Analysis combining correlated glaucoma traits identifies five new risk loci for open-angle glaucoma.
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ABSTRACT:
SUBMITTER: Gharahkhani P
PROVIDER: S-EPMC5814451 | biostudies-literature | 2018 Feb
REPOSITORIES: biostudies-literature
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Analysis combining correlated glaucoma traits identifies five new risk loci for open-angle glaucoma.
Gharahkhani Puya P Burdon Kathryn P KP Cooke Bailey Jessica N JN Hewitt Alex W AW Law Matthew H MH Pasquale Louis R LR Kang Jae H JH Haines Jonathan L JL Souzeau Emmanuelle E Zhou Tiger T Siggs Owen M OM Landers John J Awadalla Mona M Sharma Shiwani S Mills Richard A RA Ridge Bronwyn B Lynn David D Casson Robert R Graham Stuart L SL Goldberg Ivan I White Andrew A Healey Paul R PR Grigg John J Lawlor Mitchell M Mitchell Paul P Ruddle Jonathan J Coote Michael M Walland Mark M Best Stephen S Vincent Andrea A Gale Jesse J RadfordSmith Graham G Whiteman David C DC Montgomery Grant W GW Martin Nicholas G NG Mackey David A DA Wiggs Janey L JL MacGregor Stuart S Craig Jamie E JE
Scientific reports 20180215 1
Open-angle glaucoma (OAG) is a major cause of blindness worldwide. To identify new risk loci for OAG, we performed a genome-wide association study in 3,071 OAG cases and 6,750 unscreened controls, and meta-analysed the results with GWAS data for intraocular pressure (IOP) and optic disc parameters (the overall meta-analysis sample size varying between 32,000 to 48,000 participants), which are glaucoma-related traits. We identified and independently validated four novel genome-wide significant as ...[more]
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Project description: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 36 385 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, 35 472 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.
| S-EPMC6251544 | biostudies-literature
Project description:Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.
| S-EPMC7904932 | biostudies-literature
Project description:Primary open-angle glaucoma (POAG) is a leading cause of irreversible vision loss, yet much of the genetic risk remains unaccounted for, especially in African-Americans who have a higher risk for developing POAG. We conduct a multiethnic genome-wide association study (GWAS) of POAG in the GERA cohort, with replication in the UK Biobank (UKB), and vice versa, GWAS in UKB with replication in GERA. We identify 24 loci (P < 5.0 × 10-8), including 14 novel, of which 9 replicate (near FMNL2, PDE7B, TMTC2, IKZF2, CADM2, DGKG, ANKH, EXOC2, and LMX1B). Functional studies support intraocular pressure-related influences of FMNL2 and LMX1B, with certain Lmx1b mutations causing high IOP and glaucoma resembling POAG in mice. The newly identified loci increase the proportion of variance explained in each GERA race/ethnicity group, with the largest gain in African-Americans (0.5-3.1%). A meta-analysis combining GERA and UKB identifies 24 additional loci. Our study provides important insights into glaucoma pathogenesis.
| S-EPMC5995837 | biostudies-literature
Project description:Glaucoma is a leading cause of blindness worldwide. The disease is characterized by a degeneration of the optic nerve, which is usually associated with elevated intraocular pressure. The common form of adult-onset primary open-angle glaucoma is inherited as a complex trait, whereas the rarer early-onset juvenile open-angle glaucoma (JOAG) exhibits autosomal dominant inheritance. Of all cases of JOAG, approximately 10%-20% are caused by mutations in the myocilin gene. We have identified 25 pedigrees that are affected with typical JOAG and that demonstrate autosomal dominant inheritance. We sequenced the myocilin gene in probands from each family and found mutations in 8% of this population. To identify novel genes responsible for JOAG, we used families that did not have myocilin mutations for a genomewide screen. Markers located on chromosomes 9q22 and 20p12 showed evidence for linkage, identifying two novel loci for early-onset open-angle glaucoma.
| S-EPMC1182098 | biostudies-literature
Project description:Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. To identify new susceptibility loci, we performed meta-analysis on genome-wide association study (GWAS) results from eight independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significantly associated SNPs in two Australian studies (1,252 cases and 2,592 controls), three European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of the top SNPs identified three new associated loci: rs35934224[T] in TXNRD2 (odds ratio (OR) = 0.78, P = 4.05 × 10(-11)) encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] in 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 new targets for preventative therapies.
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Project description:BackgroundRecent studies suggest that glaucoma is a neurodegenerative disease in which secondary degenerative losses occur after primary insult by raised Intraocular pressure (IOP) or by other associated factors. It has been reported that polymorphisms in the IL1A and IL1B genes are associated with Primary Open Angle Glaucoma (POAG). The purpose of our study was to investigate the role of these polymorphisms in eastern Indian POAG patients.MethodsThe study involved 315 unrelated POAG patients, consisting of 116 High Tension Glaucoma (HTG) patients with intra ocular pressure (IOP) > 21 mmHg and 199 non-HTG patients (presenting IOP < 20 mmHg), and 301 healthy controls from eastern India. Genotypes were determined by polymerase chain reaction and restriction digestion for three single nucleotide polymorphisms (SNPs): IL1A (-889C/T; rs1800587), IL1B (-511C/T; rs16944) and IL1B (3953C/T; rs1143634). Haplotype frequency was determined by Haploview 4.1 software. The association of individual SNPs and major haplotypes was evaluated using chi-square statistics. The p-value was corrected for multiple tests by Bonferroni method.ResultsNo significant difference was observed in the allele and genotype frequencies for IL1A and IL1B SNPs between total pool of POAG patients and controls. However, on segregating the patient pool to HTG and non-HTG groups, weak association was observed for IL1A polymorphism (-889C/T) where -889C allele was found to portray risk (OR = 1.380; 95% CI = 1.041-1.830; p = 0.025) for non-HTG patients. Similarly, 3953T allele of IL1B polymorphism (+3953C/T) was observed to confer risk to HTG group (OR = 1.561; 95% CI = 1.022-2.385; p = 0.039). On haplotype analysis it was observed that TTC was significantly underrepresented in non-HTG patients (OR = 0.538; 95% CI = 0.356- 0.815; p = 0.003) while TCT haplotype was overrepresented in HTG patients (OR = 1.784; 95% CI = 1.084- 2.937; p = 0.022) compared to control pool. However, after correction for multiple tests by Bonferroni method, an association of only TTC haplotype with non-HTG cases sustained (pcorrected = 0.015) and expected to confer protection.ConclusionThe study suggests that the genomic region containing the IL1 gene cluster influences the POAG pathogenesis mostly in non-HTG patients in eastern India. A similar study in additional and larger cohorts of patients in other population groups is necessary to further substantiate the observation.
| S-EPMC2909939 | biostudies-literature
Project description:PurposeTo determine if open-angle glaucoma (OAG)-associated single nucleotide polymorphisms (SNPs) are associated with incident glaucoma and if such genetic information is useful in OAG risk prediction.DesignCase-control from within a population-based longitudinal study.Methodsstudy population: Individuals aged over 49 years of age living in the Blue Mountains region west of Sydney and enrolled in the Blue Mountains Eye Study. observation: Cases for this sub-study (n = 67) developed incident OAG between baseline and 10-year visits, in either eye, while controls (n = 1919) had no evidence for OAG at any visit. All participants had an ocular examination and DNA genotyped for reported OAG risk SNPs. main outcome measure: Incident OAG.ResultsTwo loci also known to be associated with cup-to-disc ratio as well as OAG (9p21 near CDKN2B-AS1 and SIX1/SIX6) were both significantly associated with incident OAG in the Blue Mountains Eye Study cohort (P = .006 and P = .004, respectively). The TMCO1 locus was nominally associated (P = .012), while the CAV1/CAV2 and 8q22 loci were not associated. Multivariate logistic regression and neural network analysis both indicated that the genetic risk factors contributed positively to the predictive models incorporating traditional risk factors.ConclusionsThis study shows that previously reported genetic variations related to OAG and cup-to-disc ratio are associated with the onset of OAG and thus may become useful in risk prediction algorithms designed to target early treatment to those most at risk of developing glaucoma.
| S-EPMC4265734 | biostudies-literature
Project description:Primary open angle glaucoma (POAG) is a characteristic optic neuropathy which progresses to irreversible vision loss. Few genes have been detected that influence POAG susceptibility and other genes are therefore likely to be involved. We analyzed carefully characterized POAG cases in a genome-wide association study (GWAS).We performed a GWAS in 387 POAG cases using public control data (WTCCC2). We also investigated the quantitative phenotypes, cup:disc ratio (CDR), central corneal thickness (CCT), and intra-ocular pressure (IOP). Promising single nucleotide polymorphisms (SNPs), based on various prioritisation criteria, were genotyped in a cohort of 294 further POAG cases and controls.We found 2 GWAS significant results in the discovery stage for association, one of which which had multiple evidence in the gene 'neural precursor cell expressed, developmentally down-regulated 9' (NEDD9; rs11961171, p=8.55E-13) and the second on chromosome 16 with no supporting evidence. Taking into account all the evidence from risk and quantitative trait ocular phenotypes we chose 86 SNPs for replication in an independent sample. Our most significant SNP was not replicated (p=0.59). We found 4 nominally significant results in the replication cohort, but none passed correction for multiple testing. Two of these, for phenotypes CDR (rs4385494, discovery p=4.51x10-5, replication p=0.029) and CCT (rs17128941, discovery p=5.52x10-6, replication=0.027), show the consistent direction of effects between the discovery and replication data. We also assess evidence for previously associated known genes and find evidence for the genes 'transmembrane and coiled-coil domains 1' (TMCO1) and 'cyclin-dependent kinase inhibitor 2B' (CDKN2B).Although we were unable to replicate any novel results for POAG risk, we did replicate two SNPs with consistent effects for CDR and CCT, though they do not withstand correction for multiple testing. There has been a range of publications in the last couple of years identifying POAG risk genes and genes involved in POAG related ocular traits. We found evidence for 3 known genes (TMCO1, CDKN2B, and S1 RNA binding domain 1 [SRBD1]) in this study. Novel rare variants, not detectable by GWAS, but by new methods such as exome sequencing may hold the key to unravelling the remaining contribution of genetics to complex diseases such as POAG.
| S-EPMC3351427 | biostudies-literature
Project description:A substantial fraction of glaucoma has a genetic basis. About 5% of primary open angle glaucoma (POAG) is currently attributed to single-gene or Mendelian forms of glaucoma (ie glaucoma caused by mutations in myocilin or optineurin). Mutations in these genes have a high likelihood of leading to glaucoma and are rarely seen in normal subjects. Other cases of POAG have a more complex genetic basis and are caused by the combined effects of many genetic and environmental risk factors, each of which do not act alone to cause glaucoma. These factors are more frequently detected in patients with POAG, but are also commonly observed in normal subjects. Additional genes that may be important in glaucoma pathogenesis have been investigated using quantitative traits approaches. Such studies have begun to identify genes that control the magnitude of important quantitative features of glaucoma that may also be important risk factors for POAG, such as central corneal thickness. Each of these different approaches to study glaucoma genetics is providing new insights into the pathogenesis of POAG.
| S-EPMC3171270 | biostudies-literature
Project description:The total RNA from control and POAG optic nerve lamina cribrosa region was isolated and subjected to analysis on U133A 2.0 affymetrix microarray chip. The results from these two analysis was compared to determine whether PAD II RNA level is altered. Purpose of the study. This study was done to determine which RNA transcripts undergo significant changes in the optic nerve between normal and cadaver primary open-angle glaucoma donors. Using donor tissues from NDRI we have performed proteomic analyses (which will be published shortly), we intend a comparison between the proteomic and RNA changes for select proteins in our study. Sample Collection and Preparation of Labeled Copy RNA; The total RNA from optic nerve was obtained using TRIZOL (Invitrogen Inc., Carlsbad, CA) with modification of recommended protocols. The optic nerve from donor eyes were carefully excised and minced into small pieces first using a scissor and then a scalpel. Prior to use tissue was washed with DEPC water and all solutions were prepared in DEPC water. The minced tissue was placed in a glass homogenizer with 1 ml TRIZOL per 100 mg of tissue and homogenized in a glass homogenizer DUALL 20 (Kimble Kontes Glass Co, Vineland, NJ) with 10 strokes cycles each at room temperature and after freezing with liquid nitrogen for 1 min for 40 cycles. This RNA was extracted with chloroform, isoamylalcohol and precipitated with sodium citrate/sodium chloride and isopropanol. The final air-dried RNA precipitate was suspended in DEPC water and stored in â??80oC prior to use. RNA was prepared for hybridization according to the GeneChip Expression Analysis Technical Manual (Affymetrix, Santa Clara, CA). The hybridization was performed at Gene Expression Array Core Facility at Case Western Reserve University (www.geacf.net). The RNA sample was cleaned using a column from a Qiagen RNeasy kit, (part # 74104 ) in accordance with the manufacturerâ??s instructions. The volume of DEPC water used to elute the RNA from the Qiagen column was dictated by the nominal mass of the loaded RNA sample. Samples were eluted in 100ml of water, precipitated with 0.5 volume of 7.5M Ammonium Acetate and 2.5 volumes of 100% ethanol at -20oC for 1 hr and centrifuged for 10 min at room temperature. The pellet was drained and washed twice in 500µl of 70% ethanol. Supernatant was aspirated. The pellet was dried briefly (less than 1 min) in a speeedvac (Savant) and re-suspended in a small volume (~ 12â??15ml) of DEPC water. A small aliquot (2ml) of the sample was used for quantitation. Cleaned RNA samples were annotated as â??clnRNAâ?? and stored at -20oC. cDNA Synthesis; The protocol recommended by Affymetrix Inc. for cDNA synthesis was used at all times. The reaction was primed by annealing an oligo-dT primer coupled to a T7 RNA polymerase promoter to the RNA sample. Whenever possible, 8 mg of clnRNA were reverse transcribed using Superscript II reverse transcriptase in a 20ml reaction at 42oC for 1 hr. Second strand synthesis was carried out immediately in a total reaction volume of 150ml in the presence of E. coli DNA polymerase I, RNAse H and DNA ligase. The reaction mixture incubated for 2 hrs at 16oC and for a further 5 min in the presence of T4 DNA pol.. The reaction was terminated by the addition of EDTA. The sample was cleaned with a Qiagen cDNA clean-up column according to the manufacturers directions. The elution buffer volume was 14ml. The eluted samples were stored overnight at -20oC. In-Vitro Transcription (IVT) reaction; In a 0.5ml microfuge tube, complementary RNA (cRNA) was generated in an IVT reaction using a BioArray High Yield ENZO kit (Affymetrix). The 40ml reaction contained 10ml of cDNA sample and was incubated at 37oC in the heating block for 4-5hrs. Samples were mixed by flicking, pulse-centrifuged and returned to the incubator once every 40 minutes. Upon completion of the reaction, IVT samples were adjusted to a volume of 100ml with DEPC-treated water and cleaned using Qiagen RNA clean-up columns. Samples were eluted in 45ml of DEPC-treated water. A 2ml-aliquot was used for quantitation. Corrected concentrations of cRNA (minus the input clnRNA) were determined. A standard fragmentation reaction volume was 40ml in a 0.5 ml microfuge tube and used 20mg of overall IVT RNA in 1X fragmentation buffer (40mM Tris acetate, pH 8.1, 100mM KOAc, 30mM MgOAc). The reaction was incubated at 94oC for 35min in a heat block. After the 35 min incubation the fragmented samples were placed on ice. The standard hybridization cocktail volume was 300ml. 150ml of 2X hybridization buffer was added (final concentrations : 100mM MES, 1M [Na+], 20mM EDTA, 0.01% Tween 20) Herring sperm and acetylated BSA were added to a final concentration of 0.1 and 0.5mg/ml respectively. The amount of fragmentation reaction containing 15mg of cRNA was added to the cocktail and the remaining volume was made up with molecular biology grade water. A 15ml aliquot of a 20X mixture of in-vitro transcripts of bacterial genes BioB BioC BioD and cre as external controls (spikes) were added to the cocktail to give final concentrations of 1.5, 5, 25 and 100pM respectively. Control oligonucleotide (5ml) was added to a final concentration of 50pM. Array Hybridization; Sample Hyridization cocktails (300ml) were removed from storage at â??20oC and thawed in a 45oC temperature block. The samples were incubated at 45oC for 5 min, incubated at 45oC for 5 min and then centrifuged at 15,000g for 5 min. This study used commercially available Affymetrix HG U133A 2.0 arrays only. These are in situ synthesized, high density oligonucleotide arrays which can interrogate 22,777 gene entities. The part number is 900444 more detailed information may be found at www.affymetrix.com website. Meanwhile, the affymetrix chip arrays were taken from their storage at 4oC and allowed to come to room temperature. The chamber was filled with 1X hybridization buffer (final concentrations : 100mM MES, 1M [Na+], 20mM EDTA, 0.01% Tween 20). The chip was then preconditioned by incubation in the hybridization oven at 45oC for 10 min. The chip was removed and the chamber drained. Sample cocktails (200ml) were then introduced into the chamber of the chips. The ports were sealed with tough-spots stickers and placed in the hybridization oven and incubated at 45oC with rotation overnight. Next day (16hr later), the incubation was terminated and the chips removed from the oven. Samples were retrieved from the chips and stored again in a freezer at -20oC. The chips were filled with buffer A and placed in a module of Fluidics 400 wash station. The chips were subjected to the Affymetrix â??EuKws4 ver 2â?? programmed series of stringent post hybridization washes, staining and post-staining washes in accordance with Affy protocols. Upon completion of the wash series (approximately 2 hrs), the chips were removed from the Fluidics station. The chips were inspected. Chips were scanned using an Agilent Gene Array scanner 3000 driven by Affymetrix GCOS software. Generation of Expression Values; Microarray Suite, version 5 (Affymetrix), was used to generate *.cel files, and a computer program (Probe Profiler, ver. 1.3.11; Corimbia Inc., Berkeley, CA) developed specifically for the GeneChip system (Affymetrix) was used to convert intensity data into quantitative estimates of gene expression for each probe set. The software identifies informative probe pairs, and down-weights the signal contribution of probe pairs that are subject to differential cross-hybridization effects or that consistently produce no signal. The software also detects and corrects for saturation artifacts, outliers, and chip defects. A probability statistic was generated for each probe set. The probability is associated with the null hypothesis that the expression level of the probe set is equal to zero (background). Genes not significantly expressed above background in any of the samples (P > 0.05) were
2008-06-12 | E-GEOD-2387 | biostudies-arrayexpress