors associated with CCT, a GWAS was also recently conducted in a Latino population.24 The study replicated involvement of the previously identified RXRA-COL5A1, FOXO1, and ZNF649 loci in Latinos. In addition, 4 novel SNPs found in the uncharacterized LOC100506532 were strongly associated with CCT in this Latino population. Conditional analysis suggested that rs3118515 in LOC100506532 is the dominant contributor to association with CCT in Latinos, as every SNP in the RXRA-COL5A1 region lost significance after conditioning on rs3118515. This novel SNP is thought to lie in a regulatory region and may be a functional variant.

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Diabetic Retinopathy

Diabetic retinopathy (DR) is the most common microvascular complication of types 1 and 2 diabetes mellitus and is a leading cause of blindness worldwide.27 It affects up to 80% of individuals who have had diabetes for longer than 15 years.27 Diabetic retinopathy is classified into 2 subtypes: (1) nonproliferative, which is characterized by microaneurysm formation and macular edema, and (2) proliferative, which is characterized by neovascularization that can result in traction retinal detachment and neovascular glaucoma.27

Several genes are associated with DR, although replication studies in different populations have been inconsistent. Meta-analyses were recently performed to further investigate these associations. One meta-analysis explored the association of paraoxonase (PON) gene polymorphisms with DR.28 PON1-L55M (rs854560) was significantly associated with DR, although PON1-Q192R (rs662) and PON2 gene polymorphisms were not strongly associated in this meta-analysis. The PON1 gene is a major antiatherosclerotic component of high-density lipoprotein.28 Other recent meta-analyses found that the VEGF gene -460T/C and -634G/C polymorphisms are strongly associated with DR, but the -2578C/A polymorphism is not.29,30 Interestingly, the CC genotype for the VEGF -634G/C polymorphism is also associated with better visual outcome after anti-VEGF treatment for diabetic macular edema.31 Meta-analyses also found strong associations with DR risk for the ICAM-1 K469E and the plasminogen activator inhibitor 1 4G/5G polymorphisms.32,33

The functional roles of selected genes associated with DR have been explored. For instance, variants in the TCF7L2 gene were found to promote pathological retinal neovascularization via ER stress-dependent up-regulation of VEGFA.34 Moreover, the receptor for advanced glycation end-product (RAGE) gene polymorphism -2245G/A was shown to up-regulate expression of nuclear factor κB (NF-κB) p65, plasma monocyte chemoattractant protein 1 (MCP-1), AOPP, and pentosidine, all of which are proinflammatory, oxidative-glycation markers.35 This suggests that RAGE gene polymorphisms may play a functional role via modulation of the NF-κB–mediated inflammatory pathway.

Genome-wide association and candidate gene studies published this past year identified several novel loci that may play a functional role in DR pathogenesis. For instance, a GWAS conducted in a Chinese population identified 3 novel loci for DR: TBC1D4-COMMD6-UCHL3 (rs9565164), LRP2-BBS5 (rs1399634), and ARL4C-SH3BP4 (rs2380261).36 These genes are involved in insulin regulation, inflammation, lipid signaling, and apoptosis, all of which are involved in DR.36 However, these findings were not replicated in an independent cohort of Hispanic patients.36 Candidate genes that were also recently found to be associated with DR risk include complement factor H (CFH) and complement factor B (CFB), the glutathione-S-transferase gene GSTM1, adiponectin (ADIPOQ), angiotensin-converting enzyme (ACE), MCP-1, osteoprotegerin (OPG), the CB1 cannabinoid receptor gene (CNR1), transmembrane protein 217 (TMEM217), mitochondrial ribosomal protein L14 (MRPL14), and the glutamate receptor GRIK2.37–44

Recent studies also explored the role of epigenetic factors in DR pathogenesis. For instance, histone methylation of the retinal SOD2 and MMP9 genes was reduced in patients with DR.45,46 These data suggest that targeting enzymes involved in histone methylation may serve as a therapeutic strategy for this potentially blinding disorder.45

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Fuchs Endothelial Corneal Dystrophy

Fuchs endothelial corneal dystrophy (FECD) is characterized by bilateral, progressive loss of corneal endothelial cells and thickening of Descemet’s membrane.47 It is a leading indication for corneal transplantation. Approximately 50% of patients with FECD have a positive family history, which suggests a strong genetic component in disease pathogenesis.48 Genes implicated in FECD include COL8A2, SLC4A11, ZEB1, LOXHD1, and TCF4.49

Given that genetic variants associated with FECD risk have mainly been studied in white and Asian populations, these variants were recently explored in African Americans.49 Variants in the COL8A2, SLC4A11, and ZEB1 genes were detected in African American patients. However, similar to the case in white and Asian populations, these variants were found in only a small fraction of patients examined, suggesting that these genes are not the major contributor to FECD pathogenesis.

Novel loci associated with FECD risk have recently been described. A study of a 3-generation family affected by FECD utilized genome-wide linkage mapping and subsequent next-generation sequencing to identify a nonsense mutation in the AGBL1 gene on chromosome 15q.50 Whereas wild-type AGBL1 has cytoplasmic localization, this truncated protein displays predominantly nuclear localization. Moreover, AGBL1 was shown to interact with the FECD-associated gene TCF4, and the AGBL1 nonsense mutation diminished this interaction. Another study explored a possible connection between oxidative stress response and FECD in a Polish population.48 Variants in RAD51, which encodes a protein involved in homologous recombination and repair of double-stranded breaks, were associated with risk for FECD in this study.

Studies examining the functional roles for genes associated with FECD risk have also been reported. One study demonstrated that SLC4A11 is involved in Na+-coupled OH transport in the corneal endothelium, suggesting a role for this gene in regulation of cellular pH.51 Studies of Col8a2 L450W/L450W and Col8a2 Q455K/Q455K knock-in mouse models of FECD were also recently performed, which revealed dilation of rough endoplasmic reticulum consistent with up-regulation of the unfolded protein response.47 Moreover, these mice exhibited increased expression of the autophagy marker Dram1, a finding that was confirmed in human FECD endothelium. These data suggest a role for altered autophagy in the pathogenesis of FECD. A whole-genome expression analysis was also performed in wild-type and Col8a2 Q455K/Q455K mutant mice.52 Compared with wild-type mice, Col8a2 Q455K/Q455K mutant mice had increased COX2 and JUN expression, both of which are involved in cell stress responses. These findings were confirmed in human FECD samples.

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Primary Open Angle Glaucoma

Glaucoma refers to a heterogeneous group of disorders that are characterized by progressive loss of retinal ganglion cells and their axons that produces characteristic glaucomatous optic neuropathy. Glaucoma is the leading cause of irreversible blindness in the world. Primary open angle glaucoma (POAG) is the most common form, accounting for a majority of glaucoma cases worldwide. Genetic factors play a significant role in POAG. For instance, linkage studies have led to identification of the MYOC, OPTN, and ASB10 (ankyrin repeat and SOCS box-containing protein 10) genes.53 Genome wide association studies have revealed several POAG-associated loci, including CDKN2B-AS1, TMCO1, caveolin 1/caveolin 2 (CAV1/CAV2), SIX1/SIX6, COL5A1/RXRA, COL8A2, SRBD1, and ELOVL5.53

In some cases, reported genetic associations for POAG have been inconsistent. For instance, TNF-α gene polymorphisms were associated with open angle glaucoma in certain populations, although this finding was not replicated in others.54 A recent meta-analysis identified an association with the TNF-α -308G/A polymorphism (rs1800629) in POAG patients.54 This variant was strongly associated with risk for high-tension glaucoma, but not in normal-tension glaucoma cases. Patients with open angle glaucoma were also found to have higher aqueous humor TNF-α levels compared with controls. The TNF-α -238G/A, -863C/A, -857C/T polymorphisms were not significantly associated with open angle glaucoma in this meta-analysis. Similar to the case with TNF-α polymorphisms, studies of CAV1/CAV2 variants in different populations have generated inconsistent findings. This year, a study was conducted to explore the association of CAV1/CAV2 variants with normal-tension glaucoma in Japanese patients.55 Three SNPs were genotyped in this population. The risk allele for 1 SNP was reversed in this population, whereas the others showed no significant association or were monomorphic. These findings suggest that known SNPs in the CAV1/CAV2 locus are not uniformly associated with normal tension glaucoma among different populations.

Several studies have performed pathway analyses for recently discovered POAG-associated loci. A meta-analysis for CAV1/CAV2 and CDKN2B-AS1 in POAG was done using data obtained from the Glaucoma Genes and Environment (GLAUGEN) study and the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) consortium. CAV1/CAV2 SNPs were found to have greater association with POAG in women and in patients with early paracentral visual field defects.56 CAV1 and CAV2 proteins inhibit endothelial nitric oxide synthase (eNOS), which can alter nitric oxide production and lead to changes in vascular tone and trabecular meshwork function. Single-nucleotide polymorphisms in CDKN2B-AS1, an antisense noncoding RNA, were found to modulate optic nerve degeneration, as POAG patients with minor alleles for these SNPs had altered cup-to-disk ratios.57

Functional studies have also elucidated potential roles for ASB10 and SIX6 in POAG. The ankyrin repeat and SOCS box-containing protein-10 (ASB10) gene was previously identified through genetic linkage studies at the GLC1F locus, although its role in glaucoma is unclear. To determine the biological function of the Asb10 protein, its expression was investigated in human trabecular meshwork cells.58 Asb10 localized to intracellular structures in human trabecular meshwork cells and colocalized with biomarkers of the ubiquitin-mediated proteasomal pathway and the autophagy-lysosomal pathways. Mutations in ASB10 could potentially affect these pathways and lead to alterations in TM outflow, thereby contributing to the pathogenesis of POAG.

An SNP in the SIX1-SIX6 locus (rs10483727) was previously identified in a GWAS study and was strongly associated with vertical cup-disk ratio and POAG.53 A recent study identified 2 missense variants in SIX6, rs33912345 (His141Asn) and rs146737847 (Glu129Lys), that were associated with vertical cup-disk ratio (rs33912345 and rs146737847) and POAG (rs33912345).59 Knockdown of SIX6 in zebrafish led to a small eye phenotype and also led to up-regulation of CDKN2B. The SIX6 gene encodes a transcription factor involved in early eye development. In another more recent study, 5 nonsynonymous coding variants in the SIX6 gene that were identified in POAG cases resulted in reduced eye size and reduced volume of the optic nerve.125 Another variant found in the SIX6 enhancer region resulted in overexpression of SIX6 in an in vitro luciferase assay. Interestingly, POAG patients who were homozygous for the risk allele for SNP rs33912345 (His 141) were found to have a thinner retinal nerve fiber layer compared with patients homozygous for the non–risk allele (Asn141).

Recent studies have also identified correlations between gene mutations and age at onset/disease severity. For instance, myocilin mutations are more prevalent in patients with advanced POAG (defined as more severe visual loss) compared with patients with clinically less severe POAG in an Australasian disease registry.60 In addition, disease-causing mutations in COL15A1 and COL18A1 have been found to influence age at onset of both juvenile and adult open angle glaucoma.61 Patients who carried a COL15A1 variant had a mean age at onset of 25 years, compared with 44 years for patients without the COL15A1 variant. Similarly, patients who carried a COL18A1 variant had a mean age at onset of 32.2 years, compared with 48.8 years for patients without the variant.

A growing number of genes are known to be associated with POAG risk, but they individually explain a relatively small fraction of the heritability of this disease. Studies published this year have identified new loci that may help explain, in part, the heritability gap. For instance, a GWAS identified SNPs in the complement component C7 gene that are strongly associated with POAG risk.25 Another study explored the association between estrogen metabolism SNPs and POAG, with analyses conducted for each gender separately and jointly.62 The estrogen SNP pathway was associated with POAG in women, but not in men. Gene-based analyses showed strong associations between the catechol-O-methyltransferase gene and both high-tension and normal-tension glaucoma in women. Another study examined the association between CNVs and intraocular pressure (IOP), a key POAG risk factor.63 An association was found between IOP and the 5q21.2 CNV locus overlapping the gene RAB9BP1. Interestingly, this CNV locus is located near the previously reported and widely replicated GLC1G locus for POAG, although the causal gene in this region remains unknown.

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Primary Angle Closure Glaucoma

Primary angle closure glaucoma (PACG) is characterized by obstruction of the iridocorneal angle by the iris, which leads to impaired aqueous humor outflow and increased IOP. Primary angle closure glaucoma is associated with increasing age, hyperopia, certain ethnicities, and female gender.64 A GWAS previously performed on a large cohort of multiple ethnicities (Chinese, Malaysian, Indian, Vietnamese, Saudi Arabian, and European) identified 3 susceptibility loci for PACG: rs11024102 in PLEKHA7, rs3753841 in COL11A1, and rs1015213 located between PCMTD1 and ST18 on chromosome 8q.64 A fourth association, rs3788317 in TXNRD2, did not reach genome-wide significance in the meta-analysis. In a more recent study, these loci were reexamined in Australian white and Nepalese data sets, which replicated the initial GWAS findings.64 In a South Indian PACG data set, however, only 1 of these associations (rs1015213) was replicated.65

Recent studies have also looked for other loci that may be associated with PACG. For instance, SNPs in frizzled-related protein (MFRP) and heat shock protein 70 (HSP70) showed possible association with primary angle closure in the Han Chinese population, although significance was lost after Bonferroni correction.66 In an Australian cohort, SNP rs3793342 in the eNOS gene showed association with PACG.67 Variants in serine protease 56 (PRSS56) have also been found to be associated with PACG.68 Lastly, SNPs rs5745718 and rs17427817 in the hepatocyte growth factor (HGF) gene were associated with decreased risk of PACG in the Han Chinese population.69

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Primary Congenital Glaucoma

Primary congenital glaucoma (PCG) presents within the first 3 years of life. It is thought to result from developmental defects of the trabecular meshwork, although the exact mechanism remains unknown.70 Genes that are associated with the disease include CYP1B1 and LTBP2.71 The GLC3B and GLC3C loci on chromosomes 1p36 and 14q24.3, respectively, have also been linked to PCG, although the associated genes at these loci remain to be determined.71

Studies published in the past year have identified potential functional roles for CYP1B1 in PCG pathogenesis. A study examining Cyp1b1-deficient (Cyp1b1−/−) mice found that these mice had elevated diurnal IOP, irregular collagen distribution in the trabecular meshwork, increased TM oxidative stress, and decreased levels of periostin, which plays an essential role in collagen fibrillogenesis.70 Taken together, these findings suggest roles for CYP1B1 in oxidative homeostasis and ultrastructural organization of TM tissue. CYP1B1 deficiency also results in attenuation of capillary morphogenesis, increased expression of thrombospondin 2 (an endogenous inhibitor of angiogenesis) and enhanced proliferation/decreased apoptosis of vascular pericytes.72,73 These findings support an important role for CYP1B1 in vascular homeostasis. In addition, CYP1B1 deficiency leads to sustained activation of NF-κB, a transcription factor involved in immune and inflammatory responses.72 Dysregulation of NF-κB activity has been observed to play a role in a number of disease states, including glaucoma.

CYP1B1 genotype-phenotype correlations are of clinical interest in PCG, as this may help provide more accurate prognosis, guide therapy, and assist in genetic counseling. Patients with PCG with a CYP1B1 mutation were found to have earlier median age at disease onset in the Han Chinese population.71 Moreover, CYP1B1 gene mutations were associated with a better surgical outcome in this population, defined as postoperative IOP of 21 mm Hg or less with or without use of glaucoma medications.71

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Keratoconus (KC) is a degenerative corneal disorder characterized by localized thinning and protrusion of the corneal stroma. This leads to varying degrees of astigmatism and high myopia. Keratoconus can cause marked visual impairment and is a leading indication for corneal transplantation. Both genetic and environmental factors are known to contribute to this disorder. Candidate genes implicated in the pathogenesis of KC include VSX1, SOD1, ZEB1, TGFB1, HGF, RAB3GAP1, IL1A, IL1B, and LOX.74

The visual system homeobox 1 (VSX1) has been examined in populations around the world, although significant associations with KC risk have not been observed in all populations. Recently, disease-causing VSX1 mutations were identified in New Zealand and Han Chinese cohorts.75,76 However, studies conducted in South Indian, Iranian, and Greek populations found no significant association between VSX1 mutations and susceptibility to KC.77–79

A candidate gene study recently performed in Poland found that SNPs rs8177178 and rs8177179 in the transferrin gene were also associated with KC.80 This suggests a potential role for disturbances in iron homeostasis and oxidative stress in the pathogenesis of this disease. To further explore the connection between oxidative stress and KC, variants in the RAD51 gene were also studied in a Polish population and found to be associated with disease risk.48 The RAD51 gene encodes a protein involved in homologous recombination and repair of double-stranded breaks.

A genome-wide linkage scan previously mapped a KC locus to the genomic region 5q14.3-q21.1.81 The calpastatin (CAST) gene is located in this region and was hypothesized to play a role in disease pathogenesis. A recent study further explored this hypothesis by examining whether variants in the CAST gene confer susceptibility to KC.81 Single-nucleotide polymorphism rs4434401 was found to be strongly associated with KC risk in 2 independent white cohorts. The CAST gene encodes an endogenous inhibitor of the calpains, which are cysteine proteases involved in cellular migration, proliferation, and apoptosis.81

There is also strong evidence for a connection between thinner CCT and risk for KC. A recent meta-analysis that included more than 20,000 patients of European and Asian descent identified 16 new loci for CCT and explored whether these loci are associated with KC.26 FOXO1 and FNDC3B variants were found to increase the risk for KC in 2 different cohorts. A replication study performed in an Australian cohort found no association between the FOXO1 and FNDC3B variants and KC risk, however.82 The CCT-associated SNPs rs1324183 (in the MPDZ-NF1B gene) and rs9938149 (between BANP and ZNF4659) were strongly associated with KC risk in the Australian cohort, although the association was via a noncorneal curvature route.82

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Leber Congenital Amaurosis

Leber congenital amaurosis (LCA) is an autosomal recessive disorder that results from dysfunction and degeneration of photoreceptors. In LCA patients with RPE65 mutations, a recombinant adeno-associated virus (rAAV) vector carrying the human RPE65 gene has been shown to improve vision without apparent adverse effects in both animal models and in clinical trials.83,84 This is one of the first successes in ocular gene-directed therapy, although the effect of this therapy on the disease process in the long term is largely unknown.

To explore this question, a recent study evaluated the effects of the gene therapy on retinal degeneration in patients with LCA and in a canine model.85 In LCA patients, RPE65 gene therapy resulted in significant visual improvement in the short term, although retinal degeneration continued to progress unabated. Similarly, in a canine model, photoreceptor loss continued unabated if the treatment was given after degeneration had already begun. These findings suggest that a combinatorial treatment strategy is needed to both improve function in the short term and slow retinal degeneration in the long term.85

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Leber Hereditary Optic Neuropathy

Leber hereditary optic neuropathy (LHON) is a mitochondrial-mediated, maternally inherited disease that leads to degeneration of retinal ganglion cells and loss of central vision in early life. It is associated with 3 point mutations in mitochondrial DNA: m.3460G>A (MT-ND1), m.11778G>A (MT-ND4), and m.14484T>C (MT-ND6).86 However, given that LHON predominantly occurs in males and has incomplete penetrance, other genetic and environmental factors may be involved.87

Single-nucleotide polymorphisms in the PARL gene, which encodes a serine protease of the inner mitochondrial membrane, were previously shown to be associated with LHON in a genome-wide linkage analysis performed in Thailand.87 To determine whether PARL may have a role in penetrance of this mitochondrial disease, the PARL gene was examined in patients with the m.11778G>A genotype who had LHON and in patients with the m.11778G>A genotype who were unaffected.87 Two SNPs, rs3749446 and rs1402000, had significantly different frequencies in the 2 groups, suggesting that PARL may be a potential modifier in the pathogenesis of LHON.

Given that point mutations in mitochondrial DNA play an important role in LHON, gene-directed therapy may offer an effective therapeutic approach for this disease. This year, an rAAV expressing NDI1 was constructed and administered as a single intravitreal injection in a murine model of LHON.88 Adeno-associated virus NDI1 administration produced a 1.5-fold reduction in retinal ganglion cell death and a 1.4-fold reduction in optic nerve atrophy. Clinical trials are also currently underway to assess the safety and efficacy of rAAV-ND4 treatments for patients with the m.11778G>A genotype.86

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Ocular Malformations

Anophthalmia and microphthalmia (A/M) are heterogeneous congenital disorders that can lead to absence of the eye or to reduced eye size, respectively. These disorders can be inherited as autosomal dominant, autosomal recessive, or X-linked traits. SOX2 gene mutations account for 10% to 15% of severe A/M cases.61 Although they account for a small percentage of cases, mutations in several other genes, including GDF6, FOXE3, OTX2, PAX6, RAX, and VSX2 have been described in A/M cases.61

During the past year, 2 separate studies identified mutations in the ALDH1A3 as causes of A/M.89,90 One study used a combination of homozygosity mapping, exome sequencing, and Sanger sequencing, whereas the other utilized whole-exome and whole-genome sequencing. Antisense morpholino studies to knockdown ALDH1A3 gene expression in zebrafish produced a significant reduction in eye size and aberrant axonal connections to the tectum.90 The ALDH1A3 gene encodes an enzyme that is involved in the formation of a retinoic acid gradient during ocular development. These studies provide evidence for a connection between dysfunctional retinoic acid synthesis and ocular malformations.

Coloboma results from a delay in closure of the optic fissure and is frequently associated with A/M. Autozygome analysis and exome sequencing were recently used to identify mutations in C12orf57, which produced a syndromic form of colobomatous microphthalmia associated with global developmental delay, intractable seizures, and corpus callosum abnormalities.91 Exome sequencing also led to identification of CYP1B1 as a potential modifier gene in colobomatous microphthalmia.92 The CYP1B1 gene regulates retinoic acid signaling, which is a necessary component for proper optic fissure closure. In addition to its potential role in colobomatous microphthalmia, CYP1B1 also has an established role in PCG and Peters anomaly.92

Studies conducted during the past year have provided a foundation to improve treatment of aniridia, a congenital disorder that results in complete or partial absence of the iris. The vast majority of aniridia cases are due to mutations or deletions of the PAX6 gene, which encodes a transcription factor necessary for eye and central nervous system development. Recently, postnatal topical application of an ataluren-containing drug formulation was found to reverse corneal, lens, and retinal defects in the Pax6Sey+/ mouse, a model for human aniridia.93 Enzyme-linked immunosorbent assay analysis confirmed that treatment promoted synthesis of a full-length Pax6 protein. Ataluren, also known as PTC124, reduces ribosomal sensitivity to stop codons. The efficacy of this drug in a mouse model of aniridia offers promise for a viable therapeutic option for patients with PAX6 nonsense mutations. Moreover, ataluren administration provides a therapeutic paradigm potentially applicable to other diseases caused by premature translational termination, including cystic fibrosis, Duchenne muscular dystrophy, and certain cancers.94

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Refractive Error

Refractive error is the most common ocular disorder worldwide, with an estimated 2.3 billion individuals affected.95 There are 3 types of refractive error: (1) myopia, which results from increased axial length of the eye, (2) hyperopia, which results from decreased axial length, and (3) astigmatism, which results from irregular corneal curvature.96 Environmental factors, such as occupations requiring extensive use of close vision and reduced time spent outside, play an important role in this disorder. Moreover, heritabilities greater than 50% in several different populations also suggest a strong genetic component.96 Several genes are associated with refractive error, although each has a very small phenotypic effect, suggesting that yet unidentified genes also play an important role in disease pathogenesis.95

Several studies published this past year have identified novel loci that may help explain, in part, the heritability gap. For instance, a GWAS performed using 7280 samples from 5 white cohorts found that SNP rs1050035 in the RBFOX1 gene was strongly associated with risk for refractive error.96 The RBFOX1 gene is a neuron-specific splicing factor that regulates alternative splicing events.96 A genome-wide meta-analysis in European and Asian populations identified 9 novel loci for ocular axial length, 5 of which were associated in 18 replication cohorts (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B).97 In the Han Chinese population, a genome-wide meta-analysis found that variants in the VIPR2 and SNTB1 genes increase risk for high myopia.98 Another GWAS performed in a European population found that variants in the platelet-derived growth factor receptor α (PDGFRA) influence corneal curvature and corneal astigmatism.99

Some of the recently identified genetic loci point toward mechanisms that may underlie the development of myopia. For instance, in a genome-wide meta-analysis for refractive error, 16 novel loci were strongly associated in both European and Asian cohorts.95 These loci include genes that function in neurotransmission (GRIA4), ion transport (KCNQ5), retinoic acid metabolism (RDH5), extracellular matrix remodeling (LAMA2 and BMP2), and eye development (SIX6 and PRSS56).95 Another GWAS in Europeans identified 20 novel associations, 10 of which were replicated in an independent cohort.100 These included genes involved in growth of retinal ganglion cells (ZIC2, SFRP1) and 5 genes involved in neuronal signaling and development.

Exome sequencing was also recently used to find genes associated with myopia, which led to identification of mutations in LRPAP1, CCDC111, LEPREL1, and SCO2 that resulted in disease development.101–104 Identification of several novel genetic associations for refractive error in the last year is encouraging. Further studies exploring the functional role of these variants may enable development of improved diagnostic and therapeutic strategies for this common disorder.

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Retinal Vascular Disease

Retinal vein occlusion (RVO) causes significant visual morbidity secondary to macular edema and neovascularization. It occurs as a result of intraluminal thrombus formation and is associated with hypertension, hyperlipidemia, diabetes, smoking, oral contraceptive use, and hypercoagulable states.105 To explore whether genetic polymorphisms in the coagulation pathway are associated with RVO risk, a candidate gene study was recently conducted in a Turkish population.106 There was a significant association between the VKORC1 -1639G>A and VKORC1 -1173 C>T polymorphisms and risk for RVO. The VKORC1 gene is a component of the vitamin K epoxide reductase complex, which is necessary for γ carboxylation of clotting factors II, VII, IX, X, and proteins C and S. However, a larger replication study conducted in patients of white descent found no significant association between the VKORC1 -1639G>A polymorphism and risk for either central or branch RVO.107

Matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) are involved in extracellular matrix turnover and contribute to several pathological processes, including vascular disorders. Notably, MMP expression is elevated during the initial phase of thrombosis, suggesting a possible role in the development of RVO.108 A candidate gene study was recently performed in a Turkish population to further explore this hypothesis.108 The MMP2-1306 C/T polymorphism was associated with risk for RVO in this population, although the TIMP2G-418C polymorphism was not.

Retinal vascular caliber is an important predictor of subsequent macrovascular disease development, including myocardial infarction and stroke. To identify genetic factors that contribute to variation in retinal arteriolar caliber, a GWAS was recently performed in 18,722 individuals of European ancestry.109 A variant (rs2194025) near the myocyte enhancer factor 2C (MEF2C) gene was significantly associated with retinal arteriolar caliber in this cohort, and this finding was replicated in a second independent cohort of 3939 European individuals. However, no significant association was found between this SNP and macrovascular disease outcomes, including coronary artery disease, stroke, myocardial infarction, and hypertension.109

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Uveal Melanoma

Uveal melanoma, which arises in the iris, ciliary body, and choroid, is the most common ocular malignancy. Prognosis is heavily influenced by chromosome 3 status: loss of 1 copy (monosomy 3) in the tumor is associated with metastatic disease, which carries a poor prognosis. On the other hand, tumors with 2 copies of chromosome 3 (disomy 3) rarely metastasize and therefore have a much more favorable prognosis. Loss-of-function mutations in the BAP1 gene have previously been shown to be associated with monosomy 3 and are therefore associated with a poorer prognosis.110

Recently, whole-exome sequencing was utilized to identify other mutations associated with uveal melanoma. Somatic mutations in EIF1AX and SF3B1 were found to occur specifically in uveal melanomas with disomy 3, which are less invasive and have a favorable prognosis.111 In another study, all SF3B1 mutations identified in uveal melanomas with disomy 3 occurred exclusively at codon 625, leading to amino acid changes at this codon.110 The SF3B1 gene encodes subunit 1 of the splicing factor 3b complex; mutations of this gene in uveal melanoma lead to differential alternative splicing of protein coding genes (ABCC5, UQCC) and long noncoding RNAs (CRNDE).112

Recent studies have also explored epigenetic factors associated with uveal melanoma metastasis. The chemokine factor CXCR4 contributes to invasion and metastatic spread, including liver metastasis of uveal melanomas. Cancer cells constitutively expressing CXCR4 were found to have higher methyltransferase activity after injection into the anterior chamber of the eye when compared with subcutaneously derived, liver-derived, or wild-type tumor cells.113 This finding suggests that the ocular microenvironment induces methylation and epigenetic down-regulation of CXCR4 expression by tumors.

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The past year has witnessed numerous advances in ocular genetics. Many of the reported discoveries have been enabled by use of more up-to-date technologies, including GWASs, whole-exome sequencing, epigenetic studies, and increasingly powerful meta-analyses. Importantly, in the last year, advances have also been made in identifying functional roles of genetic variants in disease pathogenesis, paving the way for translation of genetic data into clinical practice. This includes use of genetic signatures for diagnosis and prognosis, prediction of treatment response, and development of targeted gene therapies. Continued research on genetic risk factors for common ocular disorders will be critical in reducing the global burden of visual impairment and blindness.

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genome-wide association study (GWAS); whole-exome sequencing; epigenetics; meta-analysis; glaucoma; age-related macular degeneration; cataract; diabetic retinopathy; refractive error; Fuchs endothelial corneal dystrophy; keratoconus; uveal melanoma

© 2014 by Asia Pacific Academy of Ophthalmology