Genome-wide association study of corneal biomechanical properties identifies over 200 loci providing insight into the genetic aetiology of ocular diseases.
Simcoe Mark J,Khwaja Anthony P,Eye U K Biobank,Consortium Vision,Hysi Pirro G,Hammond Christopher J
Human molecular genetics
Corneal hysteresis and corneal resistance factor are parameters which reflect the dynamic biomechanical properties of the cornea and have been shown to be biomarkers of corneal disease. In this genome-wide association study of over 100 000 participants we identified over 200 genetic loci, all but eight novel, significantly associated with either one or both of these traits. In addition to providing key insights into the genetic architecture underlying normal corneal function, these results identify many candidate loci in the study of corneal diseases that lead to severe visual impairment. Additionally, using Mendelian randomisation we were able to identify causal relationships between corneal biomechanics and intraocular pressure measurements which help elucidate the relationship between corneal properties and glaucoma.
Regional pathology in glaucoma--an overlooked link to neuroprotective strategies.
Clarke Margo S
Primary open-angle glaucoma (POAG) is the second commonest cause of blindness in the world. It is a neurodegenerative disease characterized by retinal ganglion cell loss. The molecular mechanism leading to glaucoma damage is unclear. Understanding the pathways that favor neuronal survival plus those that predispose to neuronal demise in POAG may have direct implications for other neurodegenerative diseases. POAG is a heterogeneous disease. A small subset of POAG patients develop damage in a highly focal form with a discrete sector of the optic nerve manifesting well delineated neuronal loss. It is hypothesized that this pattern of nerve loss indicates the optic nerve is not molecularly homogeneous. Genetic analysis of patients with isolated focal forms of POAG may enable new genes to be identified in glaucoma. Finding the responsible genes in POAG is a critical first step. The potential implications are earlier disease detection with resultant optimized visual preservation. Future treatment options could develop that include altered gene regulation, gene silencing or introducing repair genes. Determining the molecular causes for regional neuronal susceptibility could lead to identification of pathways underlying disease and ultimately effective patient-specific neuroprotective strategies.
Clinical implications of recent advances in primary open-angle glaucoma genetics.
Choquet Hélène,Wiggs Janey L,Khawaja Anthony P
Eye (London, England)
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 analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma.
Bailey Jessica N Cooke,Loomis Stephanie J,Kang Jae H,Allingham R Rand,Gharahkhani Puya,Khor Chiea Chuen,Burdon Kathryn P,Aschard Hugues,Chasman Daniel I,Igo Robert P,Hysi Pirro G,Glastonbury Craig A,Ashley-Koch Allison,Brilliant Murray,Brown Andrew A,Budenz Donald L,Buil Alfonso,Cheng Ching-Yu,Choi Hyon,Christen William G,Curhan Gary,De Vivo Immaculata,Fingert John H,Foster Paul J,Fuchs Charles,Gaasterland Douglas,Gaasterland Terry,Hewitt Alex W,Hu Frank,Hunter David J,Khawaja Anthony P,Lee Richard K,Li Zheng,Lichter Paul R,Mackey David A,McGuffin Peter,Mitchell Paul,Moroi Sayoko E,Perera Shamira A,Pepper Keating W,Qi Qibin,Realini Tony,Richards Julia E,Ridker Paul M,Rimm Eric,Ritch Robert,Ritchie Marylyn,Schuman Joel S,Scott William K,Singh Kuldev,Sit Arthur J,Song Yeunjoo E,Tamimi Rulla M,Topouzis Fotis,Viswanathan Ananth C,Verma Shefali Setia,Vollrath Douglas,Wang Jie Jin,Weisschuh Nicole,Wissinger Bernd,Wollstein Gadi,Wong Tien Y,Yaspan Brian L,Zack Donald J,Zhang Kang,Study Epic-Norfolk Eye, ,Weinreb Robert N,Pericak-Vance Margaret A,Small Kerrin,Hammond Christopher J,Aung Tin,Liu Yutao,Vithana Eranga N,MacGregor Stuart,Craig Jamie E,Kraft Peter,Howell Gareth,Hauser Michael A,Pasquale Louis R,Haines Jonathan L,Wiggs Janey L
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.
Genome-wide analyses identify 68 new loci associated with intraocular pressure and improve risk prediction for primary open-angle glaucoma.
Khawaja Anthony P,Cooke Bailey Jessica N,Wareham Nicholas J,Scott Robert A,Simcoe Mark,Igo Robert P,Song Yeunjoo E,Wojciechowski Robert,Cheng Ching-Yu,Khaw Peng T,Pasquale Louis R,Haines Jonathan L,Foster Paul J,Wiggs Janey L,Hammond Chris J,Hysi Pirro G, ,
Glaucoma is the leading cause of irreversible blindness globally . Despite its gravity, the disease is frequently undiagnosed in the community . Raised intraocular pressure (IOP) is the most important risk factor for primary open-angle glaucoma (POAG). Here we present a meta-analysis of 139,555 European participants, which identified 112 genomic loci associated with IOP, 68 of which are novel. These loci suggest a strong role for angiopoietin-receptor tyrosine kinase signaling, lipid metabolism, mitochondrial function and developmental processes underlying risk for elevated IOP. In addition, 48 of these loci were nominally associated with glaucoma in an independent cohort, 14 of which were significant at a Bonferroni-corrected threshold. Regression-based glaucoma-prediction models had an area under the receiver operating characteristic curve (AUROC) of 0.76 in US NEIGHBORHOOD study participants and 0.74 in independent glaucoma cases from the UK Biobank. Genetic-prediction models for POAG offer an opportunity to target screening and timely therapy to individuals most at risk.