19 research outputs found
Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases
Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r =-0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r =-0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation
5-HT2 Receptor-Mediated Phosphoinositide Hydrolysis in Bovine Ciliary Epithelium
The serotonin 2 (5-HT2) receptor antagonists, MCI-9042 (Anplag®) and ketanserin, have been shown to lower intraocular pressure in rabbits (1) and humans (2). The mechanism of action of these drugs has not been determined, but it is hypothesized that 5-HT2 receptors, and possibly α-adrenergic receptors, (3) may regulate in part aqueous humor production via an intracellular signal transduction pathway in the ciliary body. We therefore examined whether 5-HT2 receptors were coupled to phosphoinositide hydrolysis in an organ culture system of isolated bovine ciliary epithelium. 5-HT stimulated [3H]inositol phosphates ([3H]InsPs) accumulation in a dose-dependent manner with a maximum increase approximately twice over the basal level. The mean EC50 value was 1.1 μM, which was calculated from four dose-response curves. The 5-HT stimulated accumulation of [3H]InsPs was inhibited by spiperone (5-HT2A/1A and dopamine 2 (D2) antagonists), M-1 (a major metabolite of MCI-9042), ketanserin (5-HT2A antagonist), SB-206553 (5- HT2B/2C antagonist), and mesulergine (5-HT2C antagonist and D2 agonist). It was not inhibited by chlorpromazine, which is a D2 receptor antagonist. Accordingly, our study demonstrates that 5-HT2 receptors are coupled to phospholipase C in bovine ciliary epithelium.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63244/1/108076803762718114.pd
Tolerance to the Miotic Effect of Sarin Vapor in Rats After Multiple Low-Level Exposures
Genetic correlations between intraocular pressure, blood pressure and primary open-angle glaucoma: a multi-cohort analysis
Item does not contain fulltextPrimary open-angle glaucoma (POAG) is the most common chronic optic neuropathy worldwide. Epidemiological studies show a robust positive relation between intraocular pressure (IOP) and POAG and modest positive association between IOP and blood pressure (BP), while the relation between BP and POAG is controversial. The International Glaucoma Genetics Consortium (n=27 558), the International Consortium on Blood Pressure (n=69 395), and the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database (n=37 333), represent genome-wide data sets for IOP, BP traits and POAG, respectively. We formed genome-wide significant variant panels for IOP and diastolic BP and found a strong relation with POAG (odds ratio and 95% confidence interval: 1.18 (1.14-1.21), P=1.8 x 10(-27)) for the former trait but no association for the latter (P=0.93). Next, we used linkage disequilibrium (LD) score regression, to provide genome-wide estimates of correlation between traits without the need for additional phenotyping. We also compared our genome-wide estimate of heritability between IOP and BP to an estimate based solely on direct measures of these traits in the Erasmus Rucphen Family (ERF; n=2519) study using Sequential Oligogenic Linkage Analysis Routines (SOLAR). LD score regression revealed high genetic correlation between IOP and POAG (48.5%, P=2.1 x 10(-5)); however, genetic correlation between IOP and diastolic BP (P=0.86) and between diastolic BP and POAG (P=0.42) were negligible. Using SOLAR in the ERF study, we confirmed the minimal heritability between IOP and diastolic BP (P=0.63). Overall, IOP shares genetic basis with POAG, whereas BP has limited shared genetic correlation with IOP or POAG
Discovery and Functional Annotation of SIX6 Variants in Primary Open-Angle Glaucoma
10.1371/journal.pgen.1004372PLoS Genetics105e100437
Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma
Ophthalmic researc
Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry
Item does not contain fulltextImportance: Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders. Objectives: To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma. Design, Settings, and Participants: A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma. Exposures: Genetic variants associated with primary open-angle glaucoma. Main Outcomes and Measures: Presence of primary open-angle glaucoma. Genome-wide significance was defined as P C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 x 10-8). The association was validated in an analysis of an additional 6937 affected individuals and 14917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P < .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 x 10-13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry. Conclusions and Relevance: In this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies
Erratum to: Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases (Nature Communications, (2018), 9, 1, (1864), 10.1038/s41467-018-03646-6)
10.1038/s41467-018-07819-1Nature Communications10115