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1. Specialist vision-language models for clinical ophthalmology

Author

Holland, Robbie, Taylor, Thomas R. P., Holmes, Christopher, Riedl, Sophie, Mai, Julia, Patsiamanidi, Maria, Mitsopoulou, Dimitra, Hager, Paul, Müller, Philip, Scholl, Hendrik P. N., Bogunović, Hrvoje, Schmidt-Erfurth, Ursula, Rueckert, Daniel, Sivaprasad, Sobha, Lotery, Andrew J., and Menten, Martin J.

Subjects
Computer Science - Artificial Intelligence
Abstract

Clinicians spend a significant amount of time reviewing medical images and transcribing their findings regarding patient diagnosis, referral and treatment in text form. Vision-language models (VLMs), which automatically interpret images and summarize their findings as text, have enormous potential to alleviate clinical workloads and increase patient access to high-quality medical care. While foundational models have stirred considerable interest in the medical community, it is unclear whether their general capabilities translate to real-world clinical utility. In this work, we show that foundation VLMs markedly underperform compared to practicing ophthalmologists on specialist tasks crucial to the care of patients with age-related macular degeneration (AMD). To address this, we initially identified the essential capabilities required for image-based clinical decision-making, and then developed a curriculum to selectively train VLMs in these skills. The resulting model, RetinaVLM, can be instructed to write reports that significantly outperform those written by leading foundation medical VLMs in disease staging (F1 score of 0.63 vs. 0.11) and patient referral (0.67 vs. 0.39), and approaches the diagnostic performance of junior ophthalmologists (who achieve 0.77 and 0.78 on the respective tasks). Furthermore, in a reader study involving two senior ophthalmologists with up to 32 years of experience, RetinaVLM's reports were found to be similarly correct (78.6% vs. 82.1%) and complete (both 78.6%) as reports written by junior ophthalmologists with up to 10 years of experience. These results demonstrate that our curriculum-based approach provides a blueprint for specializing generalist foundation medical VLMs to handle real-world clinical tasks., Comment: Submitted to Nature Medicine

Published
2024

2. Deep-learning-based clustering of OCT images for biomarker discovery in age-related macular degeneration (Pinnacle study report 4)

Author

Holland, Robbie, Kaye, Rebecca, Hagag, Ahmed M., Leingang, Oliver, Taylor, Thomas R. P., Bogunović, Hrvoje, Schmidt-Erfurth, Ursula, Scholl, Hendrik P. N., Rueckert, Daniel, Lotery, Andrew J., Sivaprasad, Sobha, and Menten, Martin J.

Subjects
Electrical Engineering and Systems Science - Image and Video Processing, Computer Science - Artificial Intelligence
Abstract

Diseases are currently managed by grading systems, where patients are stratified by grading systems into stages that indicate patient risk and guide clinical management. However, these broad categories typically lack prognostic value, and proposals for new biomarkers are currently limited to anecdotal observations. In this work, we introduce a deep-learning-based biomarker proposal system for the purpose of accelerating biomarker discovery in age-related macular degeneration (AMD). It works by first training a neural network using self-supervised contrastive learning to discover, without any clinical annotations, features relating to both known and unknown AMD biomarkers present in 46,496 retinal optical coherence tomography (OCT) images. To interpret the discovered biomarkers, we partition the images into 30 subsets, termed clusters, that contain similar features. We then conduct two parallel 1.5-hour semi-structured interviews with two independent teams of retinal specialists that describe each cluster in clinical language. Overall, both teams independently identified clearly distinct characteristics in 27 of 30 clusters, of which 23 were related to AMD. Seven were recognised as known biomarkers already used in established grading systems and 16 depicted biomarker combinations or subtypes that are either not yet used in grading systems, were only recently proposed, or were unknown. Clusters separated incomplete from complete retinal atrophy, intraretinal from subretinal fluid and thick from thin choroids, and in simulation outperformed clinically-used grading systems in prognostic value. Overall, contrastive learning enabled the automatic proposal of AMD biomarkers that go beyond the set used by clinically established grading systems. Ultimately, we envision that equipping clinicians with discovery-oriented deep-learning tools can accelerate discovery of novel prognostic biomarkers.

Published
2024

3. Clustering disease trajectories in contrastive feature space for biomarker discovery in age-related macular degeneration

Author

Holland, Robbie, Leingang, Oliver, Holmes, Christopher, Anders, Philipp, Kaye, Rebecca, Riedl, Sophie, Paetzold, Johannes C., Ezhov, Ivan, Bogunović, Hrvoje, Schmidt-Erfurth, Ursula, Fritsche, Lars, Scholl, Hendrik P. N., Sivaprasad, Sobha, Lotery, Andrew J., Rueckert, Daniel, and Menten, Martin J.

Subjects
Electrical Engineering and Systems Science - Image and Video Processing, Computer Science - Computer Vision and Pattern Recognition
Abstract

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. Current grading systems based on imaging biomarkers only coarsely group disease stages into broad categories and are unable to predict future disease progression. It is widely believed that this is due to their focus on a single point in time, disregarding the dynamic nature of the disease. In this work, we present the first method to automatically discover biomarkers that capture temporal dynamics of disease progression. Our method represents patient time series as trajectories in a latent feature space built with contrastive learning. Then, individual trajectories are partitioned into atomic sub-sequences that encode transitions between disease states. These are clustered using a newly introduced distance metric. In quantitative experiments we found our method yields temporal biomarkers that are predictive of conversion to late AMD. Furthermore, these clusters were highly interpretable to ophthalmologists who confirmed that many of the clusters represent dynamics that have previously been linked to the progression of AMD, even though they are currently not included in any clinical grading system., Comment: Submitted to MICCAI2023

Published
2023

5. Metadata-enhanced contrastive learning from retinal optical coherence tomography images

Author

Holland, Robbie, Leingang, Oliver, Bogunović, Hrvoje, Riedl, Sophie, Fritsche, Lars, Prevost, Toby, Scholl, Hendrik P. N., Schmidt-Erfurth, Ursula, Sivaprasad, Sobha, Lotery, Andrew J., Rueckert, Daniel, and Menten, Martin J.

Subjects
Computer Science - Computer Vision and Pattern Recognition
Abstract

Deep learning has potential to automate screening, monitoring and grading of disease in medical images. Pretraining with contrastive learning enables models to extract robust and generalisable features from natural image datasets, facilitating label-efficient downstream image analysis. However, the direct application of conventional contrastive methods to medical datasets introduces two domain-specific issues. Firstly, several image transformations which have been shown to be crucial for effective contrastive learning do not translate from the natural image to the medical image domain. Secondly, the assumption made by conventional methods, that any two images are dissimilar, is systematically misleading in medical datasets depicting the same anatomy and disease. This is exacerbated in longitudinal image datasets that repeatedly image the same patient cohort to monitor their disease progression over time. In this paper we tackle these issues by extending conventional contrastive frameworks with a novel metadata-enhanced strategy. Our approach employs widely available patient metadata to approximate the true set of inter-image contrastive relationships. To this end we employ records for patient identity, eye position (i.e. left or right) and time series information. In experiments using two large longitudinal datasets containing 170,427 retinal OCT images of 7,912 patients with age-related macular degeneration (AMD), we evaluate the utility of using metadata to incorporate the temporal dynamics of disease progression into pretraining. Our metadata-enhanced approach outperforms both standard contrastive methods and a retinal image foundation model in five out of six image-level downstream tasks related to AMD. Due to its modularity, our method can be quickly and cost-effectively tested to establish the potential benefits of including available metadata in contrastive pretraining.

Published
2022

6. Zfp503/Nlz2 Is Required for RPE Differentiation and Optic Fissure Closure

Author

Boobalan, Elangovan, Thompson, Amy H, Alur, Ramakrishna P, McGaughey, David M, Dong, Lijin, Shih, Grace, Vieta-Ferrer, Emile R, Onojafe, Ighovie F, Kalaskar, Vijay K, Arno, Gavin, Lotery, Andrew J, Guan, Bin, Bender, Chelsea, Memon, Omar, Brinster, Lauren, Soleilhavoup, Clement, Panman, Lia, Badea, Tudor C, Minella, Andrea, Lopez, Antonio Jacobo, Thomasy, Sara M, Moshiri, Ala, Blain, Delphine, Hufnagel, Robert B, Cogliati, Tiziana, Bharti, Kapil, and Brooks, Brian P

Subjects
Biomedical and Clinical Sciences, Ophthalmology and Optometry, Pediatric, Neurosciences, Biotechnology, Genetics, Eye Disease and Disorders of Vision, Aetiology, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Underpinning research, Eye, Animals, Humans, Mice, Coloboma, Gene Expression Regulation, Developmental, Homeodomain Proteins, Intracellular Signaling Peptides and Proteins, Melanins, Mice, Knockout, Nerve Tissue Proteins, Neuropeptides, Retina, Retinal Pigment Epithelium, Zebrafish, Zfp503, NLZ2, coloboma, development, optic fissure, Biological Sciences, Medical and Health Sciences, Ophthalmology & Optometry, Ophthalmology and optometry
Abstract

PurposeUveal coloboma is a congenital eye malformation caused by failure of the optic fissure to close in early human development. Despite significant progress in identifying genes whose regulation is important for executing this closure, mutations are detected in a minority of cases using known gene panels, implying additional genetic complexity. We have previously shown knockdown of znf503 (the ortholog of mouse Zfp503) in zebrafish causes coloboma. Here we characterize Zfp503 knockout (KO) mice and evaluate transcriptomic profiling of mutant versus wild-type (WT) retinal pigment epithelium (RPE)/choroid.MethodsZfp503 KO mice were generated by gene targeting using homologous recombination. Embryos were characterized grossly and histologically. Patterns and level of developmentally relevant proteins/genes were examined with immunostaining/in situ hybridization. The transcriptomic profile of E11.5 KO RPE/choroid was compared to that of WT.ResultsZfp503 is dynamically expressed in developing mouse eyes, and loss of its expression results in uveal coloboma. KO embryos exhibit altered mRNA levels and expression patterns of several key transcription factors involved in eye development, including Otx2, Mitf, Pax6, Pax2, Vax1, and Vax2, resulting in a failure to maintain the presumptive RPE, as evidenced by reduced melanin pigmentation and its differentiation into a neural retina-like lineage. Comparison of RNA sequencing data from WT and KO E11.5 embryos demonstrated reduced expression of melanin-related genes and significant overlap with genes known to be dynamically regulated at the optic fissure.ConclusionsThese results demonstrate a critical role of Zfp503 in maintaining RPE fate and optic fissure closure.

Published
2022

8. Comprehensive functional characterization of complement factor I rare variant genotypes identified in the SCOPE geographic atrophy cohort

Author

Arora, Rashi, Dennis, Marcus, Flaxel, Christina, Hall, Edward, Hoyng, Carel, Charbel Issa, Peter, Leveziel, Nicolas, Molnár, Fanni, Navarro, Rafael, Schneiderman, Todd, Steel, David, Tadayoni, Ramin, Tezel, Tongalp, Weber, Michel, Hallam, Thomas M., Andreadi, Anneliza, Sharp, Scott J., Brocklebank, Vicky, Gardenal, Emanuela, Dreismann, Anna, Lotery, Andrew J., Marchbank, Kevin J., Harris, Claire L., Jones, Amy V., and Kavanagh, David

Published
2024
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9. Central serous chorioretinopathy: An evidence-based treatment guideline

Author

Feenstra, Helena M.A., van Dijk, Elon H.C., Cheung, Chui Ming Gemmy, Ohno-Matsui, Kyoko, Lai, Timothy Y.Y., Koizumi, Hideki, Larsen, Michael, Querques, Giuseppe, Downes, Susan M., Yzer, Suzanne, Breazzano, Mark P., Subhi, Yousif, Tadayoni, Ramin, Priglinger, Siegfried G., Pauleikhoff, Laurenz J.B., Lange, Clemens A.K., Loewenstein, Anat, Diederen, Roselie M.H., Schlingemann, Reinier O., Hoyng, Carel B., Chhablani, Jay K., Holz, Frank G., Sivaprasad, Sobha, Lotery, Andrew J., Yannuzzi, Lawrence A., Freund, K. Bailey, and Boon, Camiel J.F.

Published
2024
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10. Periodontitis and Outer Retinal Thickness: a Cross-Sectional Analysis of the United Kingdom Biobank Cohort

Author

Allen, Naomi, Aslam, Tariq, Atan, Denize, Balaskas, Konsantinos, Barman, Sarah A., Barrett, Jenny H., Bishop, Paul, Black, Graeme, Braithwaite, Tasanee, Carare, Roxana O., Chakravarthy, Usha, Chan, Michelle, Chua, Sharon Y.L., Day, Alexander, Desai, Parul, Dhillon, Bal, Dick, Andrew D., Doney, Alexander, Egan, Cathy, Ennis, Sarah, Foster, Paul, Fruttiger, Marcus, Gallacher, John E.J., Garway-Heath, David F., Gibson, Jane, Guggenheim, Jeremy A., Hammond, Chris J., Hardcastle, Alison, Harding, Simon P., Hogg, Ruth E., Hysi, Pirro, Keane, Pearse A., Khaw, Sir Peng T., Khawaja, Anthony P., Lascaratos, Gerassimos, Littlejohns, Thoams, Lotery, Andrew J., Luben, Robert, Luthert, Phil, Macgillivray, Tom, Mackie, Sarah, McGuinness, Bernadette, McKay, Gareth J., McKibbin, Martin, Moore, Tony, Morgan, James E., O’Sullivan, Eoin, Oram, Richard, Owen, Chris G., Patel, Praveen, Paterson, Euan, Peto, Tunde, Petzold, Axel, Rahi, Jugnoo S., Rudnikca, Alicja R., Sattar, Naveed, Self, Jay, Sergouniotis, Panagiotis, Sivaprasad, Sobha, Steel, David, Stratton, Irene, Strouthidis, Nicholas, Sudlow, Cathie, Sun, Zihan, Tapp, Robyn, Thomas, Dhanes, Trucco, Emanuele, Tufail, Adnan, Vitart, Veronique, Viswanathan, Ananth C., Weedon, Mike, Williams, Cathy, Williams, Katie, Woodside, Jayne V., Yates, Max M., Yip, Jennifer, Zheng, Yalin, Wagner, Siegfried K., Patel, Praveen J., Huemer, Josef, Khalid, Hagar, Stuart, Kelsey V., Chu, Colin J., Williamson, Dominic J., Struyven, Robbert R., Romero-Bascones, David, Foster, Paul J., Balaskas, Konstantinos, Cortina-Borja, Mario, Chapple, Iain, Dietrich, Thomas, and Denniston, Alastair K.

Published
2024
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11. Large-scale multitrait genome-wide association analyses identify hundreds of glaucoma risk loci

Author

Han, Xikun, Gharahkhani, Puya, Hamel, Andrew R., Ong, Jue Sheng, Rentería, Miguel E., Mehta, Puja, Dong, Xianjun, Pasutto, Francesca, Hammond, Christopher, Young, Terri L., Hysi, Pirro, Lotery, Andrew J., Jorgenson, Eric, Choquet, Hélène, Hauser, Michael, Cooke Bailey, Jessica N., Nakazawa, Toru, Akiyama, Masato, Shiga, Yukihiro, Fuller, Zachary L., Wang, Xin, Hewitt, Alex W., Craig, Jamie E., Pasquale, Louis R., Mackey, David A., Wiggs, Janey L., Khawaja, Anthony P., Segrè, Ayellet V., and MacGregor, Stuart

Published
2023
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15. Clustering Disease Trajectories in Contrastive Feature Space for Biomarker Proposal in Age-Related Macular Degeneration

Author

Holland, Robbie, Leingang, Oliver, Holmes, Christopher, Anders, Philipp, Kaye, Rebecca, Riedl, Sophie, Paetzold, Johannes C., Ezhov, Ivan, Bogunović, Hrvoje, Schmidt-Erfurth, Ursula, Scholl, Hendrik P. N., Sivaprasad, Sobha, Lotery, Andrew J., Rueckert, Daniel, Menten, Martin J., Goos, Gerhard, Founding Editor, Hartmanis, Juris, Founding Editor, Bertino, Elisa, Editorial Board Member, Gao, Wen, Editorial Board Member, Steffen, Bernhard, Editorial Board Member, Yung, Moti, Editorial Board Member, Greenspan, Hayit, editor, Madabhushi, Anant, editor, Mousavi, Parvin, editor, Salcudean, Septimiu, editor, Duncan, James, editor, Syeda-Mahmood, Tanveer, editor, and Taylor, Russell, editor

Published
2023
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17. IMPG2-Related Maculopathy

Author

Birtel, Johannes, Caswell, Richard, De Silva, Samantha R., Herrmann, Philipp, Rehman, Salwah, Lotery, Andrew J., Mahroo, Omar A., Michaelides, Michel, Webster, Andrew R., MacLaren, Robert E., and Charbel Issa, Peter

Published
2024
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20. Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries.

Author

Gharahkhani, Puya, Jorgenson, Eric, Hysi, Pirro, Khawaja, Anthony P, Pendergrass, Sarah, Han, Xikun, Ong, Jue Sheng, Hewitt, Alex W, Segrè, Ayellet V, Rouhana, John M, Hamel, Andrew R, Igo, Robert P, Choquet, Helene, Qassim, Ayub, Josyula, Navya S, Cooke Bailey, Jessica N, Bonnemaijer, Pieter WM, Iglesias, Adriana, Siggs, Owen M, Young, Terri L, Vitart, Veronique, Thiadens, Alberta AHJ, Karjalainen, Juha, Uebe, Steffen, Melles, Ronald B, Nair, K Saidas, Luben, Robert, Simcoe, Mark, Amersinghe, Nishani, Cree, Angela J, Hohn, Rene, Poplawski, Alicia, Chen, Li Jia, Rong, Shi-Song, Aung, Tin, Vithana, Eranga Nishanthie, NEIGHBORHOOD consortium, ANZRAG consortium, Biobank Japan project, FinnGen study, UK Biobank Eye and Vision Consortium, GIGA study group, 23 and Me Research Team, Tamiya, Gen, Shiga, Yukihiro, Yamamoto, Masayuki, Nakazawa, Toru, Currant, Hannah, Birney, Ewan, Wang, Xin, Auton, Adam, Lupton, Michelle K, Martin, Nicholas G, Ashaye, Adeyinka, Olawoye, Olusola, Williams, Susan E, Akafo, Stephen, Ramsay, Michele, Hashimoto, Kazuki, Kamatani, Yoichiro, Akiyama, Masato, Momozawa, Yukihide, Foster, Paul J, Khaw, Peng T, Morgan, James E, Strouthidis, Nicholas G, Kraft, Peter, Kang, Jae H, Pang, Chi Pui, Pasutto, Francesca, Mitchell, Paul, Lotery, Andrew J, Palotie, Aarno, van Duijn, Cornelia, Haines, Jonathan L, Hammond, Chris, Pasquale, Louis R, Klaver, Caroline CW, Hauser, Michael, Khor, Chiea Chuen, Mackey, David A, Kubo, Michiaki, Cheng, Ching-Yu, Craig, Jamie E, MacGregor, Stuart, and Wiggs, Janey L

Subjects
NEIGHBORHOOD consortium, ANZRAG consortium, Biobank Japan project, FinnGen study, UK Biobank Eye and Vision Consortium, GIGA study group, and Me Research Team, Humans, Glaucoma, Open-Angle, Genetic Predisposition to Disease, Genotype, Polymorphism, Single Nucleotide, Asian Continental Ancestry Group, European Continental Ancestry Group, Genome-Wide Association Study, Genetic Loci, Glaucoma, Open-Angle, Polymorphism, Single Nucleotide
Abstract

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.

Published
2021

23. Exploring healthy retinal aging with deep learning

Author

Menten, Martin J., Holland, Robbie, Leingang, Oliver, Bogunovic´, Hrvoje, Hagag, Ahmed M., Kaye, Rebecca, Riedl, Sophie, Traber, Ghislaine L., Hassan, Osama N., Pawlowski, Nick, Glocker, Ben, Fritsche, Lars G., Scholl, Hendrik P. N, Sivaprasad, Sobha, Schmidt-Erfurth, Ursula, Rueckert, Daniel, and Lotery, Andrew J.

Published
2023
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24. Multi-trait genome-wide association study identifies new loci associated with optic disc parameters

Author

Bonnemaijer, Pieter WM, Leeuwen, Elisabeth M van, Iglesias, Adriana I, Gharahkhani, Puya, Vitart, Veronique, Khawaja, Anthony P, Simcoe, Mark, Höhn, René, Cree, Angela J, Igo, Rob P, Gerhold-Ay, Aslihan, Nickels, Stefan, Wilson, James F, Hayward, Caroline, Boutin, Thibaud S, Polašek, Ozren, Aung, Tin, Khor, Chiea Chuen, Amin, Najaf, Lotery, Andrew J, Wiggs, Janey L, Cheng, Ching-Yu, Hysi, Pirro G, Hammond, Christopher J, Thiadens, Alberta AHJ, MacGregor, Stuart, Klaver, Caroline CW, and Duijn, Cornelia M van

Subjects
Genetics, Eye Disease and Disorders of Vision, Neurodegenerative, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Case-Control Studies, Computational Biology, Gene Expression Profiling, Genetic Association Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Glaucoma, Humans, Molecular Sequence Annotation, Optic Disk, Optic Nerve Diseases, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Quantitative Trait, Heritable, Signal Transduction, International Glaucoma Genetics Consortium, NEIGHBORHOOD consortium, UK Biobank Eye and Vision Consortium, Genome-wide association studies, Optic nerve diseases
Abstract

A new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG); intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants; rs11158547 in PPP1R36-PLEKHG3 and rs1028727 near SERPINE3 at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is hampered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH.

Published
2019

25. Genome-wide meta-analysis identifies 22 loci for normal tension glaucoma with significant overlap with high tension glaucoma.

Author

Diaz-Torres, Santiago, He, Weixiong, Yu, Regina, Han, Xikun, Hamel, Andrew R., Young, Terri L., Lotery, Andrew J., Jorgenson, Eric, Choquet, Hélène, Hauser, Michael, Cooke Bailey, Jessica N., Nakazawa, Toru, Shiga, Yukihiro, Segrè, Ayellet V., Khawaja, Anthony P., Hammond, Christopher J., Hysi, Pirro G., Pasquale, Louis R., Wu, Yeda, and Kubo, Michiaki

Subjects
OPEN-angle glaucoma, INTRAOCULAR pressure, DRUG target, GLAUCOMA, NEUROPROTECTIVE agents
Abstract

Primary open-angle glaucoma typically presents as two subtypes. This study aimed to elucidate the shared and distinct genetic architectures of normal-tension (NTG) and high-tension glaucoma (HTG), motivated by the need to develop intraocular pressure (IOP)-independent drug targets for the disease. We conducted a comprehensive multi-ethnic meta-analysis, prioritized variants based on functional annotation, and explored drug-gene interactions. We further assessed the genetic overlap between NTG and HTG using pairwise GWAS analysis. We identified 22 risk loci associated with NTG, 17 of which have not previously been reported for NTG. Two loci, BMP4 and TBKBP1, have not previously been associated with glaucoma at the genome-wide significance level. Our results indicate that while there is a significant overlap in risk loci between tension subtypes, the magnitude of the effect tends to be lower in NTG compared to HTG, particularly for IOP-related loci. Additionally, we identified a potential role for biologic immunomodulatory treatments as neuroprotective agents. This study investigates the genetic similarities and differences between two subtypes of glaucoma (normal tension and high tension). Multi-ethnic meta-analysis reveals overlapping risk loci, with a lower effect magnitude in normal tension glaucoma. The authors also use their gene discovery approach to highlight possible neuro-protective drug targets for glaucoma. [ABSTRACT FROM AUTHOR]

Published
2024
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27. Home-Monitoring Vision Tests to Detect Active Neovascular Age-Related Macular Degeneration

Author

Hogg, Ruth E., primary, Sivaprasad, Sobha, additional, Wickens, Robin, additional, O’Connor, Sean, additional, Gidman, Eleanor, additional, Ward, Elizabeth, additional, Treanor, Charlene, additional, Peto, Tunde, additional, Burton, Ben J. L., additional, Knox, Paul, additional, Lotery, Andrew J., additional, Donnelly, Michael, additional, Rogers, Chris A., additional, and Reeves, Barnaby C., additional

Published
2024
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28. Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma

Author

Hamel, Andrew R., Yan, Wenjun, Rouhana, John M., Monovarfeshani, Aboozar, Jiang, Xinyi, Mehta, Puja A., Advani, Jayshree, Luo, Yuyang, Liang, Qingnan, Rajasundaram, Skanda, Shrivastava, Arushi, Duchinski, Katherine, Mantena, Sreekar, Wang, Jiali, van Zyl, Tavé, Pasquale, Louis R., Swaroop, Anand, Gharahkhani, Puya, Khawaja, Anthony P., MacGregor, Stuart, Hewitt, Alex W., Schuster, Alexander K., Viswanathan, Ananth C., Lotery, Andrew J., Cree, Angela J., Pang, Calvin P., Brandl, Caroline, Klaver, Caroline C.W., Hayward, Caroline, Khor, Chiea Chuen, Cheng, Ching Yu, Hammond, Christopher J., van Duijn, Cornelia, Mackey, David A., Stefansson, Einer, Vithana, Eranga N., Pasutto, Francesca, Jonansson, Fridbert, Thorleifsson, Gudmar, Koh, Jacyline, Wilson, James F., Craig, Jamie E., Vergroesen, Joëlle E., Fingert, John H., Jonas, Jost B., Stefánsson, Kári, Burdon, Kathryn P., Chen, Li Jia, Driessen, Sjoerd J., Ramdas, Wishal D., de Vries, VA (Victor), Hamel, Andrew R., Yan, Wenjun, Rouhana, John M., Monovarfeshani, Aboozar, Jiang, Xinyi, Mehta, Puja A., Advani, Jayshree, Luo, Yuyang, Liang, Qingnan, Rajasundaram, Skanda, Shrivastava, Arushi, Duchinski, Katherine, Mantena, Sreekar, Wang, Jiali, van Zyl, Tavé, Pasquale, Louis R., Swaroop, Anand, Gharahkhani, Puya, Khawaja, Anthony P., MacGregor, Stuart, Hewitt, Alex W., Schuster, Alexander K., Viswanathan, Ananth C., Lotery, Andrew J., Cree, Angela J., Pang, Calvin P., Brandl, Caroline, Klaver, Caroline C.W., Hayward, Caroline, Khor, Chiea Chuen, Cheng, Ching Yu, Hammond, Christopher J., van Duijn, Cornelia, Mackey, David A., Stefansson, Einer, Vithana, Eranga N., Pasutto, Francesca, Jonansson, Fridbert, Thorleifsson, Gudmar, Koh, Jacyline, Wilson, James F., Craig, Jamie E., Vergroesen, Joëlle E., Fingert, John H., Jonas, Jost B., Stefánsson, Kári, Burdon, Kathryn P., Chen, Li Jia, Driessen, Sjoerd J., Ramdas, Wishal D., and de Vries, VA (Victor)

Abstract

Primary open-angle glaucoma (POAG), characterized by retinal ganglion cell death, is a leading cause of irreversible blindness worldwide. However, its molecular and cellular causes are not well understood. Elevated intraocular pressure (IOP) is a major risk factor, but many patients have normal IOP. Colocalization and Mendelian randomization analysis of >240 POAG and IOP genome-wide association study (GWAS) loci and overlapping expression and splicing quantitative trait loci (e/sQTLs) in 49 GTEx tissues and retina prioritizes causal genes for 60% of loci. These genes are enriched in pathways implicated in extracellular matrix organization, cell adhesion, and vascular development. Analysis of single-nucleus RNA-seq of glaucoma-relevant eye tissues reveals that the POAG and IOP colocalizing genes and genome-wide associations are enriched in specific cell types in the aqueous outflow pathways, retina, optic nerve head, peripapillary sclera, and choroid. This study nominates IOP-dependent and independent regulatory mechanisms, genes, and cell types that may contribute to POAG pathogenesis.

Published
2024

32. Inequalities in Uptake and Use of Digital Applications for Home-Monitoring of Neovascular Age-Related Macular Degeneration in an Elderly Visually Impaired Population: The MONARCH Study

Author

Hogg, Ruth E., primary, Wickens, Robin, additional, O'Connor, Sean, additional, Gidman, Eleanor, additional, Ward, Elizabeth, additional, Peto, Tunde, additional, Burton, Benjamen J. L., additional, Knox, Paul, additional, Lotery, Andrew J., additional, Sivaprasad, Sobha, additional, Donnelly, Michael, additional, Rogers, Chris A., additional, and Reeves, Barnaby C., additional

Published
2024
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34. Periodontitis and outer retinal thickness: A cross-sectional analysis of the UK Biobank cohort

Author

Wagner, Siegfried K., primary, Patel, Praveen J., additional, Huemer, Josef, additional, Khalid, Hagar, additional, Stuart, Kelsey V., additional, Chu, Colin J., additional, Williamson, Dominic J., additional, Struyven, Robbert R., additional, Romero-Bascones, David, additional, Foster, Paul J., additional, Khawaja, Anthony P., additional, Petzold, Axel, additional, Balaskas, Konstantinos, additional, Cortina-Borja, Mario, additional, Chapple, Iain, additional, Dietrich, Thomas, additional, Rahi, Jugnoo S., additional, Denniston, Alastair K., additional, Keane, Pearse A., additional, Allen, Naomi, additional, Aslam, Tariq, additional, Atan, Denize, additional, Balaskas, Konsantinos, additional, Barman, Sarah A., additional, Barrett, Jenny H., additional, Bishop, Paul, additional, Black, Graeme, additional, Braithwaite, Tasanee, additional, Carare, Roxana O., additional, Chakravarthy, Usha, additional, Chan, Michelle, additional, Chua, Sharon Y.L., additional, Day, Alexander, additional, Desai, Parul, additional, Dhillon, Bal, additional, Dick, Andrew D., additional, Doney, Alexander, additional, Egan, Cathy, additional, Ennis, Sarah, additional, Foster, Paul, additional, Fruttiger, Marcus, additional, Gallacher, John E.J., additional, Garway-Heath, David F., additional, Gibson, Jane, additional, Guggenheim, Jeremy A., additional, Hammond, Chris J., additional, Hardcastle, Alison, additional, Harding, Simon P., additional, Hogg, Ruth E., additional, Hysi, Pirro, additional, Khaw, Sir Peng T., additional, Lascaratos, Gerassimos, additional, Littlejohns, Thoams, additional, Lotery, Andrew J., additional, Luben, Robert, additional, Luthert, Phil, additional, Macgillivray, Tom, additional, Mackie, Sarah, additional, McGuinness, Bernadette, additional, McKay, Gareth J., additional, McKibbin, Martin, additional, Moore, Tony, additional, Morgan, James E., additional, O’Sullivan, Eoin, additional, Oram, Richard, additional, Owen, Chris G., additional, Patel, Praveen, additional, Paterson, Euan, additional, Peto, Tunde, additional, Rudnikca, Alicja R., additional, Sattar, Naveed, additional, Self, Jay, additional, Sergouniotis, Panagiotis, additional, Sivaprasad, Sobha, additional, Steel, David, additional, Stratton, Irene, additional, Strouthidis, Nicholas, additional, Sudlow, Cathie, additional, Sun, Zihan, additional, Tapp, Robyn, additional, Thomas, Dhanes, additional, Trucco, Emanuele, additional, Tufail, Adnan, additional, Vitart, Veronique, additional, Viswanathan, Ananth C., additional, Weedon, Mike, additional, Williams, Cathy, additional, Williams, Katie, additional, Woodside, Jayne V., additional, Yates, MaxM., additional, Yip, Jennifer, additional, and Zheng, Yalin, additional

Published
2024
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38. Initial results from a first-in-human gene therapy trial on X-linked retinitis pigmentosa caused by mutations in RPGR

Author

Cehajic-Kapetanovic, Jasmina, Xue, Kanmin, Martinez-Fernandez de la Camara, Cristina, Nanda, Anika, Davies, Alexandra, Wood, Laura J., Salvetti, Anna Paola, Fischer, M. Dominik, Aylward, James W., Barnard, Alun R., Jolly, Jasleen K., Luo, Edmond, Lujan, Brandon J., Ong, Tuyen, Girach, Aniz, Black, Graeme C. M., Gregori, Ninel Z., Davis, Janet L., Rosa, Potyra R., Lotery, Andrew J., Lam, Byron L., Stanga, Paulo E., and MacLaren, Robert E.

Published
2020
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40. Central serous chorioretinopathy: Towards an evidence-based treatment guideline

Author

van Rijssen, Thomas J., van Dijk, Elon H.C., Yzer, Suzanne, Ohno-Matsui, Kyoko, Keunen, Jan E.E., Schlingemann, Reinier O., Sivaprasad, Sobha, Querques, Giuseppe, Downes, Susan M., Fauser, Sascha, Hoyng, Carel B., Piccolino, Felice Cardillo, Chhablani, Jay K., Lai, Timothy Y.Y., Lotery, Andrew J., Larsen, Michael, Holz, Frank G., Freund, K. Bailey, Yannuzzi, Lawrence A., and Boon, Camiel J.F.

Published
2019
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41. Vision-Related Quality of Life in Patients with Diabetic Macular Edema Treated with Intravitreal Aflibercept: The AQUA Study

Author

Adan, Alfredo, Alexik, Mikulas, Ali, Fareed, Amaro, Miguel, Balciuniene, Vilma-Jurate, Bandello, Francesco M., Arias Barquet, Lluis, Beck, Anna, Bell, Katharina, Boscia, Francesco, Bures, Anniken, Carneiro, Ângela, Chow, David R., Cimbalas, Andrius, Dahlke, Claudia, Deepali, Varma, Dickinson, John D., Dollin, Michael, Eandi, Chiara, Emmerich, Karl-Heinz, Feltgen, Nicolas, Pereira Figueira, João, Findl, Oliver, Gajdošová, Monika, Gale, Richard P., John Galic, Ivan, Garweg, Justus, Gasser-Steiner, Vanessa, Giunta, Michel, Gonder, John R., Grzybowski, Andrzej, Hamouz, Jan, Hattenbach, Lars-Olof, Holz, Frank G., Jesia, Hasan, Kaluzny, Jozef, Kerenyi, Agnes, Kertes, Peter J., Koch, Frank, Kodjikan, Laurent, Lederer, David E., Liehneova, Ivana, Lorenz, Katrin, Lotery, Andrew J., McKibbin, Martin, Menon, Geeta V., Michalewska, Zofia, Midena, Edoardo, Nicolo, Massimo, Papp, Andras, Pavlovičová, Gabriela, Peiretti, Enrico, Vaz-Pereira, Sara, Perri, Paolo, Petropoulos, Ioannis, Queguiner, Frederic, Raczynska, Krystyna, Sararols-Ramsay, Laura, Rękas, Marek, Ricci, Federico, Romanowska-Dixon, Bozena, Sachs, Helmut G., Mohand-Said, Saddek, Sandner, Dirk, Schmidt-Erfurth, Ursula, Sekundo, Walter, Seres, Andras, Sivaprasad, Sobha, Souied, Eric, Castro de Sousa, João, Stankiewicz, Andrzej, Štefaničková, Jana, Struhárová, Katarína, Studnicka, Jan, Cervera Taulet, Enrique, Taylor, Simon, Teper, Slawomir, Vajas, Attila, Cava Valenciano, Carlos, Varsányi, Balázs, Viola, Francesco, Virgili, Gianni, Wagenfeld, Lars, Walters, Gavin, Wiedemann, Peter, Zarnowski, Tomasz, Garweg, Justus G., Stefanickova, Jana, Hoyng, Carel, Schmelter, Thomas, Niesen, Tobias, and Sowade, Olaf

Published
2019
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42. Meta-analysis of genome-wide association studies identifies novel loci that influence cupping and the glaucomatous process.

Author

Springelkamp, Henriët, Höhn, René, Mishra, Aniket, Hysi, Pirro G, Khor, Chiea-Chuen, Loomis, Stephanie J, Bailey, Jessica N Cooke, Gibson, Jane, Thorleifsson, Gudmar, Janssen, Sarah F, Luo, Xiaoyan, Ramdas, Wishal D, Vithana, Eranga, Nongpiur, Monisha E, Montgomery, Grant W, Xu, Liang, Mountain, Jenny E, Gharahkhani, Puya, Lu, Yi, Amin, Najaf, Karssen, Lennart C, Sim, Kar-Seng, van Leeuwen, Elisabeth M, Iglesias, Adriana I, Verhoeven, Virginie JM, Hauser, Michael A, Loon, Seng-Chee, Despriet, Dominiek DG, Nag, Abhishek, Venturini, Cristina, Sanfilippo, Paul G, Schillert, Arne, Kang, Jae H, Landers, John, Jonasson, Fridbert, Cree, Angela J, van Koolwijk, Leonieke ME, Rivadeneira, Fernando, Souzeau, Emmanuelle, Jonsson, Vesteinn, Menon, Geeta, Blue Mountains Eye Study—GWAS group, Weinreb, Robert N, de Jong, Paulus TVM, Oostra, Ben A, Uitterlinden, André G, Hofman, Albert, Ennis, Sarah, Thorsteinsdottir, Unnur, Burdon, Kathryn P, NEIGHBORHOOD Consortium, Wellcome Trust Case Control Consortium 2 (WTCCC2), Spector, Timothy D, Mirshahi, Alireza, Saw, Seang-Mei, Vingerling, Johannes R, Teo, Yik-Ying, Haines, Jonathan L, Wolfs, Roger CW, Lemij, Hans G, Tai, E-Shyong, Jansonius, Nomdo M, Jonas, Jost B, Cheng, Ching-Yu, Aung, Tin, Viswanathan, Ananth C, Klaver, Caroline CW, Craig, Jamie E, Macgregor, Stuart, Mackey, David A, Lotery, Andrew J, Stefansson, Kari, Bergen, Arthur AB, Young, Terri L, Wiggs, Janey L, Pfeiffer, Norbert, Wong, Tien-Yin, Pasquale, Louis R, Hewitt, Alex W, van Duijn, Cornelia M, and Hammond, Christopher J

Subjects
Blue Mountains Eye Study—GWAS group, NEIGHBORHOOD Consortium, Wellcome Trust Case Control Consortium 2, Optic Nerve, Optic Disk, Humans, Glaucoma, Case-Control Studies, Gene Expression Profiling, Gene Frequency, Genotype, Phenotype, Polymorphism, Single Nucleotide, Asian Continental Ancestry Group, European Continental Ancestry Group, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Human Genome, Genetics, Neurodegenerative, Eye Disease and Disorders of Vision, Neurosciences, 2.1 Biological and endogenous factors, Eye
Abstract

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.

Published
2014

47. Genome-wide association study of age-related macular degeneration identifies associated variants in the TNXB–FKBPL–NOTCH4 region of chromosome 6p21.3

Author

Cipriani, Valentina, Leung, Hin-Tak, Plagnol, Vincent, Bunce, Catey, Khan, Jane C, Shahid, Humma, Moore, Anthony T, Harding, Simon P, Bishop, Paul N, Hayward, Caroline, Campbell, Susan, Armbrecht, Ana Maria, Dhillon, Baljean, Deary, Ian J, Campbell, Harry, Dunlop, Malcolm, Dominiczak, Anna F, Mann, Samantha S, Jenkins, Sharon A, Webster, Andrew R, Bird, Alan C, Lathrop, Mark, Zelenika, Diana, Souied, Eric H, Sahel, José-Alain, Léveillard, Thierry, Cree, Angela J, Gibson, Jane, Ennis, Sarah, Lotery, Andrew J, Wright, Alan F, Clayton, David G, and Yates, John RW

Subjects
Genetics, Macular Degeneration, Prevention, Aging, Eye Disease and Disorders of Vision, Clinical Research, Human Genome, Neurodegenerative, 2.1 Biological and endogenous factors, Aetiology, Eye, Aged, Aged, 80 and over, Case-Control Studies, Chromosomes, Human, Pair 6, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Haplotypes, Humans, Immunophilins, Linear Models, Logistic Models, Male, Odds Ratio, Polymorphism, Single Nucleotide, Principal Component Analysis, Proto-Oncogene Proteins, Receptor, Notch4, Receptors, Notch, Sequence Analysis, DNA, Tacrolimus Binding Proteins, Tenascin, French AMD Investigators, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Age-related macular degeneration (AMD) is a leading cause of visual loss in Western populations. Susceptibility is influenced by age, environmental and genetic factors. Known genetic risk loci do not account for all the heritability. We therefore carried out a genome-wide association study of AMD in the UK population with 893 cases of advanced AMD and 2199 controls. This showed an association with the well-established AMD risk loci ARMS2 (age-related maculopathy susceptibility 2)-HTRA1 (HtrA serine peptidase 1) (P =2.7 × 10(-72)), CFH (complement factor H) (P =2.3 × 10(-47)), C2 (complement component 2)-CFB (complement factor B) (P =5.2 × 10(-9)), C3 (complement component 3) (P =2.2 × 10(-3)) and CFI (P =3.6 × 10(-3)) and with more recently reported risk loci at VEGFA (P =1.2 × 10(-3)) and LIPC (hepatic lipase) (P =0.04). Using a replication sample of 1411 advanced AMD cases and 1431 examined controls, we confirmed a novel association between AMD and single-nucleotide polymorphisms on chromosome 6p21.3 at TNXB (tenascin XB)-FKBPL (FK506 binding protein like) [rs12153855/rs9391734; discovery P =4.3 × 10(-7), replication P =3.0 × 10(-4), combined P =1.3 × 10(-9), odds ratio (OR) = 1.4, 95% confidence interval (CI) = 1.3-1.6] and the neighbouring gene NOTCH4 (Notch 4) (rs2071277; discovery P =3.2 × 10(-8), replication P =3.8 × 10(-5), combined P =2.0 × 10(-11), OR = 1.3, 95% CI = 1.2-1.4). These associations remained significant in conditional analyses which included the adjacent C2-CFB locus. TNXB, FKBPL and NOTCH4 are all plausible AMD susceptibility genes, but further research will be needed to identify the causal variants and determine whether any of these genes are involved in the pathogenesis of AMD.

Published
2012

49. Comparison of Novel Volumetric Microperimetry Metrics in Intermediate Age-Related Macular Degeneration: PINNACLE Study Report 3

Author

Anders, Philipp, primary, Traber, Ghislaine L., additional, Pfau, Maximilian, additional, Riedl, Sophie, additional, Hagag, Ahmed M., additional, Camenzind, Hanna, additional, Mai, Julia, additional, Kaye, Rebecca, additional, Bogunović, Hrvoje, additional, Fritsche, Lars G., additional, Rueckert, Daniel, additional, Schmidt-Erfurth, Ursula, additional, Sivaprasad, Sobha, additional, Lotery, Andrew J., additional, and Scholl, Hendrik P. N., additional

Published
2023
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