Primary Open-angle Glaucoma Locus Research Articles

GWAS-by-subtraction reveals an IOP-independent component of primary open angle glaucoma

The etiology of primary open angle glaucoma is constituted by both intraocular pressure-dependent and intraocular pressure-independent mechanisms. However, GWASs of traits affecting primary open angle glaucoma through mechanisms independent of intraocular pressure remains limited. Here, we address this gap by subtracting the genetic effects of a GWAS for intraocular pressure from a GWAS for primary open angle glaucoma to reveal the genetic contribution to primary open angle glaucoma via intraocular pressure-independent mechanisms. Seventeen independent genome-wide significant SNPs were associated with the intraocular pressure-independent component of primary open angle glaucoma. Of these, 7 are located outside known normal tension glaucoma loci, 11 are located outside known intraocular pressure loci, and 2 are novel primary open angle glaucoma loci. The intraocular pressure-independent genetic component of primary open angle glaucoma is associated with glaucoma endophenotypes, while the intraocular pressure-dependent component is associated with blood pressure and vascular permeability. A genetic risk score for the intraocular pressure-independent component of primary open angle glaucoma is associated with 26 different retinal micro-vascular features, which contrasts with the genetic risk score for the intraocular pressure-dependent component. Increased understanding of these intraocular pressure-dependent and intraocular pressure-independent components provides insights into the pathogenesis of glaucoma.

Lessons From The Glaucoma Foundation Think Tank 2023: A Patient-Centric Approach to Glaucoma.

The main takeaways also included that BIG DATA repositories and AI are important combinatory tools to foster novel strategies to prevent and stabilize glaucoma and, in the future, recover vision loss from the disease. To summarize the main topics discussed during the 28th Annual Glaucoma Foundation Think Tank Meeting "A Patient-Centric Approach to Glaucoma" held in New York on June 9 and 10, 2023. The highlights of the sessions on BIG DATA, genetics, modifiable lifestyle risk factors, female sex hormones, and neuroprotection in the field of primary open angle glaucoma (POAG) were summarized. The researchers discussed the importance of BIG DATA repositories available at national and international levels for POAG research, including the United Kingdom Biobank. Combining genotyped large cohorts worldwide, facilitated by artificial intelligence (AI) and machine-learning approaches, led to the milestone discovery of 312 genome-wide significant disease loci for POAG. While these loci could be combined into a polygenic risk score with clinical utility, Think Tank meeting participants also provided analytical epidemiological evidence that behavioral risk factors modify POAG polygenetic risk, citing specific examples related to caffeine and alcohol use. The impact of female sex hormones on POAG pathophysiology was discussed, as was neuroprotection and the potential use of AI to help mitigate specific challenges faced in clinical trials and speed approval of neuroprotective agents. The experts agreed on the importance of genetics in defining individual POAG risk and highlighted the additional crucial role of lifestyle, gender, blood pressure, and vascular risk factors. The main takeaways also included that BIG DATA repositories and AI are important combinatory tools to foster novel strategies to prevent and stabilize glaucoma and, in the future, recover vision loss from the disease.

Clinical implications of recent advances in primary open-angle glaucoma genetics.

Over the last decade, genetic studies, including genome-wide association studies (GWAS), have accelerated the discovery of genes and genomic regions contributing to primary open-angle glaucoma (POAG), a leading cause of irreversible vision loss. Here, we review the findings of genetic studies of POAG published in English prior to September 2019. In total, 74 genomic regions have been associated at a genome-wide level of significance with POAG susceptibility. Recent POAG GWAS provide not only insight into global and ethnic-specific genetic risk factors for POAG susceptibility across populations of diverse ancestry, but also important functional insights underlying biological mechanisms of glaucoma pathogenesis. In this review, we also summarize the genetic overlap between POAG, glaucoma endophenotypes, such as intraocular pressure and vertical cup-disc ratio(VCDR), and other eye disorders. We also discuss approaches recently developed to increase power for POAG locus discovery and to predict POAG risk. Finally, we discuss the recent development of POAG gene-based therapies and future strategies to treat glaucoma effectively. Understanding the genetic architecture of POAG is essential for an earlier diagnosis of this common eye disorder, predictive testing of at-risk patients, and design of gene-based targeted medical therapies none of which are currently available.

Genome-wide association study of primary open-angle glaucoma in continental and admixed African populations

Primary open angle glaucoma (POAG) is a complex disease with a major genetic contribution. Its prevalence varies greatly among ethnic groups, and is up to five times more frequent in black African populations compared to Europeans. So far, worldwide efforts to elucidate the genetic complexity of POAG in African populations has been limited. We conducted a genome-wide association study in 1113 POAG cases and 1826 controls from Tanzanian, South African and African American study samples. Apart from confirming evidence of association at TXNRD2 (rs16984299; OR[T] 1.20; P = 0.003), we found that a genetic risk score combining the effects of the 15 previously reported POAG loci was significantly associated with POAG in our samples (OR 1.56; 95% CI 1.26–1.93; P = 4.79 × 10−5). By genome-wide association testing we identified a novel candidate locus, rs141186647, harboring EXOC4 (OR[A] 0.48; P = 3.75 × 10−8), a gene transcribing a component of the exocyst complex involved in vesicle transport. The low frequency and high degree of genetic heterogeneity at this region hampered validation of this finding in predominantly West-African replication sets. Our results suggest that established genetic risk factors play a role in African POAG, however, they do not explain the higher disease load. The high heterogeneity within Africans remains a challenge to identify the genetic commonalities for POAG in this ethnicity, and demands studies of extremely large size.

Genome-wide association study identifies seven novel susceptibility loci for primary open-angle glaucoma.

Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide for which 15 disease-associated loci had been discovered. Among them, only 5 loci have been associated with POAG in Asians. We carried out a genome-wide association study and a replication study that included a total of 7378 POAG cases and 36385 controls from a Japanese population. After combining the genome-wide association study and the two replication sets, we identified 11 POAG-associated loci, including 4 known (CDKN2B-AS1, ABCA1, SIX6 and AFAP1) and 7 novel loci (FNDC3B, ANKRD55-MAP3K1, LMX1B, LHPP, HMGA2, MEIS2 and LOXL1) at a genome-wide significance level (P < 5.0×10-8), bringing the total number of POAG-susceptibility loci to 22. The 7 novel variants were subsequently evaluated in a multiethnic population comprising non-Japanese East Asians (1008 cases, 591 controls), Europeans (5008 cases, 35472 controls) and Africans (2341 cases, 2037 controls). The candidate genes located within the new loci were related to ocular development (LMX1B, HMGA2 and MAP3K1) and glaucoma-related phenotypes (FNDC3B, LMX1B and LOXL1). Pathway analysis suggested epidermal growth factor receptor signaling might be involved in POAG pathogenesis. Genetic correlation analysis revealed the relationships between POAG and systemic diseases, including type 2 diabetes and cardiovascular diseases. These results improve our understanding of the genetic factors that affect the risk of developing POAG and provide new insight into the genetic architecture of POAG in Asians.

Genetics of glaucoma.

Genetic and genomic studies, including genome-wide association studies (GWAS) have accelerated the discovery of genes contributing to glaucoma, the leading cause of irreversible blindness world-wide. Glaucoma can occur at all ages, with Mendelian inheritance typical for the rare early onset disease (before age 40) and complex inheritance evident in common adult-onset forms of disease. Recent studies have suggested possible therapeutic targets for some patients with early-onset glaucoma based on the molecular and cellular events caused by MYOC, OPTN and TBK1 mutations. Diagnostic genetic tests using early-onset glaucoma genes are also proving useful for pre-symptomatic disease detection and genetic counseling. Recent GWAS completed for three types of common adult-onset glaucoma have identified novel loci for POAG (primary-open-angle glaucoma) (ABCA1, AFAP1, GMDS, PMM2, TGFBR3, FNDC3B, ARHGEF12, GAS7, FOXC1, ATXN2, TXNRD2); PACG (primary angle-closure glaucoma (EPDR1, CHAT, GLIS3, FERMT2, DPM2-FAM102); and exfoliation syndrome (XFS) glaucoma (CACNA1A). In total sixteen genomic regions have been associated with POAG (including the normal tension glaucoma (NTG) subgroup), 8 with PACG and 2 with XFS. These studies are defining important biological pathways and processes that contribute to disease pathogenesis.

Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma.

Primary open angle glaucoma (POAG) is a leading cause of blindness world-wide. To identify new susceptibility loci, we meta-analyzed GWAS results from 8 independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significant SNPs in two Australian studies (1,252 cases and 2,592 controls), 3 European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of top SNPs identified three novel loci: rs35934224[T] within TXNRD2 (odds ratio (OR) = 0.78, P = 4.05×10−11 encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] within ATXN2 (OR = 1.17, P = 8.73×10−10), and rs2745572[A] upstream of FOXC1 (OR = 1.17, P = 1.76×10−10). Using RT-PCR and immunohistochemistry, we show TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head. These results identify new pathways underlying POAG susceptibility and suggest novel targets for preventative therapies.

Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma

Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma

A Genetic Variant in TGFBR3-CDC7 Is Associated with Visual Field Progression in Primary Open-Angle Glaucoma Patients from Singapore

To investigate whether known genetic loci for primary open-angle glaucoma (POAG) are associated with visual field (VF) progression in patients from a Singaporean Chinese population. Retrospective study. Patients with 5 or more reliable VF measurements who were being followed up at a Singapore hospital. Visual field progression was identified using Progressor software version 3.7 (Medisoft, Leeds, United Kingdom) and defined by pointwise linear regression (PLR) criteria as follows: any 2 contiguous points in the same hemifield progressing (≤-1.00 dB/year for inner points and ≤-2.00 dB/year for edge points; P < 0.01). Single nucleotide polymorphisms (SNPs) and their proxies from 10 POAG-associated loci (CAV1-CAV2, CDKN2B-AS1, SIX1-SIX6, an intergenic region on chromosome 8q22, ABCA1, GAS7, AFAP1, GMDS, PMM2, and TGFBR3-CDC7) identified from genome-wide association studies were tested for association with VF progression using logistic regression with an additive genetic model adjusting for age, gender, average intraocular pressure (IOP), central corneal thickness (CCT), and baseline vertical cup-to-disc ratio (VCDR). Visual field progression. Of the 1334 patients included in the study, 469 subjects (35.1%) completed 5 or more reliable VF measurements (mean follow-up, 9.01 years; standard deviation, 5.00 years). The mean age of patients was 59.6 years (standard deviation, 9.0 years); 305 patients were men and all were Chinese. The average IOP in eyes fulfilling PLR progression was 16.5 mmHg versus 17.7 mmHg in those who did not (P= 0.52). Univariate analysis revealed that increased VCDR (P= 0.003), reduced CCT (P= 0.045), and reduced superior and inferior retinal nerve fiber layer thickness (P= 0.01, respectively) were associated with VF progression. No clinical or structural features were associated significantly with VF progression on multivariate analysis. The rs1192415 index SNP in TGFBR3-CDC7 (P= 0.002; odds ratio, 6.71 per risk allele) was the only SNP associated with VF progression. The presence of the index SNP rs1192415 (TGFBR3-CDC7) was associated with VF progression in POAG patients. These findings warrant further investigation in independent cohorts.

Exome Sequencing Identifies a Missense Variant in EFEMP1 Co-Segregating in a Family with Autosomal Dominant Primary Open-Angle Glaucoma.

Primary open-angle glaucoma (POAG) is a clinically important and genetically heterogeneous cause of progressive vision loss as a result of retinal ganglion cell death. Here we have utilized trio-based, whole-exome sequencing to identify the genetic defect underlying an autosomal dominant form of adult-onset POAG segregating in an African-American family. Exome sequencing identified a novel missense variant (c.418C>T, p.Arg140Trp) in exon-5 of the gene coding for epidermal growth factor (EGF) containing fibulin-like extracellular matrix protein 1 (EFEMP1) that co-segregated with disease in the family. Linkage and haplotype analyses with microsatellite markers indicated that the disease interval overlapped a known POAG locus (GLC1H) on chromosome 2p. The p.Arg140Trp substitution was predicted in silico to have damaging effects on protein function and transient expression studies in cultured cells revealed that the Trp140-mutant protein exhibited increased intracellular accumulation compared with wild-type EFEMP1. In situ hybridization of the mouse eye with oligonucleotide probes detected the highest levels of EFEMP1 transcripts in the ciliary body, cornea, inner nuclear layer of the retina, and the optic nerve head. The recent finding that a common variant near EFEMP1 was associated with optic nerve-head morphology supports the possibility that the EFEMP1 variant identified in this POAG family may be pathogenic.

Exome array analysis identifies CAV1/CAV2 as a susceptibility locus for intraocular pressure.

Intraocular pressure (IOP) is an important clinical parameter in the evaluation of ocular health. Elevated IOP is a major risk factor for primary open-angle glaucoma (POAG). The goal of this study was to identify rare and less common variants that influence IOP. We performed an exome array analysis in a subset of 1660 individuals from a population-based cohort, the Beaver Dam Eye Study. Associations with IOP were tested on 45,849 single nucleotide variants and 12,390 autosomal genes across the genome. Intraocular pressure was suggestively associated with novel variants located in FAR2 at 12p11.22 (rs4931170, P = 1.2 × 10(-5)), in GGA3 at 17q25.1 (rs52809447, P = 6.7 × 10(-5)), and in PKDREJ at 22q13.31 (rs7291444, P = 7.4 × 10(-5)). Gene-based analysis found suggestive associations between IOP and the genes HAP1, MTBP, FREM3, and PHF12. We successfully replicated the associations with GAS7 (P = 7.4 × 10(-3)) for IOP, and also identified a previously reported POAG locus in the CAV1/CAV2 region to be associated with IOP (P = 3.3 × 10(-3)). This association was confirmed in a meta-analysis with three published genome-wide association studies (Pcombined = 4.0 × 10(-11)). Our results suggest that novel genetic variants and genes with multiple, less common variants may play a role in the control of IOP. The implication of the caveolin genes, CAV1/CAV2, as a common genetic factor influencing both IOP variations and POAG may provide new insights of the underlying mechanism leading to glaucoma and glaucomatous visual field loss.

Genetics of primary open angle glaucoma

Glaucoma is a neurodegenerative disease and one of the leading causes of irreversible blindness, affecting over 60 million people worldwide. At the present time, glaucoma is clinically defined, but the exact etiology is unknown. Genetic studies are one approach to identify the molecules and pathways involved in disease pathogenesis. Familial aggregation of primary open-angle glaucoma (POAG) has long been recognized, and the analysis of POAG families with a Mendelian inheritance form of this disease has been employed to identify multiple loci linked to them. Some causative genes, such as myocilin, optineurin and WD repeat domain 36, have been identified. However, most cases of POAG are considered to be a prevalent, multifactorial disorder. Several association studies have been conducted for candidate genes, and genome-wide association studies recently identified new susceptibility loci for POAG, namely, S1 RNA binding domain 1 region on chromosome 2p21, the caveolin 1 and caveolin 2 regions on 7q31, transmembrane and coiled-coil domain 1 region on 1q24, cyclin-dependent kinase inhibitor 2B antisense RNA on 9p21, the SIX1 and SIX6 regions on 14q24 and, possibly, the regulatory region of 8q22. Further analysis of clinical manifestations caused by specific genes and functional analysis of these genes will contribute to the development of new strategies for the diagnosis and treatment of POAG.

The vast complexity of primary open angle glaucoma: Disease genes, risks, molecular mechanisms and pathobiology

Primary open angle glaucoma (POAG) is a complex progressive optic nerve neuropathy triggered by both environmental and genetic risk factors. Several ocular tissues, including the ciliary body, trabecular meshwork and optic nerve head, and perhaps even brain tissues, are involved in a chain of pathological events leading to POAG. Genetic risk evidence for POAG came from family linkage-studies implicating a small number of disease genes (MYOC, OPTN, WDR36). Recent Genome Wide Association Studies (GWAS) identified a large number of new POAG loci and disease genes, such as CAV1, CDKN2B and GAS7. In the current study, we reviewed over 120 family and GWA studies. We selected in total 65 (candidate) POAG disease genes and proceeded to assess their function, mRNA expression in POAG relevant eye tissues and possible changes in disease state. We found that the proteins corresponding to these 65 (candidate) POAG disease genes take part in as few as four common functional molecular networks. Functions attributed to these 4 networks were developmental (dys)function, lipid metabolism, and inflammatory processes. For the 65 POAG disease genes, we reviewed the available (transgenic) mouse models of POAG, which may be useful for future functional studies. Finally, we showed that the 65 (candidate) POAG genes substantially increased the specificity and sensitivity of a discriminative POAG risk test. This suggests that personal risk assessment and personalized medicine for POAG are on the horizon. Taken together, the data presented are essential to comprehend the role of genetic variation in POAG, and may provide leads to understand the pathophysiology of POAG as well as other neurodegenerative disorders, such as Alzheimer's disease.

ScreeningADAMTS10in Dog Populations Supports Gly661Arg as the Glaucoma-Causing Variant in Beagles

Previously, we mapped the disease locus in the beagle model of autosomal recessive primary open angle glaucoma (POAG) to a 4-Mb interval on chromosome 20, and identified a Gly661Arg variant in ADAMTS10 as the candidate disease-causing variant. The purpose of this study was to test the hypothesis that the Gly661Arg variant of ADAMTS10 causes glaucoma by genotyping dogs of various breeds affected and unaffected by primary glaucoma. Dogs of various breeds, affected or unaffected with primary glaucoma, were genotyped for the Gly661Arg variant of ADAMTS10, as well as 7 other nonsynonymous single nucleotide polymorphisms (SNPs) in other genes in the beagle POAG locus that segregate with disease. Alternate allele frequencies were calculated with 95% confidence intervals and comparisons made to expected allele frequency relative to disease prevalence or between cases and controls. For the nonsynonymous SNPs other than the ADAMTS10 variant, control dogs were identified that were homozygous for the alternative alleles, ruling out those variants as causative. None of the nonsynonymous SNPs were found associated with primary glaucoma in American cocker spaniels. The Gly661Arg variant of ADAMTS10 was the only variant with minor allele frequency consistent with the prevalence of primary glaucoma in the general beagle population. The only dog found homozygous for the Gly661Arg variant of ADAMTS10 was an affected beagle, unrelated to the POAG colony. These findings support the Gly661Arg mutation of ADAMTS10 as the likely cause of POAG in beagles.

A Genome-Wide Association Study for Primary Open Angle Glaucoma and Macular Degeneration Reveals Novel Loci

Glaucoma and age-related macular degeneration (AMD) are the two leading causes of visual loss in the United States. We utilized a novel study design to perform a genome-wide association for both primary open angle glaucoma (POAG) and AMD. This study design utilized a two-stage process for hypothesis generation and validation, in which each disease cohort was utilized as a control for the other. A total of 400 POAG patients and 400 AMD patients were ascertained and genotyped at 500,000 loci. This study identified a novel association of complement component 7 (C7) to POAG. Additionally, an association of central corneal thickness, a known risk factor for POAG, was found to be associated with ribophorin II (RPN2). Linked monogenic loci for POAG and AMD were also evaluated for evidence of association, none of which were found to be significantly associated. However, several yielded putative associations requiring validation. Our data suggest that POAG is more genetically complex than AMD, with no common risk alleles of large effect.

Identification of a Novel Locus for Autosomal Dominant Primary Open Angle Glaucoma on 4q35.1-q35.2

Primary open angle glaucoma is the most prevalent type of glaucoma and the leading cause of irreversible blindness worldwide. The genetic basis is poorly understood. Of 14 loci associated with this disease, only two genes have been identified, accounting for approximately 4% of cases. The authors investigated the genetic cause of primary open angle glaucoma in a large four-generation family with an apparent autosomal dominant mode of inheritance. Twenty-three family members underwent comprehensive phenotyping by a single ophthalmologist, and the MYOC gene was sequenced in all affected family members for whom DNA was available. Parametric genomewide linkage analysis was performed on 10 affected family members and one unaffected family member. Within the critical region, mutation analysis of candidate genes LRP2BP, CYP4V2, and UFSP2 was carried out by direct sequencing. No mutations were identified in MYOC. Genomewide linkage analysis generated one significant LOD score of 3.1 (maximum affected-only LOD score of 2.8) centered on chromosome 4 at 4q35.1-q35.2, a critical region that does not contain any of the previously reported primary open angle glaucoma loci. A 1.866-Mb (7.2 cM) region was identified containing 17 known or hypothetical genes. No mutations were identified in the candidate genes LRPB2BP, CYP4V2, and UFSP2. This study identifies a new primary open angle glaucoma locus, GLC1Q, in a region on chromosome 4 not previously associated with glaucoma.

Mapping of the Disease Locus and Identification of ADAMTS10 As a Candidate Gene in a Canine Model of Primary Open Angle Glaucoma

Primary open angle glaucoma (POAG) is a leading cause of blindness worldwide, with elevated intraocular pressure as an important risk factor. Increased resistance to outflow of aqueous humor through the trabecular meshwork causes elevated intraocular pressure, but the specific mechanisms are unknown. In this study, we used genome-wide SNP arrays to map the disease gene in a colony of Beagle dogs with inherited POAG to within a single 4 Mb locus on canine chromosome 20. The Beagle POAG locus is syntenic to a previously mapped human quantitative trait locus for intraocular pressure on human chromosome 19. Sequence capture and next-generation sequencing of the entire canine POAG locus revealed a total of 2,692 SNPs segregating with disease. Of the disease-segregating SNPs, 54 were within exons, 8 of which result in amino acid substitutions. The strongest candidate variant causes a glycine to arginine substitution in a highly conserved region of the metalloproteinase ADAMTS10. Western blotting revealed ADAMTS10 protein is preferentially expressed in the trabecular meshwork, supporting an effect of the variant specific to aqueous humor outflow. The Gly661Arg variant in ADAMTS10 found in the POAG Beagles suggests that altered processing of extracellular matrix and/or defects in microfibril structure or function may be involved in raising intraocular pressure, offering specific biochemical targets for future research and treatment strategies.

Reply to Liu et al.: Differential effects of chromosome 2p16.3 variants on glaucoma in African derived populations

We appreciate the letter by Liu et al. (1) and commend them on their work (1). We are encouraged that they have confirmed association of primary open-angle glaucoma (POAG) with rs12994401, although it is to the opposite allele from that seen in the Barbados population (2). These results, in addition to the presence of a monogenic POAG locus in this region, provide substantive confirmation of a locus for POAG (3). The inverse association of risk alleles between African Americans is not completely surprising given the high degree of genetic diversity in African and African-derived populations (4) and previously described divergent levels and patterns of linkage disequilibrium (LD) in African subpopulations (5). The situation becomes even more complex when migration patterns to the Caribbean islands are considered (6). We agree with the conclusion by Liu et al. (1) that rs12994401 most likely represents a tagging SNP that is in linkage disequilibrium with a yet unidentified causative SNP in this region.

Gene Expression Profiles of Human Trabecular Meshwork Cells Induced by Triamcinolone and Dexamethasone

Triamcinolone acetonide (TA) and dexamethasone (DEX) are corticosteroids commonly used for ocular inflammation, but both can cause ocular hypertension. In this study, the differential gene expression profile of human trabecular meshwork (TM) cells in response to treatment by TA in comparison with DEX was investigated. Total RNA was extracted from cultured human TM cells treated with TA or DEX and used for microarray gene expression analysis. The microarray experiments were repeated three times. Differentially expressed genes were identified by an empiric Bayes approach and confirmed by real-time quantitative PCR. TA (0.1 mg/mL) treatment resulted in 15 genes upregulated and 12 genes downregulated, whereas 1 mg/mL TA resulted in 36 genes upregulated and 21 genes downregulated. These genes were mainly associated with acute-phase response, cell adhesion, cell cycle and growth, growth factor, ion binding, metabolism, proteolysis and transcription factor. Two genes, MYOC and GAS1, were upregulated, and three genes, SENP1, ZNF343, and SOX30, were downregulated by both TA and DEX treatment. Eight differentially expressed genes were located in known primary open-angle glaucoma (POAG) loci, including MYOC, SOAT1, CYP27A1, SPOCK, SEMA6A, EGR1, GAS1, and ATP10A. Differential gene expression profiles of human TM cells treated by TA and DEX, and a dosage effect by TA, were revealed by microarray technology. TA and DEX treatment shared several differentially expressed genes, suggesting a common mechanism to cause ocular hypertension. Some differentially expressed genes located in the known POAG loci are potential candidates for glaucoma genes.

Confirmation of the Adult-Onset Primary Open Angle Glaucoma Locus GLC1B at 2cen-q13 in an Australian Family

Primary open-angle glaucoma (POAG) is genetically heterogeneous, with 6 named POAG loci GLC1A-F mapped and genes myocilin (MYOC) and optineurin (OPTN) identified at 2 of the loci. Using penetrance-model-free methods, we screened the POAG loci GLC1A-F in an extended Australian pedigree, using 3–5 markers within each locus. p values of less than 0.05 were obtained empirically using SimWalk2 and exactly using Genehunter for 2 markers within the GLC1B region on chromosome 2. Fine mapping of this region produced pvalues of 0.01 or less at 5 markers flanked by D2S1897 and D2S2269. The 9 cM haplotype of interest overlaps the original GLC1B region. These results provide supportive evidence for the GLC1B locus on chromosome 2cen-q13 and verify the existence of POAG susceptibility gene in this region, increasing the likelihood of gene identification.