Density of Common Complex Ocular Traits in the Aging Eye: Analysis of Secondary Traits in Genome-Wide Association Studies

Genetic association studies are identifying genetic risks for common complex ocular traits such as age-related macular degeneration (AMD). The subjects used for discovery of these loci have been largely from clinic-based, case-control studies. Typically, only the primary phenotype (e.g., AMD) being studied is systematically documented and other complex traits (e.g., affecting the eye) are largely ignored. The purpose of this study was to characterize these other or secondary complex ocular traits present in the cases and controls of clinic-based studies being used for genetic study of AMD. The records of 100 consecutive new patients (of any diagnosis) age 60 or older for which all traits affecting the eye had been recorded systematically were reviewed. The average patient had 3.5 distinct diagnoses. A subset of 10 complex traits was selected for further study because they were common and could be reliably diagnosed. The density of these 10 complex ocular traits increased by 0.017 log-traits/year (P = 0.03), ranging from a predicted 2.74 at age 60 to 4.45 at age 90. Trait-trait association was observed only between AMD and primary vitreomacular traction (P = 0.0009). Only 1% of subjects age 60 or older had no common complex traits affecting the eye. Extrapolations suggested that a study of 2000 similar subjects would have sufficient power to detect genetic association with an odds ratio of 2.0 or less for 4 of these 10 traits. In conclusion, the high prevalence of complex traits affecting the aging eye and the inherent biases in referral patterns leads to the potential for confounding by undocumented secondary traits within case-control studies. In addition to the primary trait, other common ocular phenotypes should be systematically documented in genetic association studies so that adjustments for potential trait-trait associations and other bias can be made and genetic risk variants identified in secondary analyses

Consensus guidelines for the use and interpretation of angiogenesis assays

The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations. This article describes in vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis and highlights critical aspects that are relevant for their execution and proper interpretation. As such, this collaborative work is the first edition of consensus guidelines on angiogenesis bioassays to serve for current and future reference

Clinical Implications of Old and New Genes for Open-Angle Glaucoma

Objective: Genome-wide association studies have revealed new insights into the genetic determinants of open-angle glaucoma (OAG). This study was performed to determine to what extent variants within established genes (MYOC, OPTN, and WDR36) and newly identified common genetic variants (ATOH7, CDKN2B, and SIX1) contribute to the risk of OAG. Design: Population-based setting, family-based setting, and a case-control study. Participants: The Rotterdam Study I cohort (N = 5312; mean age +/- standard deviation [SD], 68.0 +/- 8.4 years). Findings were replicated in the Genetic Research in Isolated Populations combined with the Erasmus Rucphen Family study (N = 1750; mean age +/- SD, 48.3 +/- 15.2 years), and a cohort from Southampton (N = 702; mean age +/- SD, 72.5 +/- 10.7 years). Methods: After identifying common variants associated with OAG within the established genes, the risk of OAG was analyzed using logistic regression. Discriminative accuracy was assessed by comparing the area under the receiver operator characteristic curve (AUC) for models, including the number of risk alleles, intraocular pressure, age, and gender, with the AUC for the same model but without the risk alleles. Main Outcome Measures: Odds ratios and AUCs of individual and combined risk alleles. Results: No consistent significant associations for the established genes (MYOC, OPTN, and WDR36) with OAG were found. However, when comparing the load of risk variants between cases and controls, 2 of 3 studies showed a significant increased risk of OAG for participants carrying more risk alleles of the 3 established genes. When combining all 6 genes, participants carrying a high number of risk alleles (highest tertile) had a 2.29-fold to 3.19-fold increase in risk of OAG compared with those carrying only a few risk alleles. The addition of the newly identified genes to IOP, age, and gender resulted in a higher AUC compared with the AUC without the newly identified genes (P = 0.027). Conclusions: A significant contribution to the risk of OAG was found for the new common variants identified by recent genome-wide association studies, but not for variants within the established genes. Participants carrying a high number of risk alleles had an approximately 3-fold increase in the risk of OAG compared with those with a low number of risk alleles. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2011; 118: 2389-2397 (C) 2011 by the American Academy of Ophthalmology

Meta-analysis of genome-wide association studies identifies novel loci that influence cupping and the glaucomatous process

Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important disease-related optic nerve parameter. In 21,094 individuals of European ancestry and 6,784 individuals of Asian ancestry, we identify 10 new loci associated with variation in VCDR. In a separate risk-score analysis of five case-control studies, Caucasians in the highest quintile have a 2.5-fold increased risk of primary open-angle glaucoma as compared with those in the lowest quintile. This study has more than doubled the known loci associated with optic disc cupping and will allow greater understanding of mechanisms involved in this common blinding condition

Role and regulation of growth plate vascularization during coupling with osteogenesis in tibial dyschondroplasia of chickens

Abstract Tibial dyschondroplasia (TD) is the most-prevalent leg disorder in fast-growing chickens; it is intractable and characterized by abnormal endochondral bone formation of proximal tibial growth-plates (TGPs). Previous studies have shown that bone is a highly vascularized tissue dependent on the coordinated coupling between angiogenesis and osteogenesis, but the underlying mechanisms of bone formation and bone remodeling are poorly defined in TD chickens. Here, we observed that inhibition of vasculogenesis and angiogenesis remarkably impaired vascular invasion in the hypertrophic chondrocyte zone of the TGPs, resulting in the massive death of chondrocytes due to a shortage of blood vessels and nutrients. Moreover, the balance of the OPG (osteoprotegerin)/RANKL (receptor activator of nuclear factor-kB ligand) system is also severely disrupted during the osteogenesis process while coupling with angiogenesis, both of which eventually lead to abnormal endochondral bone formation in TD chickens. Thus, the process of vascular formation in endochondral bone appears to initiate the pathological changes in TD, and improvement of this process during coupling with osteogenesis may be a potential therapeutic approach to treat this intractable disease