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2. Systems genomics in age-related macular degeneration

Author

Hollander, Anneke I den, Mullins, Robert F, Orozco, Luz D, Voigt, Andrew P, Chen, Hsu-Hsin, Strunz, Tobias, Grassmann, Felix, Haines, Jonathan L, Kuiper, Jonas JW, Tumminia, Santa J, Allikmets, Rando, Hageman, Gregory S, Stambolian, Dwight, Klaver, Caroline CW, Boeke, Jef D, Chen, Hao, Honigberg, Lee, Katti, Suresh, Frazer, Kelly A, Weber, Bernhard HF, and Gorin, Michael B

Subjects
Biomedical and Clinical Sciences, Ophthalmology and Optometry, Macular Degeneration, Neurosciences, Eye Disease and Disorders of Vision, Human Genome, Stem Cell Research, Neurodegenerative, Biotechnology, Genetics, Stem Cell Research - Induced Pluripotent Stem Cell, Aging, Stem Cell Research - Induced Pluripotent Stem Cell - Human, 2.1 Biological and endogenous factors, Aetiology, Eye, Humans, Retinal Pigment Epithelium, Complement System Proteins, Choroid, Proteins, Genomics, Polymorphism, Single Nucleotide, Complement Factor H, High-Temperature Requirement A Serine Peptidase 1, Age-related macular degeneration, Omics, Systems genomics, Single cell sequencing, Expression quantitative trait locus, Complement system, iPSc-RPE, Induced pluripotent stem cells, Clinical trial, Polygenic risk scores, Medical Biochemistry and Metabolomics, Opthalmology and Optometry, Ophthalmology & Optometry, Ophthalmology and optometry
Abstract

Genomic studies in age-related macular degeneration (AMD) have identified genetic variants that account for the majority of AMD risk. An important next step is to understand the functional consequences and downstream effects of the identified AMD-associated genetic variants. Instrumental for this next step are 'omics' technologies, which enable high-throughput characterization and quantification of biological molecules, and subsequent integration of genomics with these omics datasets, a field referred to as systems genomics. Single cell sequencing studies of the retina and choroid demonstrated that the majority of candidate AMD genes identified through genomic studies are expressed in non-neuronal cells, such as the retinal pigment epithelium (RPE), glia, myeloid and choroidal cells, highlighting that many different retinal and choroidal cell types contribute to the pathogenesis of AMD. Expression quantitative trait locus (eQTL) studies in retinal tissue have identified putative causal genes by demonstrating a genetic overlap between gene regulation and AMD risk. Linking genetic data to complement measurements in the systemic circulation has aided in understanding the effect of AMD-associated genetic variants in the complement system, and supports that protein QTL (pQTL) studies in plasma or serum samples may aid in understanding the effect of genetic variants and pinpointing causal genes in AMD. A recent epigenomic study fine-mapped AMD causal variants by determing regulatory regions in RPE cells differentiated from induced pluripotent stem cells (iPSC-RPE). Another approach that is being employed to pinpoint causal AMD genes is to produce synthetic DNA assemblons representing risk and protective haplotypes, which are then delivered to cellular or animal model systems. Pinpointing causal genes and understanding disease mechanisms is crucial for the next step towards clinical translation. Clinical trials targeting proteins encoded by the AMD-associated genomic loci C3, CFB, CFI, CFH, and ARMS2/HTRA1 are currently ongoing, and a phase III clinical trial for C3 inhibition recently showed a modest reduction of lesion growth in geographic atrophy. The EYERISK consortium recently developed a genetic test for AMD that allows genotyping of common and rare variants in AMD-associated genes. Polygenic risk scores (PRS) were applied to quantify AMD genetic risk, and may aid in predicting AMD progression. In conclusion, genomic studies represent a turning point in our exploration of AMD. The results of those studies now serve as a driving force for several clinical trials. Expanding to omics and systems genomics will further decipher function and causality from the associations that have been reported, and will enable the development of therapies that will lessen the burden of AMD.

Published
2022

5. Inflammatory adipose activates a nutritional immunity pathway leading to retinal dysfunction.

Author

Sterling, Jacob, Baumann, Bailey, Foshe, Sierra, Voigt, Andrew, Guttha, Samyuktha, Alnemri, Ahab, McCright, Sam, Li, Mingyao, Zauhar, Randy, Montezuma, Sandra, Kapphahn, Rebecca, Chavali, Venkata, Hill, David, Ferrington, Deborah, Stambolian, Dwight, Mullins, Robert, Merrick, David, and Dunaief, Joshua

Subjects
CP: Immunology, IL-1β, age-related macular degeneration, high fat diet, iron, macrophage, microglia, neuroinflammation, nutritional immunity, visceral adipose, Adipose Tissue, Humans, Iron, Macular Degeneration, Oxidative Stress, Retina, Retinal Pigment Epithelium
Abstract

Age-related macular degeneration (AMD), the leading cause of irreversible blindness among Americans over 50, is characterized by dysfunction and death of retinal pigment epithelial (RPE) cells. The RPE accumulates iron in AMD, and iron overload triggers RPE cell death in vitro and in vivo. However, the mechanism of RPE iron accumulation in AMD is unknown. We show that high-fat-diet-induced obesity, a risk factor for AMD, drives systemic and local inflammatory circuits upregulating interleukin-1β (IL-1β). IL-1β upregulates RPE iron importers and downregulates iron exporters, causing iron accumulation, oxidative stress, and dysfunction. We term this maladaptive, chronic activation of a nutritional immunity pathway the cellular iron sequestration response (CISR). RNA sequencing (RNA-seq) analysis of choroid and retina from human donors revealed that hallmarks of this pathway are present in AMD microglia and macrophages. Together, these data suggest that inflamed adipose tissue, through the CISR, can lead to RPE pathology in AMD.

Published
2022

6. Rare variant analyses across multiethnic cohorts identify novel genes for refractive error

Author

Musolf, Anthony M., Haarman, Annechien E. G., Luben, Robert N., Ong, Jue-Sheng, Patasova, Karina, Trapero, Rolando Hernandez, Marsh, Joseph, Jain, Ishika, Jain, Riya, Wang, Paul Zhiping, Lewis, Deyana D., Tedja, Milly S., Iglesias, Adriana I., Li, Hengtong, Cowan, Cameron S., Biino, Ginevra, Klein, Alison P., Duggal, Priya, Mackey, David A., Hayward, Caroline, Haller, Toomas, Metspalu, Andres, Wedenoja, Juho, Pärssinen, Olavi, Cheng, Ching-Yu, Saw, Seang-Mei, Stambolian, Dwight, Hysi, Pirro G., Khawaja, Anthony P., Vitart, Veronique, Hammond, Christopher J., van Duijn, Cornelia M., Verhoeven, Virginie J. M., Klaver, Caroline C. W., and Bailey-Wilson, Joan E.

Published
2023
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7. Automated identification of clinical features from sparsely annotated 3-dimensional medical imaging.

Author

Rakocz, Nadav, Chiang, Jeffrey N, Nittala, Muneeswar G, Corradetti, Giulia, Tiosano, Liran, Velaga, Swetha, Thompson, Michael, Hill, Brian L, Sankararaman, Sriram, Haines, Jonathan L, Pericak-Vance, Margaret A, Stambolian, Dwight, Sadda, Srinivas R, and Halperin, Eran

Abstract

One of the core challenges in applying machine learning and artificial intelligence to medicine is the limited availability of annotated medical data. Unlike in other applications of machine learning, where an abundance of labeled data is available, the labeling and annotation of medical data and images require a major effort of manual work by expert clinicians who do not have the time to annotate manually. In this work, we propose a new deep learning technique (SLIVER-net), to predict clinical features from 3-dimensional volumes using a limited number of manually annotated examples. SLIVER-net is based on transfer learning, where we borrow information about the structure and parameters of the network from publicly available large datasets. Since public volume data are scarce, we use 2D images and account for the 3-dimensional structure using a novel deep learning method which tiles the volume scans, and then adds layers that leverage the 3D structure. In order to illustrate its utility, we apply SLIVER-net to predict risk factors for progression of age-related macular degeneration (AMD), a leading cause of blindness, from optical coherence tomography (OCT) volumes acquired from multiple sites. SLIVER-net successfully predicts these factors despite being trained with a relatively small number of annotated volumes (hundreds) and only dozens of positive training examples. Our empirical evaluation demonstrates that SLIVER-net significantly outperforms standard state-of-the-art deep learning techniques used for medical volumes, and its performance is generalizable as it was validated on an external testing set. In a direct comparison with a clinician panel, we find that SLIVER-net also outperforms junior specialists, and identifies AMD progression risk factors similarly to expert retina specialists.

Published
2021

8. A new polygenic score for refractive error improves detection of children at risk of high myopia but not the prediction of those at risk of myopic macular degeneration

Author

Bailey-Wilson, Joan E., Baird, Paul N., Barathi, Veluchamy A., Biino, Ginevra, Burdon, Kathryn P., Campbell, Harry, Chen, Li Jia, Cheng, Ching-Yu, Chew, Emily Y., Craig, Jamie E., Deangelis, Margaret M., Delcourt, Cécile, Ding, Xiaohu, Fan, Qiao, Fossarello, Maurizio, Foster, Paul J., Gharahkhani, Puya, Guggenheim, Jeremy A., Guo, Xiaobo, Haarman, Annechien E.G., Haller, Toomas, Hammond, Christopher J., Han, Xikun, Hayward, Caroline, He, Mingguang, Hewitt, Alex W., Hoang, Quan, Hysi, Pirro G., Iglesias, Adriana I., Igo, Robert P., Iyengar, Sudha K., Jonas, Jost B., Kähönen, Mika, Kaprio, Jaakko, Khawaja, Anthony P., Klein, Barbara E., Lass, Jonathan H., Lee, Kris, Lehtimäki, Terho, Lewis, Deyana, Li, Qing, Li, Shi-Ming, Lyytikäinen, Leo-Pekka, MacGregor, Stuart, Mackey, David A., Martin, Nicholas G., Meguro, Akira, Metspalu, Andres, Middlebrooks, Candace, Miyake, Masahiro, Mizuki, Nobuhisa, Musolf, Anthony, Nickels, Stefan, Oexle, Konrad, Pang, Chi Pui, Pärssinen, Olavi, Paterson, Andrew D., Pfeiffer, Norbert, Polasek, Ozren, Rahi, Jugnoo S., Raitakari, Olli, Rudan, Igor, Sahebjada, Srujana, Saw, Seang-Mei, Simpson, Claire L., Stambolian, Dwight, Tai, E-Shyong, Tedja, Milly S., Tideman, J. Willem L., Tsujikawa, Akitaka, van Duijn, Cornelia M., Verhoeven, Virginie J.M., Vitart, Veronique, Wang, Ningli, Wang, Ya Xing, Wedenoja, Juho, Wei, Wen Bin, Williams, Cathy, Williams, Katie M., Wilson, James F., Wojciechowski, Robert, Yam, Jason C.S., Yamashiro, Kenji, Yap, Maurice K.H., Yazar, Seyhan, Yip, Shea Ping, Young, Terri L., Zhou, Xiangtian, Allen, Naomi, Aslam, Tariq, Atan, Denize, Barman, Sarah, Barrett, Jenny, Bishop, Paul, Black, Graeme, Bunce, Catey, Carare, Roxana, Chakravarthy, Usha, Chan, Michelle, Chua, Sharon, Cipriani, Valentina, Day, Alexander, Desai, Parul, Dhillon, Bal, Dick, Andrew, Doney, Alexander, Egan, Cathy, Ennis, Sarah, Foster, Paul, Fruttiger, Marcus, Gallacher, John, Garway-Heath, David, Gibson, Jane, Gore, Dan, Guggenheim, Jeremy, Hammond, Chris, Hardcastle, Alison, Harding, Simon, Hogg, Ruth, Hysi, Pirro, Keane, Pearse A., Khaw, Peng Tee, Khawaja, Anthony, Lascaratos, Gerassimos, Littlejohns, Thomas, Lotery, Andrew, Luthert, Phil, MacGillivray, Tom, Mackie, Sarah, McGuinness, Bernadette, McKay, Gareth, McKibbin, Martin, Mitry, Danny, Moore, Tony, Morgan, James, Muthy, Zaynah, O'Sullivan, Eoin, Owen, Chris, Patel, Praveen, Paterson, Euan, Peto, Tunde, Petzold, Axel, Pontikos, Nikolas, Rahi, Jugnoo, Rudnicka, Alicja, Self, Jay, Sergouniotis, Panagiotis, Sivaprasad, Sobha, Steel, David, Stratton, Irene, Strouthidis, Nicholas, Sudlow, Cathie, Tapp, Robyn, Thaung, Caroline, Thomas, Dhanes, Trucco, Emanuele, Tufail, Adnan, Vernon, Stephen, Viswanathan, Ananth, Williams, Katie, Woodside, Jayne, Yates, Max, Yip, Jennifer, Zheng, Yalin, Clark, Rosie, Lee, Samantha Sze-Yee, Du, Ran, Wang, Yining, Kneepkens, Sander C.M., Charng, Jason, Huang, Yu, Hunter, Michael L., Jiang, Chen, Tideman, J.Willem L., Melles, Ronald B., Klaver, Caroline C.W., Choquet, Hélène, and Ohno-Matsui, Kyoko

Published
2023
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9. Effective refractive error coverage in adults aged 50 years and older: estimates from population-based surveys in 61 countries

Author

Bron, Alain, Cheng, Ching-Yu, Fernandes, Arthur, Friedman, David, Gazzard, Andrew, Kahloun, Rim, Kempen, John, Khairallah, Moncef, Lansingh, Van C, Leasher, Janet, Leveziel, Nicolas, Limburg, Hans, Nowak, Michal, Pesudovs, Konrad, Peto, Tunde, Rossetti, Luca, Tahhan, Nina, Varma, Rohit, Alemayehu, Wondu, Arditi, Aries, Dana, Reza, Del Monte, Monte, Deva, jenny, Dreer, Laura, Ehrlich, Josh, Ellwein, Leon, Hammond, Billy, Hartnett, Mary E, Ingram, April, Khanna, Rohit, Kim, Judy, Lim, Jennifer, Morse, Alan, Musch, David, Parodi, Maurizio B, Ramulu, Pradeep, Robin, Alan, Serle, Janet, Shen, Tueng, Sitorus, Rita S, Stambolian, Dwight, Topouzis, Fotis, Tsilimbaris, Miltiadis, Virgili, Gianni, West, Sheila, Ababora, Jafer K, AlSawahli, Heba, Andriamanjato, Hery Harimanitra, Barrenechea, Rosario, Batlle, Juan F, Burnett, Anthea M, Finger, Robert P, Gallarreta, Marcelo, Gomez-Bastar, Pedro A, Gurung, Reeta, Jain, Elesh, Kabona, George E, Kalua, Khumbo, Kandeke, Levi, Karimurio, Jefitha, Kikira, Susan A, Kulkarni, Sucheta, Mathenge, Wanjiku, Mishra, Sailesh Kumar, Mohammadi, Seyed Farzad, Mörchen, Manfred, Muhammad, Nasiru, Mutati, Grace C, Nano, Maria Eugenia, Németh, János, Paduca, Ala, Páez, Alexander, Rabiu, M Mansur, Rif'ati, Lutfah, Salowi, Mohamad Aziz, Sapkota, Yuddha D, Sargent, Nicholas, Thoufeeq, Ubeydulla, Villalobos, Astrid V, Xiao, Biaxiang, Yee Melgar, Mariano, Zhang, Xiu Juan, Bourne, Rupert Richard Alexander, Cicinelli, Maria Vittoria, Sedighi, Tabassom, Tapply, Ian H, McCormick, Ian, Jonas, Jost B, Congdon, Nathan G, Ramke, Jacqueline, Naidoo, Kovin S, Fricke, Timothy R, Burton, Matthew J, Müller, Andreas, Bikbov, Mukharram M, Furtado, João M, Kyari, Fatima, He, Mingguang, Wang, Ya Xing, Vijaya, Lingam, Nangia, Vinay, Brian, Garry, Emamian, Mohammad Hassan, Fotouhi, Akbar, Hashemi, Hassan, Khandekar, Rajiv B, Marmamula, Srinivas, Salomão, Solange, George, Ronnie, Kazakbaeva, Gyulli, Braithwaite, Tasanee, Casson, Robert J, Iwase, Aiko, Gupta, Noopur, Abdianwall, Mohammad H, Wong, Tien Y, Wang, Ningli, Taylor, Hugh R, Flaxman, Seth R, Keel, Stuart, and Resnikoff, Serge

Published
2022
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10. Correction: A 32 kb Critical Region Excluding Y402H in CFH Mediates Risk for Age-Related Macular Degeneration

Author

Sivakumaran, Theru A, Igo, Robert P, Kidd, Jeffrey M, Itsara, Andy, Kopplin, Laura J, Chen, Wei, Hagstrom, Stephanie A, Peachey, Neal S, Francis, Peter J, Klein, Michael L, Chew, Emily Y, Ramprasad, Vedam L, Tay, Wan-Ting, Mitchell, Paul, Seielstad, Mark, Stambolian, Dwight E, Edwards, Albert O, Lee, Kristine E, Leontiev, Dmitry V, Jun, Gyungah, Wang, Yang, Tian, Liping, Qiu, Feiyou, Henning, Alice K, LaFramboise, Thomas, Sen, Parveen, Aarthi, Manoharan, George, Ronnie, Raman, Rajiv, Das, Manmath Kumar, Vijaya, Lingam, Kumaramanickavel, Govindasamy, Wong, Tien Y, Swaroop, Anand, Abecasis, Goncalo R, Klein, Ronald, Klein, Barbara EK, Nickerson, Deborah A, Eichler, Evan E, and Iyengar, Sudha K

Subjects
Biomedical and Clinical Sciences, Ophthalmology and Optometry, General Science & Technology
Abstract

[This corrects the article DOI: 10.1371/journal.pone.0025598.].

Published
2018

12. Causes of blindness and vision impairment in 2020 and trends over 30 years, and prevalence of avoidable blindness in relation to VISION 2020: the Right to Sight: an analysis for the Global Burden of Disease Study

Author

Steinmetz, Jaimie D, Bourne, Rupert R A, Briant, Paul Svitil, Flaxman, Seth R, Taylor, Hugh R B, Jonas, Jost B, Abdoli, Amir Aberhe, Abrha, Woldu Aberhe, Abualhasan, Ahmed, Abu-Gharbieh, Eman Girum, Adal, Tadele Girum, Afshin, Ashkan, Ahmadieh, Hamid, Alemayehu, Wondu, Alemzadeh, Sayyed Amirpooya Samir, Alfaar, Ahmed Samir, Alipour, Vahid, Androudi, Sofia, Arabloo, Jalal, Arditi, Aries Berhe, Aregawi, Brhane Berhe, Arrigo, Alessandro, Ashbaugh, Charlie, Ashrafi, Elham Debalkie, Atnafu, Desta Debalkie, Bagli, Eleni Amin, Baig, Atif Amin Winfried, Bärnighausen, Till Winfried, Battaglia Parodi, Maurizio, Beheshti, Mahya Srikanth, Bhagavathula, Akshaya Srikanth, Bhardwaj, Nikha, Bhardwaj, Pankaj, Bhattacharyya, Krittika, Bijani, Ali, Bikbov, Mukharram, Bottone, Michele, Braithwaite, Tasanee M, Bron, Alain M, Burugina Nagaraja, Sharath A, Butt, Zahid A, Caetano dos Santos, Florentino Luciano L, Carneiro, Vera L James, Casson, Robert James, Cheng, Ching-Yu Jasmine, Choi, Jee-Young Jasmine, Chu, Dinh-Toi, Cicinelli, Maria Vittoria M, Coelho, João M G, Congdon, Nathan G A, Couto, Rosa A A, Cromwell, Elizabeth A M, Dahlawi, Saad M, Dai, Xiaochen, Dana, Reza, Dandona, Lalit, Dandona, Rakhi A, Del Monte, Monte A, Derbew Molla, Meseret, Dervenis, Nikolaos Alemayehu, Desta, Abebaw Alemayehu P, Deva, Jenny P, Diaz, Daniel, Djalalinia, Shirin E, Ehrlich, Joshua R, Elayedath, Rajesh Rashad, Elhabashy, Hala Rashad B, Ellwein, Leon B, Emamian, Mohammad Hassan, Eskandarieh, Sharareh, Farzadfar, Farshad G, Fernandes, Arthur G, Fischer, Florian S, Friedman, David S M, Furtado, João M, Gaidhane, Shilpa, Gazzard, Gus, Gebremichael, Berhe, George, Ronnie, Ghashghaee, Ahmad, Gilani, Syed Amir, Golechha, Mahaveer, Hamidi, Samer Randall, Hammond, Billy Randall R, Hartnett, Mary Elizabeth R Kusuma, Hartono, Risky Kusuma, Hashi, Abdiwahab I, Hay, Simon I, Hayat, Khezar, Heidari, Golnaz, Ho, Hung Chak, Holla, Ramesh, Househ, Mowafa J, Huang, John J Emmanuel, Ibitoye, Segun Emmanuel M, Ilic, Irena M D, Ilic, Milena D D, Ingram, April D Naghibi, Irvani, Seyed Sina Naghibi, Islam, Sheikh Mohammed Shariful, Itumalla, Ramaiah, Jayaram, Shubha Prakash, Jha, Ravi Prakash, Kahloun, Rim, Kalhor, Rohollah, Kandel, Himal, Kasa, Ayele Semachew, Kavetskyy, Taras A, Kayode, Gbenga A H, Kempen, John H, Khairallah, Moncef, Khalilov, Rovshan Ahmad, Khan, Ejaz Ahmad C, Khanna, Rohit C, Khatib, Mahalaqua Nazli Ahmed, Khoja, Tawfik Ahmed E, Kim, Judy E, Kim, Yun Jin, Kim, Gyu Ri, Kisa, Sezer, Kisa, Adnan, Kosen, Soewarta, Koyanagi, Ai, Kucuk Bicer, Burcu, Kulkarni, Vaman P, Kurmi, Om P, Landires, Iván Charles, Lansingh, Van Charles L, Leasher, Janet L E, LeGrand, Kate E, Leveziel, Nicolas, Limburg, Hans, Liu, Xuefeng, Madhava Kunjathur, Shilpashree, Maleki, Shokofeh, Manafi, Navid, Mansouri, Kaweh, McAlinden, Colm Gebremichael, Meles, Gebrekiros Gebremichael M, Mersha, Abera M, Michalek, Irmina Maria R, Miller, Ted R, Misra, Sanjeev, Mohammad, Yousef, Mohammadi, Seyed Farzad Abdu, Mohammed, Jemal Abdu H, Mokdad, Ali H, Moni, Mohammad Ali Al, Montasir, Ahmed Al R, Morse, Alan R Fentaw, Mulaw, Getahun Fentaw C, Naderi, Mehdi, Naderifar, Homa S, Naidoo, Kovin S, Naimzada, Mukhammad David, Nangia, Vinay, Narasimha Swamy, Sreenivas Muhammad, Naveed, Dr Muhammad, Negash, Hadush Lan, Nguyen, Huong Lan, Nunez-Samudio, Virginia Akpojene, Ogbo, Felix Akpojene, Ogundimu, Kolawole T, Olagunju, Andrew T E, Onwujekwe, Obinna E, Otstavnov, Nikita O, Owolabi, Mayowa O, Pakshir, Keyvan, Panda-Jonas, Songhomitra, Parekh, Utsav, Park, Eun-Cheol, Pasovic, Maja, Pawar, Shrikant, Pesudovs, Konrad, Peto, Tunde Quang, Pham, Hai Quang, Pinheiro, Marina, Podder, Vivek, Rahimi-Movaghar, Vafa, Rahman, Mohammad Hifz Ur Y, Ramulu, Pradeep Y, Rathi, Priya, Rawaf, Salman Laith, Rawaf, David Laith, Rawal, Lal, Reinig, Nickolas M, Renzaho, Andre M, Rezapour, Aziz L, Robin, Alan L, Rossetti, Luca, Sabour, Siamak, Safi, Sare, Sahebkar, Amirhossein, Sahraian, Mohammad Ali M, Samy, Abdallah M, Sathian, Brijesh, Saya, Ganesh Kumar, Saylan, Mete A, Shaheen, Amira A Ali, Shaikh, Masood Ali T, Shen, Tueng T, Shibuya, Kenji Shibabaw, Shiferaw, Wondimeneh Shibabaw, Shigematsu, Mika, Shin, Jae Il, Silva, Juan Carlos, Silvester, Alexander A, Singh, Jasvinder A, Singhal, Deepika S, Sitorus, Rita S, Skiadaresi, Eirini Yurievich, Skryabin, Valentin Yurievich Aleksandrovna, Skryabina, Anna Aleksandrovna, Soheili, Amin Bekele, Sorrie, Muluken Bekele A R C, Sousa, Raúl A R C T, Sreeramareddy, Chandrashekhar T, Stambolian, Dwight Girma, Tadesse, Eyayou Girma, Tahhan, Nina Ismail, Tareque, Md Ismail, Topouzis, Fotis Xuan, Tran, Bach Xuan, Tsegaye, Gebiyaw K, Tsilimbaris, Miltiadis K, Varma, Rohit, Virgili, Gianni, Vongpradith, Avina Thu, Vu, Giang Thu, Wang, Ya Xing, Wang, Ningli Hailay, Weldemariam, Abrha Hailay K, West, Sheila K Gebeyehu, Wondmeneh, Temesgen Gebeyehu Y, Wong, Tien Y, Yaseri, Mehdi, Yonemoto, Naohiro, Yu, Chuanhua Sergeevich, Zastrozhin, Mikhail Sergeevich, Zhang, Zhi-Jiang R, Zimsen, Stephanie R, Resnikoff, Serge, and Vos, Theo

Published
2021
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13. Trends in prevalence of blindness and distance and near vision impairment over 30 years: an analysis for the Global Burden of Disease Study

Author

Bourne, Rupert, Steinmetz, Jaimie D, Flaxman, Seth, Briant, Paul Svitil, Taylor, Hugh R, Resnikoff, Serge, Casson, Robert James, Abdoli, Amir, Abu-Gharbieh, Eman, Afshin, Ashkan, Ahmadieh, Hamid, Akalu, Yonas, Alamneh, Alehegn Aderaw, Alemayehu, Wondu, Alfaar, Ahmed Samir, Alipour, Vahid, Anbesu, Etsay Woldu, Androudi, Sofia, Arabloo, Jalal, Arditi, Aries, Asaad, Malke, Bagli, Eleni, Baig, Atif Amin, Bärnighausen, Till Winfried, Battaglia Parodi, Maurizio, Bhagavathula, Akshaya Srikanth, Bhardwaj, Nikha, Bhardwaj, Pankaj, Bhattacharyya, Krittika, Bijani, Ali, Bikbov, Mukharram, Bottone, Michele, Braithwaite, Tasanee, Bron, Alain M, Butt, Zahid A, Cheng, Ching-Yu, Chu, Dinh-Toi, Cicinelli, Maria Vittoria, Coelho, João M, Dagnew, Baye, Dai, Xiaochen, Dana, Reza, Dandona, Lalit, Dandona, Rakhi, Del Monte, Monte A, Deva, Jenny P, Diaz, Daniel, Djalalinia, Shirin, Dreer, Laura E, Ehrlich, Joshua R, Ellwein, Leon B, Emamian, Mohammad Hassan, Fernandes, Arthur G, Fischer, Florian, Friedman, David S, Furtado, João M, Gaidhane, Abhay Motiramji, Gaidhane, Shilpa, Gazzard, Gus, Gebremichael, Berhe, George, Ronnie, Ghashghaee, Ahmad, Golechha, Mahaveer, Hamidi, Samer, Hammond, Billy Randall, Hartnett, Mary Elizabeth R, Hartono, Risky Kusuma, Hay, Simon I, Heidari, Golnaz, Ho, Hung Chak, Hoang, Chi Linh, Househ, Mowafa, Ibitoye, Segun Emmanuel, Ilic, Irena M, Ilic, Milena D, Ingram, April D, Irvani, Seyed Sina Naghibi, Jha, Ravi Prakash, Kahloun, Rim, Kandel, Himal, Kasa, Ayele Semachew, Kempen, John H, Keramati, Maryam, Khairallah, Moncef, Khan, Ejaz Ahmad, Khanna, Rohit C, Khatib, Mahalaqua Nazli, Kim, Judy E, Kim, Yun Jin, Kisa, Sezer, Kisa, Adnan, Koyanagi, Ai, Kurmi, Om P, Lansingh, Van Charles, Leasher, Janet L, Leveziel, Nicolas, Limburg, Hans, Majdan, Marek, Manafi, Navid, Mansouri, Kaweh, McAlinden, Colm, Mohammadi, Seyed Farzad, Mohammadian-Hafshejani, Abdollah, Mohammadpourhodki, Reza, Mokdad, Ali H, Moosavi, Delaram, Morse, Alan R, Naderi, Mehdi, Naidoo, Kovin S, Nangia, Vinay, Nguyen, Cuong Tat, Nguyen, Huong Lan Thi, Ogundimu, Kolawole, Olagunju, Andrew T, Ostroff, Samuel M, Panda-Jonas, Songhomitra, Pesudovs, Konrad, Peto, Tunde, Quazi Syed, Zahiruddin, Rahman, Mohammad Hifz Ur, Ramulu, Pradeep Y, Rawaf, Salman, Rawaf, David Laith, Reinig, Nickolas, Robin, Alan L, Rossetti, Luca, Safi, Sare, Sahebkar, Amirhossein, Samy, Abdallah M, Saxena, Deepak, Serle, Janet B, Shaikh, Masood Ali, Shen, Tueng T, Shibuya, Kenji, Shin, Jae Il, Silva, Juan Carlos, Silvester, Alexander, Singh, Jasvinder A, Singhal, Deepika, Sitorus, Rita S, Skiadaresi, Eirini, Skirbekk, Vegard, Soheili, Amin, Sousa, Raúl A R C, Spurlock, Emma Elizabeth, Stambolian, Dwight, Taddele, Biruk Wogayehu, Tadesse, Eyayou Girma, Tahhan, Nina, Tareque, Md Ismail, Topouzis, Fotis, Tran, Bach Xuan, Travillian, Ravensara S, Tsilimbaris, Miltiadis K, Varma, Rohit, Virgili, Gianni, Wang, Ya Xing, Wang, Ningli, West, Sheila K, Wong, Tien Y, Zaidi, Zoubida, Zewdie, Kaleab Alemayehu, Jonas, Jost B, and Vos, Theo

Published
2021
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15. Rare and common variants in extracellular matrix gene Fibrillin 2 (FBN2) are associated with macular degeneration

Author

Ratnapriya, Rinki, Zhan, Xiaowei, Fariss, Robert N, Branham, Kari E, Zipprer, David, Chakarova, Christina F, Sergeev, Yuri V, Campos, Maria M, Othman, Mohammad, Friedman, James S, Maminishkis, Arvydas, Waseem, Naushin H, Brooks, Matthew, Rajasimha, Harsha K, Edwards, Albert O, Lotery, Andrew, Klein, Barbara E, Truitt, Barbara J, Li, Bingshan, Schaumberg, Debra A, Morgan, Denise J, Morrison, Margaux A, Souied, Eric, Tsironi, Evangelia E, Grassmann, Felix, Fishman, Gerald A, Silvestri, Giuliana, Scholl, Hendrik PN, Kim, Ivana K, Ramke, Jacqueline, Tuo, Jingsheng, Merriam, Joanna E, Merriam, John C, Park, Kyu Hyung, Olson, Lana M, Farrer, Lindsay A, Johnson, Matthew P, Peachey, Neal S, Lathrop, Mark, Baron, Robert V, Igo, Robert P, Klein, Ronald, Hagstrom, Stephanie A, Kamatani, Yoichiro, Martin, Tammy M, Jiang, Yingda, Conley, Yvette, Sahel, Jose-Alan, Zack, Donald J, Chan, Chi-Chao, Pericak-Vance, Margaret A, Jacobson, Samuel G, Gorin, Michael B, Klein, Michael L, Allikmets, Rando, Iyengar, Sudha K, Weber, Bernhard H, Haines, Jonathan L, Léveillard, Thierry, Deangelis, Margaret M, Stambolian, Dwight, Weeks, Daniel E, Bhattacharya, Shomi S, Chew, Emily Y, Heckenlively, John R, Abecasis, Gonçalo R, and Swaroop, Anand

Subjects
Eye Disease and Disorders of Vision, Human Genome, Neurodegenerative, Genetics, Clinical Research, Macular Degeneration, Aging, 2.1 Biological and endogenous factors, Aetiology, Eye, Adult, Aged, Amino Acid Sequence, Bruch Membrane, DNA Mutational Analysis, Exome, Extracellular Matrix, Fibrillin-2, Fibrillins, Genetic Association Studies, Genetic Variation, High-Throughput Nucleotide Sequencing, Humans, Male, Meta-Analysis as Topic, Microfilament Proteins, Middle Aged, Models, Molecular, Molecular Sequence Data, Mutation, Pedigree, Protein Conformation, Protein Stability, Retina, Sequence Alignment, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Neurodegenerative diseases affecting the macula constitute a major cause of incurable vision loss and exhibit considerable clinical and genetic heterogeneity, from early-onset monogenic disease to multifactorial late-onset age-related macular degeneration (AMD). As part of our continued efforts to define genetic causes of macular degeneration, we performed whole exome sequencing in four individuals of a two-generation family with autosomal dominant maculopathy and identified a rare variant p.Glu1144Lys in Fibrillin 2 (FBN2), a glycoprotein of the elastin-rich extracellular matrix (ECM). Sanger sequencing validated the segregation of this variant in the complete pedigree, including two additional affected and one unaffected individual. Sequencing of 192 maculopathy patients revealed additional rare variants, predicted to disrupt FBN2 function. We then undertook additional studies to explore the relationship of FBN2 to macular disease. We show that FBN2 localizes to Bruch's membrane and its expression appears to be reduced in aging and AMD eyes, prompting us to examine its relationship with AMD. We detect suggestive association of a common FBN2 non-synonymous variant, rs154001 (p.Val965Ile) with AMD in 10 337 cases and 11 174 controls (OR = 1.10; P-value = 3.79 × 10(-5)). Thus, it appears that rare and common variants in a single gene--FBN2--can contribute to Mendelian and complex forms of macular degeneration. Our studies provide genetic evidence for a key role of elastin microfibers and Bruch's membrane in maintaining blood-retina homeostasis and establish the importance of studying orphan diseases for understanding more common clinical phenotypes.

Published
2014

16. Genome-wide meta-analysis of myopia and hyperopia provides evidence for replication of 11 loci.

Author

Simpson, Claire L, Wojciechowski, Robert, Oexle, Konrad, Murgia, Federico, Portas, Laura, Li, Xiaohui, Verhoeven, Virginie JM, Vitart, Veronique, Schache, Maria, Hosseini, S Mohsen, Hysi, Pirro G, Raffel, Leslie J, Cotch, Mary Frances, Chew, Emily, Klein, Barbara EK, Klein, Ronald, Wong, Tien Yin, van Duijn, Cornelia M, Mitchell, Paul, Saw, Seang Mei, Fossarello, Maurizio, Wang, Jie Jin, DCCT/EDIC Research Group, Polašek, Ozren, Campbell, Harry, Rudan, Igor, Oostra, Ben A, Uitterlinden, André G, Hofman, Albert, Rivadeneira, Fernando, Amin, Najaf, Karssen, Lennart C, Vingerling, Johannes R, Döring, Angela, Bettecken, Thomas, Bencic, Goran, Gieger, Christian, Wichmann, H-Erich, Wilson, James F, Venturini, Cristina, Fleck, Brian, Cumberland, Phillippa M, Rahi, Jugnoo S, Hammond, Chris J, Hayward, Caroline, Wright, Alan F, Paterson, Andrew D, Baird, Paul N, Klaver, Caroline CW, Rotter, Jerome I, Pirastu, Mario, Meitinger, Thomas, Bailey-Wilson, Joan E, and Stambolian, Dwight

Subjects
DCCT/EDIC Research Group, Eye, Humans, Hyperopia, Myopia, Genetic Predisposition to Disease, Genetic Markers, Age of Onset, Linkage Disequilibrium, Phenotype, Polymorphism, Single Nucleotide, Alleles, Adult, Aged, Aged, 80 and over, Middle Aged, European Continental Ancestry Group, Female, Male, Genetic Association Studies, and over, Polymorphism, Single Nucleotide, General Science & Technology
Abstract

Refractive error (RE) is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness) and hyperopia (farsightedness), which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p = 1.25×10(-8)), which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE) refractive error. We observed two genome-wide significant associations with hyperopia. These regions overlapped with loci on 15q14 (minimum p value = 9.11×10(-11)) and 8q12 (minimum p value 1.82×10(-11)) previously reported for MSE and myopia age at onset. We also used an intermarker linkage- disequilibrium-based method for calculating the effective number of tests in targeted regional replication analyses. We analyzed myopia (which represents the closest phenotype in our data to the one used by Kiefer et al.) and showed replication of 10 additional loci associated with myopia previously reported by Kiefer et al. This is the first replication of these loci using myopia as the trait under analysis. "Replication-level" association was also seen between hyperopia and 12 of Kiefer et al.'s published loci. For the loci that show evidence of association to both myopia and hyperopia, the estimated effect of the risk alleles were in opposite directions for the two traits. This suggests that these loci are important contributors to variation of refractive error across the distribution.

Published
2014

17. Patterns of Gene Expression, Splicing, and Allele-Specific Expression Vary among Macular Tissues and Clinical Stages of Age-Related Macular Degeneration

Author

Shwani, Treefa, primary, Zhang, Charles, additional, Owen, Leah A., additional, Shakoor, Akbar, additional, Vitale, Albert T., additional, Lillvis, John H., additional, Barr, Julie L., additional, Cromwell, Parker, additional, Finley, Robert, additional, Husami, Nadine, additional, Au, Elizabeth, additional, Zavala, Rylee A., additional, Graves, Elijah C., additional, Zhang, Sarah X., additional, Farkas, Michael H., additional, Ammar, David A., additional, Allison, Karen M., additional, Tawfik, Amany, additional, Sherva, Richard M., additional, Li, Mingyao, additional, Stambolian, Dwight, additional, Kim, Ivana K., additional, Farrer, Lindsay A., additional, and DeAngelis, Margaret M., additional

Published
2023
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18. Whole genome sequencing of 4,787 individuals identifies gene-based rare variants in age-related macular degeneration

Author

Kwong, Alan, primary, Zawistowski, Matthew, additional, Fritsche, Lars G, additional, Zhan, Xiaowei, additional, Bragg-Gresham, Jennifer, additional, Branham, Kari E, additional, Advani, Jayshree, additional, Othman, Mohammad, additional, Ratnapriya, Rinki, additional, Teslovich, Tanya M, additional, Stambolian, Dwight, additional, Chew, Emily Y, additional, Abecasis, Gonçalo R, additional, and Swaroop, Anand, additional

Published
2023
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20. Identification of a rare coding variant in complement 3 associated with age-related macular degeneration.

Author

Zhan, Xiaowei, Larson, David, Wang, Chaolong, Koboldt, Daniel, Sergeev, Yuri, Fulton, Robert, Fulton, Lucinda, Fronick, Catrina, Branham, Kari, Bragg-Gresham, Jennifer, Jun, Goo, Hu, Youna, Kang, Hyun, Liu, Dajiang, Othman, Mohammad, Brooks, Matthew, Ratnapriya, Rinki, Boleda, Alexis, Grassmann, Felix, von Strachwitz, Claudia, Olson, Lana, Buitendijk, Gabriëlle, Hofman, Albert, van Duijn, Cornelia, Cipriani, Valentina, Shahid, Humma, Jiang, Yingda, Conley, Yvette, Morgan, Denise, Kim, Ivana, Johnson, Matthew, Cantsilieris, Stuart, Richardson, Andrea, Guymer, Robyn, Luo, Hongrong, Ouyang, Hong, Licht, Christoph, Pluthero, Fred, Zhang, Mindy, Zhang, Kang, Baird, Paul, Blangero, John, Klein, Michael, Farrer, Lindsay, DeAngelis, Margaret, Weeks, Daniel, Yates, John, Klaver, Caroline, Pericak-Vance, Margaret, Haines, Jonathan, Weber, Bernhard, Wilson, Richard, Heckenlively, John, Chew, Emily, Stambolian, Dwight, Mardis, Elaine, Swaroop, Anand, Abecasis, Goncalo, Gorin, Michael, and Moore, Anthony

Subjects
Aging, Complement C3, Complement Factor H, Complement Pathway, Alternative, Gene Frequency, Genetic Variation, Genotype, Macular Degeneration, Polymorphism, Single Nucleotide
Abstract

Macular degeneration is a common cause of blindness in the elderly. To identify rare coding variants associated with a large increase in risk of age-related macular degeneration (AMD), we sequenced 2,335 cases and 789 controls in 10 candidate loci (57 genes). To increase power, we augmented our control set with ancestry-matched exome-sequenced controls. An analysis of coding variation in 2,268 AMD cases and 2,268 ancestry-matched controls identified 2 large-effect rare variants: previously described p.Arg1210Cys encoded in the CFH gene (case frequency (fcase) = 0.51%; control frequency (fcontrol) = 0.02%; odds ratio (OR) = 23.11) and newly identified p.Lys155Gln encoded in the C3 gene (fcase = 1.06%; fcontrol = 0.39%; OR = 2.68). The variants suggest decreased inhibition of C3 by complement factor H, resulting in increased activation of the alternative complement pathway, as a key component of disease biology.

Published
2013

21. Nine Loci for Ocular Axial Length Identified through Genome-wide Association Studies, Including Shared Loci with Refractive Error

Author

Cheng, Ching-Yu, Schache, Maria, Ikram, M Kamran, Young, Terri L, Guggenheim, Jeremy A, Vitart, Veronique, MacGregor, Stuart, Verhoeven, Virginie JM, Barathi, Veluchamy A, Liao, Jiemin, Hysi, Pirro G, Bailey-Wilson, Joan E, St. Pourcain, Beate, Kemp, John P, McMahon, George, Timpson, Nicholas J, Evans, David M, Montgomery, Grant W, Mishra, Aniket, Wang, Ya Xing, Wang, Jie Jin, Rochtchina, Elena, Polasek, Ozren, Wright, Alan F, Amin, Najaf, van Leeuwen, Elisabeth M, Wilson, James F, Pennell, Craig E, van Duijn, Cornelia M, de Jong, Paulus TVM, Vingerling, Johannes R, Zhou, Xin, Chen, Peng, Li, Ruoying, Tay, Wan-Ting, Zheng, Yingfeng, Chew, Merwyn, Error and Myopia, Consortium for Refractive, Cohort, 1958 British Birth, Rahi, Jugnoo S, cohort, Aichi, Yoshimura, Nagahisa, Yamashiro, Kenji, Miyake, Masahiro, ALIENOR, Delcourt, Cécile, Maubaret, Cecilia, ALSPAC, Williams, Cathy, Northstone, Kate, Ring, Susan M, Davey-Smith, George, ANZRAG, Craig, Jamie E, Burdon, Kathryn P, Fogarty, Rhys D, AREDS1a, Iyengar, Sudha K, Igo, Robert P, Chew, Emily, Janmahasathian, Sarayut, AREDS1b, AREDS1c, Stambolian, Dwight, Wilson, Joan E Bailey, BATS, Lu, Yi, Study, Beijing Eye, Jonas, Jost B, Xu, Liang, Saw, Seang-Mei, BMES, Baird, Paul N, Mitchell, Paul, CIEMS, Nangia, Vinay, CROATIA-Korčula, Hayward, Caroline, CROATIA-Split, Campbell, Harry, CROATIA-Vis, Rudan, Igor, Vatavuk, Zoran, DCCT, Paterson, Andrew D, Hosseini, S Mohsen, GWAS, FECD Fuchs Dystrophy, Fondran, Jeremy R, Study, Myopia, Feng, Sheng, and Study, Erasmus Rucphen Family

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Allied Health and Rehabilitation Science, Health Sciences, Ophthalmology and Optometry, Human Genome, Eye Disease and Disorders of Vision, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Eye, Adolescent, Adult, Aged, Asian People, Axial Length, Eye, Eye Proteins, Female, Gene Expression, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Refractive Errors, Signal Transduction, White People, Consortium for Refractive Error and Myopia, Fuchs' Genetics Multi-Center Study Group, Wellcome Trust Case Control Consortium 2, Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions, and Complications Research Group, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways.

Published
2013

24. Global causes of blindness and distance vision impairment 1990–2020: a systematic review and meta-analysis

Author

Bourne, Rupert, Ackland, Peter, Arditi, Aries, Barkana, Yaniv, Bozkurt, Banu, Braithwaite, Tasanee, Bron, Alain, Budenz, Donald, Cai, Feng, Casson, Robert, Chakravarthy, Usha, Choi, Jaewan, Cicinelli, Maria Vittoria, Congdon, Nathan, Dana, Reza, Dandona, Rakhi, Dandona, Lalit, Das, Aditi, Dekaris, Iva, Del Monte, Monte, deva, Jenny, Dreer, Laura, Ellwein, Leon, Frazier, Marcela, Frick, Kevin, Friedman, David, Furtado, Joao, Gao, Hua, Gazzard, Gus, George, Ronnie, Gichuhi, Stephen, Gonzalez, Victor, Hammond, Billy, Hartnett, Mary Elizabeth, He, Minguang, Hejtmancik, James, Hirai, Flavio, Huang, John, Ingram, April, Javitt, Jonathan, Jonas, Jost, Joslin, Charlotte, Keeffe, Jill, Kempen, John, Khairallah, Moncef, Khanna, Rohit, Kim, Judy, Lambrou, George, Lansingh, Van Charles, Lanzetta, Paolo, Leasher, Janet, Lim, Jennifer, LIMBURG, Hans, Mansouri, Kaweh, Mathew, Anu, Morse, Alan, Munoz, Beatriz, Musch, David, Naidoo, Kovin, Nangia, Vinay, Palaiou, Maria, Parodi, Maurizio Battaglia, Pena, Fernando Yaacov, Pesudovs, Konrad, Peto, Tunde, Quigley, Harry, Raju, Murugesan, Ramulu, Pradeep, Rankin, Zane, Resnikoff, Serge, Reza, Dana, Robin, Alan, Rossetti, Luca, Saaddine, Jinan, Sandar, Mya, Serle, Janet, Shen, Tueng, Shetty, Rajesh, Sieving, Pamela, Silva, Juan Carlos, Silvester, Alex, Sitorus, Rita S., Stambolian, Dwight, Stevens, Gretchen, Taylor, Hugh, Tejedor, Jaime, Tielsch, James, Tsilimbaris, Miltiadis, van Meurs, Jan, Varma, Rohit, Virgili, Gianni, Wang, Ya Xing, Wang, Ning-Li, West, Sheila, Wiedemann, Peter, Wong, Tien, Wormald, Richard, Zheng, Yingfeng, Flaxman, Seth R, Bourne, Rupert R A, Cicinelli, Maria V, Jonas, Jost B, Kempen, John H, Limburg, Hans, Stevens, Gretchen A, Tahhan, Nina, Wong, Tien Y, and Taylor, Hugh R

Published
2017
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25. A 32 kb critical region excluding Y402H in CFH mediates risk for age-related macular degeneration.

Author

Sivakumaran, Theru A, Igo, Robert P, Kidd, Jeffrey M, Itsara, Andy, Kopplin, Laura J, Chen, Wei, Hagstrom, Stephanie A, Peachey, Neal S, Francis, Peter J, Klein, Michael L, Chew, Emily Y, Ramprasad, Vedam L, Tay, Wan-Ting, Mitchell, Paul, Seielstad, Mark, Stambolian, Dwight E, Edwards, Albert O, Lee, Kristine E, Leontiev, Dmitry V, Jun, Gyungah, Wang, Yang, Tian, Liping, Qiu, Feiyou, Henning, Alice K, LaFramboise, Thomas, Sen, Parveen, Aarthi, Manoharan, George, Ronnie, Raman, Rajiv, Das, Manmath Kumar, Vijaya, Lingam, Kumaramanickavel, Govindasamy, Wong, Tien Y, Swaroop, Anand, Abecasis, Goncalo R, Klein, Ronald, Klein, Barbara EK, Nickerson, Deborah A, Eichler, Evan E, and Iyengar, Sudha K

Subjects
Humans, Macular Degeneration, Genetic Predisposition to Disease, Complement Factor H, Risk Factors, Cohort Studies, Reproducibility of Results, Base Sequence, Base Pairing, Haplotypes, Linkage Disequilibrium, Mutation, Polymorphism, Single Nucleotide, Multigene Family, Reference Standards, Molecular Sequence Data, DNA Copy Number Variations, Polymorphism, Single Nucleotide, General Science & Technology
Abstract

Complement factor H shows very strong association with Age-related Macular Degeneration (AMD), and recent data suggest that multiple causal variants are associated with disease. To refine the location of the disease associated variants, we characterized in detail the structural variation at CFH and its paralogs, including two copy number polymorphisms (CNP), CNP147 and CNP148, and several rare deletions and duplications. Examination of 34 AMD-enriched extended families (N = 293) and AMD cases (White N = 4210 Indian = 134; Malay = 140) and controls (White N = 3229; Indian = 117; Malay = 2390) demonstrated that deletion CNP148 was protective against AMD, independent of SNPs at CFH. Regression analysis of seven common haplotypes showed three haplotypes, H1, H6 and H7, as conferring risk for AMD development. Being the most common haplotype H1 confers the greatest risk by increasing the odds of AMD by 2.75-fold (95% CI = [2.51, 3.01]; p = 8.31×10(-109)); Caucasian (H6) and Indian-specific (H7) recombinant haplotypes increase the odds of AMD by 1.85-fold (p = 3.52×10(-9)) and by 15.57-fold (P = 0.007), respectively. We identified a 32-kb region downstream of Y402H (rs1061170), shared by all three risk haplotypes, suggesting that this region may be critical for AMD development. Further analysis showed that two SNPs within the 32 kb block, rs1329428 and rs203687, optimally explain disease association. rs1329428 resides in 20 kb unique sequence block, but rs203687 resides in a 12 kb block that is 89% similar to a noncoding region contained in ΔCNP148. We conclude that causal variation in this region potentially encompasses both regulatory effects at single markers and copy number.

Published
2011

26. Magnitude, temporal trends, and projections of the global prevalence of blindness and distance and near vision impairment: a systematic review and meta-analysis

Author

Bourne, Rupert, Ackland, Peter, Arditi, Aries, Barkana, Yaniv, Bozkurt, Banu, BRAITHWAITE, TASANEE, Bron, Alain, Budenz, Donald, Cai, Feng, Casson, Robert, Chakravarthy, Usha, Choi, Jaewan, Cicinelli, Maria Vittoria, Congdon, Nathan, Dana, Reza, Dandona, Rakhi, Dandona, Lalit, Das, Aditi, Dekaris, Iva, Del Monte, Monte, Deva, Jenny, Dreer, Laura, Ellwein, Leon, Frazier, Marcela, Frick, Kevin, Friedman, David, Furtado, Joao, Gao, Hua, Gazzard, Gus, George, Ronnie, Gichuhi, Stephen, Gonzalez, Victor, Hammond, Billy, Hartnett, Mary Elizabeth, He, Minguang, Hejtmancik, James, Hirai, Flavio, Huang, John, Ingram, April, Javitt, Jonathan, Jonas, Jost, Joslin, Charlotte, Keeffe, Jill, Kempen, John, Khairallah, Moncef, Khanna, Rohit, Kim, Judy, Lambrou, George, Lansingh, Van Charles, Lanzetta, Paolo, Leasher, Janet, Lim, Jennifer, LIMBURG, Hans, Mansouri, Kaweh, Mathew, Anu, Morse, Alan, Munoz, Beatriz, Musch, David, Naidoo, Kovin, Nangia, Vinay, PALAIOU, MARIA, Parodi, Maurizio Battaglia, Pena, Fernando Yaacov, Pesudovs, Konrad, Peto, Tunde, Quigley, Harry, Raju, Murugesan, Ramulu, Pradeep, Resnikoff, Serge, Robin, Alan, Rossetti, Luca, Saaddine, Jinan, SANDAR, MYA, Serle, Janet, Shen, Tueng, Shetty, Rajesh, Sieving, Pamela, Silva, Juan Carlos, Silvester, Alex, Sitorus, Rita S, Stambolian, Dwight, Stevens, Gretchen, Taylor, Hugh, Tejedor, Jaime, Tielsch, James, Tsilimbaris, Miltiadis, van Meurs, Jan, Varma, Rohit, Virgili, Gianni, Volmink, Jimmy, Wang, Ya Xing, Wang, Ning-Li, West, Sheila, Wiedemann, Peter, Wong, Tien, Wormald, Richard, Zheng, Yingfeng, Bourne, Rupert R A, Flaxman, Seth R, Braithwaite, Tasanee, Cicinelli, Maria V, Jonas, Jost B, Kempen, John H, Limburg, Hans, Stevens, Gretchen A, Tahhan, Nina, Wong, Tien Y, and Taylor, Hugh R

Published
2017
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29. Assessment of intraretinal hyperreflective foci using multimodal imaging in eyes with age‐related macular degeneration.

Author

Oncel, Deniz, Corradetti, Giulia, He, Ye, Ashrafkhorasani, Maryam, Nittala, Muneeswar Gupta, Stambolian, Dwight, Pericak‐Vance, Margaret A., Haines, Jonathan L., and Sadda, Srinivas R.

Subjects
MACULAR degeneration, OPTICAL coherence tomography, HYPERPIGMENTATION
Abstract

Purpose: This study aimed to investigate the correspondence between intraretinal hyperreflective foci (IHRF) identified on optical coherence tomography (OCT) B‐scans with hyperpigmentation on colour fundus photography (CFP) or hyperreflectivity on infrared reflectance (IR) images in eyes with age‐related macular degeneration (AMD). Methods: Flash CFP, IR images and OCT B‐scans obtained at the same visit were evaluated. Individual IHRF identified on OCT B‐scans were assessed for the qualitative presence or absence of a hypotransmission tail into the choroid. The corresponding IR image obtained at the time of OCT acquisition was analysed for the presence or absence of hyperreflectivity in this region. The IR images were manually registered to the CFP image, and CFP images were inspected for the presence or absence of hyperpigmentation at the location of IHRF. Results: From 122 eyes, a total of 494 IHRF were evaluated. For the primary analysis of qualitative presence or absence of hyperpigmentation on CFP and hyperreflectivity on IR at the locations corresponding to IHRF on OCT, 301 (61.0%) of the IHRFs demonstrated evidence of hyperpigmentation on CFP, while only 115 (23.3%) showed evidence of hyperreflectivity on IR. The qualitative determination of the presence or absence of an abnormality on CFP or IR were significantly different (p < 0.0001). 327 (66.2%) of the IHRF showed hypotransmission, and 80.4% of these IHRF showed hyperpigmentation on CFP, though only 23.9% (p < 0.0001) demonstrated hyperreflectivity on IR. Conclusions: Less than two‐thirds of IHRF evident on OCT manifest as hyperpigmentation on colour photos, though IHRF with posterior shadowing are more likely to be evident as pigment. IR imaging appears to be even more poorly sensitive for visualizing IHRF. [ABSTRACT FROM AUTHOR]

Published
2024
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32. Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error

Author

Tedja, Milly S., Wojciechowski, Robert, Hysi, Pirro G., Eriksson, Nicholas, Furlotte, Nicholas A., Verhoeven, Virginie J. M., Iglesias, Adriana I., Meester-Smoor, Magda A., Tompson, Stuart W., Fan, Qiao, Khawaja, Anthony P., Cheng, Ching-Yu, Höhn, René, Yamashiro, Kenji, Wenocur, Adam, Grazal, Clare, Haller, Toomas, Metspalu, Andres, Wedenoja, Juho, Jonas, Jost B., Wang, Ya Xing, Xie, Jing, Mitchell, Paul, Foster, Paul J., Klein, Barbara E. K., Klein, Ronald, Paterson, Andrew D., Hosseini, S. Mohsen, Shah, Rupal L., Williams, Cathy, Teo, Yik Ying, Tham, Yih Chung, Gupta, Preeti, Zhao, Wanting, Shi, Yuan, Saw, Woei-Yuh, Tai, E-Shyong, Sim, Xue Ling, Huffman, Jennifer E., Polašek, Ozren, Hayward, Caroline, Bencic, Goran, Rudan, Igor, Wilson, James F., The CREAM Consortium, 23andMe Research Team, UK Biobank Eye and Vision Consortium, Joshi, Peter K., Tsujikawa, Akitaka, Matsuda, Fumihiko, Whisenhunt, Kristina N., Zeller, Tanja, van der Spek, Peter J., Haak, Roxanna, Meijers-Heijboer, Hanne, van Leeuwen, Elisabeth M., Iyengar, Sudha K., Lass, Jonathan H., Hofman, Albert, Rivadeneira, Fernando, Uitterlinden, André G., Vingerling, Johannes R., Lehtimäki, Terho, Raitakari, Olli T., Biino, Ginevra, Concas, Maria Pina, Schwantes-An, Tae-Hwi, Igo, Jr, Robert P., Cuellar-Partida, Gabriel, Martin, Nicholas G., Craig, Jamie E., Gharahkhani, Puya, Williams, Katie M., Nag, Abhishek, Rahi, Jugnoo S., Cumberland, Phillippa M., Delcourt, Cécile, Bellenguez, Céline, Ried, Janina S., Bergen, Arthur A., Meitinger, Thomas, Gieger, Christian, Wong, Tien Yin, Hewitt, Alex W., Mackey, David A., Simpson, Claire L., Pfeiffer, Norbert, Pärssinen, Olavi, Baird, Paul N., Vitart, Veronique, Amin, Najaf, van Duijn, Cornelia M., Bailey-Wilson, Joan E., Young, Terri L., Saw, Seang-Mei, Stambolian, Dwight, MacGregor, Stuart, Guggenheim, Jeremy A., Tung, Joyce Y., Hammond, Christopher J., and Klaver, Caroline C. W.

Published
2018
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34. A new polygenic score for refractive error improves detection of children at risk of high myopia but not the prediction of those at risk of myopic macular degeneration

Author

Clark, Rosie, primary, Lee, Samantha Sze-Yee, additional, Du, Ran, additional, Wang, Yining, additional, Kneepkens, Sander C.M., additional, Charng, Jason, additional, Huang, Yu, additional, Hunter, Michael L., additional, Jiang, Chen, additional, Tideman, J.Willem L., additional, Melles, Ronald B., additional, Klaver, Caroline C.W., additional, Mackey, David A., additional, Williams, Cathy, additional, Choquet, Hélène, additional, Ohno-Matsui, Kyoko, additional, Guggenheim, Jeremy A., additional, Bailey-Wilson, Joan E., additional, Baird, Paul N., additional, Barathi, Veluchamy A., additional, Biino, Ginevra, additional, Burdon, Kathryn P., additional, Campbell, Harry, additional, Chen, Li Jia, additional, Cheng, Ching-Yu, additional, Chew, Emily Y., additional, Craig, Jamie E., additional, Deangelis, Margaret M., additional, Delcourt, Cécile, additional, Ding, Xiaohu, additional, Fan, Qiao, additional, Fossarello, Maurizio, additional, Foster, Paul J., additional, Gharahkhani, Puya, additional, Guo, Xiaobo, additional, Haarman, Annechien E.G., additional, Haller, Toomas, additional, Hammond, Christopher J., additional, Han, Xikun, additional, Hayward, Caroline, additional, He, Mingguang, additional, Hewitt, Alex W., additional, Hoang, Quan, additional, Hysi, Pirro G., additional, Iglesias, Adriana I., additional, Igo, Robert P., additional, Iyengar, Sudha K., additional, Jonas, Jost B., additional, Kähönen, Mika, additional, Kaprio, Jaakko, additional, Khawaja, Anthony P., additional, Klein, Barbara E., additional, Lass, Jonathan H., additional, Lee, Kris, additional, Lehtimäki, Terho, additional, Lewis, Deyana, additional, Li, Qing, additional, Li, Shi-Ming, additional, Lyytikäinen, Leo-Pekka, additional, MacGregor, Stuart, additional, Martin, Nicholas G., additional, Meguro, Akira, additional, Metspalu, Andres, additional, Middlebrooks, Candace, additional, Miyake, Masahiro, additional, Mizuki, Nobuhisa, additional, Musolf, Anthony, additional, Nickels, Stefan, additional, Oexle, Konrad, additional, Pang, Chi Pui, additional, Pärssinen, Olavi, additional, Paterson, Andrew D., additional, Pfeiffer, Norbert, additional, Polasek, Ozren, additional, Rahi, Jugnoo S., additional, Raitakari, Olli, additional, Rudan, Igor, additional, Sahebjada, Srujana, additional, Saw, Seang-Mei, additional, Simpson, Claire L., additional, Stambolian, Dwight, additional, Tai, E-Shyong, additional, Tedja, Milly S., additional, Tideman, J. Willem L., additional, Tsujikawa, Akitaka, additional, van Duijn, Cornelia M., additional, Verhoeven, Virginie J.M., additional, Vitart, Veronique, additional, Wang, Ningli, additional, Wang, Ya Xing, additional, Wedenoja, Juho, additional, Wei, Wen Bin, additional, Williams, Katie M., additional, Wilson, James F., additional, Wojciechowski, Robert, additional, Yam, Jason C.S., additional, Yamashiro, Kenji, additional, Yap, Maurice K.H., additional, Yazar, Seyhan, additional, Yip, Shea Ping, additional, Young, Terri L., additional, Zhou, Xiangtian, additional, Allen, Naomi, additional, Aslam, Tariq, additional, Atan, Denize, additional, Barman, Sarah, additional, Barrett, Jenny, additional, Bishop, Paul, additional, Black, Graeme, additional, Bunce, Catey, additional, Carare, Roxana, additional, Chakravarthy, Usha, additional, Chan, Michelle, additional, Chua, Sharon, additional, Cipriani, Valentina, additional, Day, Alexander, additional, Desai, Parul, additional, Dhillon, Bal, additional, Dick, Andrew, additional, Doney, Alexander, additional, Egan, Cathy, additional, Ennis, Sarah, additional, Foster, Paul, additional, Fruttiger, Marcus, additional, Gallacher, John, additional, Garway-Heath, David, additional, Gibson, Jane, additional, Gore, Dan, additional, Guggenheim, Jeremy, additional, Hammond, Chris, additional, Hardcastle, Alison, additional, Harding, Simon, additional, Hogg, Ruth, additional, Hysi, Pirro, additional, Keane, Pearse A., additional, Khaw, Peng Tee, additional, Khawaja, Anthony, additional, Lascaratos, Gerassimos, additional, Littlejohns, Thomas, additional, Lotery, Andrew, additional, Luthert, Phil, additional, MacGillivray, Tom, additional, Mackie, Sarah, additional, McGuinness, Bernadette, additional, McKay, Gareth, additional, McKibbin, Martin, additional, Mitry, Danny, additional, Moore, Tony, additional, Morgan, James, additional, Muthy, Zaynah, additional, O'Sullivan, Eoin, additional, Owen, Chris, additional, Patel, Praveen, additional, Paterson, Euan, additional, Peto, Tunde, additional, Petzold, Axel, additional, Pontikos, Nikolas, additional, Rahi, Jugnoo, additional, Rudnicka, Alicja, additional, Self, Jay, additional, Sergouniotis, Panagiotis, additional, Sivaprasad, Sobha, additional, Steel, David, additional, Stratton, Irene, additional, Strouthidis, Nicholas, additional, Sudlow, Cathie, additional, Tapp, Robyn, additional, Thaung, Caroline, additional, Thomas, Dhanes, additional, Trucco, Emanuele, additional, Tufail, Adnan, additional, Vernon, Stephen, additional, Viswanathan, Ananth, additional, Williams, Katie, additional, Woodside, Jayne, additional, Yates, Max, additional, Yip, Jennifer, additional, and Zheng, Yalin, additional

Published
2023
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35. AMISH EYE STUDY: Baseline Spectral Domain Optical Coherence Tomography Characteristics of Age-Related Macular Degeneration

Author

Nittala, Muneeswar G., Song, Yeunjoo E., Sardell, Rebecca, Adams, Larry D., Pan, Samuel, Velaga, Swetha B., Horst, Violet, Dana, Debra, Caywood, Laura, Laux, Renee, Fuzzell, Denise, Fuzzell, Sarada, Scott, William K., Cooke Bailey, Jessica N., Igo, Robert P., Jr, Haines, Jonathan, Pericak-Vance, Margaret A., Sadda, SriniVas R., and Stambolian, Dwight

Published
2019
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37. Patterns of gene expression and allele-specific expression vary among macular tissues and clinical stages of Age-related Macular Degeneration

Author

Zhang, Charles, primary, Barr, Julie L, additional, Owen, Leah A., additional, Shakoor, Akbar, additional, Vitale, Albert T, additional, Lillvis, John H, additional, Husami, Nadine, additional, Cromwell, Parker, additional, Finley, Robert, additional, Au, Elizabeth, additional, Haider, Neena B, additional, Zavala, Rylee A, additional, Graves, Elijah C, additional, Li, Mingyao, additional, Tawfik, Amany, additional, Zhang, Sarah X, additional, Stambolian, Dwight, additional, Farkas, Michael H, additional, Kim, Ivana K, additional, Sherva, Richard M, additional, Farrer, Lindsay, additional, and DeAngelis, Margaret M, additional

Published
2022
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38. Systems genomics in age-related macular degeneration

Author

den Hollander, Anneke I., primary, Mullins, Robert F., additional, Orozco, Luz D., additional, Voigt, Andrew P., additional, Chen, Hsu-Hsin, additional, Strunz, Tobias, additional, Grassmann, Felix, additional, Haines, Jonathan L., additional, Kuiper, Jonas J.W., additional, Tumminia, Santa J., additional, Allikmets, Rando, additional, Hageman, Gregory S., additional, Stambolian, Dwight, additional, Klaver, Caroline C.W., additional, Boeke, Jef D., additional, Chen, Hao, additional, Honigberg, Lee, additional, Katti, Suresh, additional, Frazer, Kelly A., additional, Weber, Bernhard H.F., additional, and Gorin, Michael B., additional

Published
2022
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39. Effective refractive error coverage in adults aged 50 years and older: estimates from population-based surveys in 61 countries

Author

Bourne, Rupert Richard Alexander, primary, Cicinelli, Maria Vittoria, additional, Sedighi, Tabassom, additional, Tapply, Ian H, additional, McCormick, Ian, additional, Jonas, Jost B, additional, Congdon, Nathan G, additional, Ramke, Jacqueline, additional, Naidoo, Kovin S, additional, Fricke, Timothy R, additional, Burton, Matthew J, additional, Müller, Andreas, additional, Bikbov, Mukharram M, additional, Furtado, João M, additional, Kyari, Fatima, additional, He, Mingguang, additional, Wang, Ya Xing, additional, Vijaya, Lingam, additional, Nangia, Vinay, additional, Brian, Garry, additional, Emamian, Mohammad Hassan, additional, Fotouhi, Akbar, additional, Hashemi, Hassan, additional, Khandekar, Rajiv B, additional, Marmamula, Srinivas, additional, Salomão, Solange, additional, George, Ronnie, additional, Kazakbaeva, Gyulli, additional, Braithwaite, Tasanee, additional, Casson, Robert J, additional, Iwase, Aiko, additional, Gupta, Noopur, additional, Abdianwall, Mohammad H, additional, Varma, Rohit, additional, Wong, Tien Y, additional, Wang, Ningli, additional, Taylor, Hugh R, additional, Flaxman, Seth R, additional, Keel, Stuart, additional, Resnikoff, Serge, additional, Bron, Alain, additional, Cheng, Ching-Yu, additional, Fernandes, Arthur, additional, Friedman, David, additional, Gazzard, Andrew, additional, Kahloun, Rim, additional, Kempen, John, additional, Khairallah, Moncef, additional, Lansingh, Van C, additional, Leasher, Janet, additional, Leveziel, Nicolas, additional, Limburg, Hans, additional, Nowak, Michal, additional, Pesudovs, Konrad, additional, Peto, Tunde, additional, Rossetti, Luca, additional, Tahhan, Nina, additional, Alemayehu, Wondu, additional, Arditi, Aries, additional, Dana, Reza, additional, Del Monte, Monte, additional, Deva, jenny, additional, Dreer, Laura, additional, Ehrlich, Josh, additional, Ellwein, Leon, additional, Hammond, Billy, additional, Hartnett, Mary E, additional, Ingram, April, additional, Khanna, Rohit, additional, Kim, Judy, additional, Lim, Jennifer, additional, Morse, Alan, additional, Musch, David, additional, Parodi, Maurizio B, additional, Ramulu, Pradeep, additional, Robin, Alan, additional, Serle, Janet, additional, Shen, Tueng, additional, Sitorus, Rita S, additional, Stambolian, Dwight, additional, Topouzis, Fotis, additional, Tsilimbaris, Miltiadis, additional, Virgili, Gianni, additional, West, Sheila, additional, Ababora, Jafer K, additional, AlSawahli, Heba, additional, Andriamanjato, Hery Harimanitra, additional, Barrenechea, Rosario, additional, Batlle, Juan F, additional, Burnett, Anthea M, additional, Finger, Robert P, additional, Gallarreta, Marcelo, additional, Gomez-Bastar, Pedro A, additional, Gurung, Reeta, additional, Jain, Elesh, additional, Kabona, George E, additional, Kalua, Khumbo, additional, Kandeke, Levi, additional, Karimurio, Jefitha, additional, Kikira, Susan A, additional, Kulkarni, Sucheta, additional, Mathenge, Wanjiku, additional, Mishra, Sailesh Kumar, additional, Mohammadi, Seyed Farzad, additional, Mörchen, Manfred, additional, Muhammad, Nasiru, additional, Mutati, Grace C, additional, Nano, Maria Eugenia, additional, Németh, János, additional, Paduca, Ala, additional, Páez, Alexander, additional, Rabiu, M Mansur, additional, Rif'ati, Lutfah, additional, Salowi, Mohamad Aziz, additional, Sapkota, Yuddha D, additional, Sargent, Nicholas, additional, Thoufeeq, Ubeydulla, additional, Villalobos, Astrid V, additional, Xiao, Biaxiang, additional, Yee Melgar, Mariano, additional, and Zhang, Xiu Juan, additional

Published
2022
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40. Optic Disc and Cup Segmentation from Color Fundus Photograph Using Graph Cut with Priors

Author

Zheng, Yuanjie, Stambolian, Dwight, O’Brien, Joan, Gee, James C., Hutchison, David, editor, Kanade, Takeo, editor, Kittler, Josef, editor, Kleinberg, Jon M., editor, Mattern, Friedemann, editor, Mitchell, John C., editor, Naor, Moni, editor, Nierstrasz, Oscar, editor, Pandu Rangan, C., editor, Steffen, Bernhard, editor, Sudan, Madhu, editor, Terzopoulos, Demetri, editor, Tygar, Doug, editor, Vardi, Moshe Y., editor, Weikum, Gerhard, editor, Mori, Kensaku, editor, Sakuma, Ichiro, editor, Sato, Yoshinobu, editor, Barillot, Christian, editor, and Navab, Nassir, editor

Published
2013
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41. Genetically low vitamin D concentrations and myopic refractive error: a Mendelian randomization study

Author

Cuellar-Partida, Gabriel, Williams, Katie M, Yazar, Seyhan, Guggenheim, Jeremy A, Hewitt, Alex W, Williams, Cathy, Wang, Jie Jin, Kho, Pik-Fang, Saw, Seang Mei, Cheng, Ching-Yu, Wong, Tien Yin, Aung, Tin, Young, Terri L, Tideman, Willem L J, Jonas, Jost B, Mitchell, Paul, Wojciechowski, Robert, Stambolian, Dwight, Hysi, Pirro, Hammond, Christopher J, Mackey, David A, Lucas, Robyn M, and MacGregor, Stuart

Published
2017
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44. Consequences of a Rare Complement Factor H Variant for Age-Related Macular Degeneration in the Amish

Author

Waksmunski, Andrea R., primary, Miskimen, Kristy, additional, Song, Yeunjoo E., additional, Grunin, Michelle, additional, Laux, Renee, additional, Fuzzell, Denise, additional, Fuzzell, Sarada, additional, Adams, Larry D., additional, Caywood, Laura, additional, Prough, Michael, additional, Stambolian, Dwight, additional, Scott, William K., additional, Pericak-Vance, Margaret A., additional, and Haines, Jonathan L., additional

Published
2022
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47. As in Real Estate, Location Matters: Cellular Expression of Complement Varies Between Macular and Peripheral Regions of the Retina and Supporting Tissues

Author

Zauhar, Randy, primary, Biber, Josef, additional, Jabri, Yassin, additional, Kim, Mijin, additional, Hu, Jian, additional, Kaplan, Lew, additional, Pfaller, Anna M., additional, Schäfer, Nicole, additional, Enzmann, Volker, additional, Schlötzer-Schrehardt, Ursula, additional, Straub, Tobias, additional, Hauck, Stefanie M., additional, Gamlin, Paul D., additional, McFerrin, Michael B., additional, Messinger, Jeffrey, additional, Strang, Christianne E., additional, Curcio, Christine A., additional, Dana, Nicholas, additional, Pauly, Diana, additional, Grosche, Antje, additional, Li, Mingyao, additional, and Stambolian, Dwight, additional

Published
2022
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48. Systems genomics in age-related macular degeneration.

Author

den Hollander, Anneke I, den Hollander, Anneke I, Mullins, Robert F, Orozco, Luz D, Voigt, Andrew P, Chen, Hsu-Hsin, Strunz, Tobias, Grassmann, Felix, Haines, Jonathan L, Kuiper, Jonas JW, Tumminia, Santa J, Allikmets, Rando, Hageman, Gregory S, Stambolian, Dwight, Klaver, Caroline CW, Boeke, Jef D, Chen, Hao, Honigberg, Lee, Katti, Suresh, Frazer, Kelly A, Weber, Bernhard HF, Gorin, Michael B, den Hollander, Anneke I, den Hollander, Anneke I, Mullins, Robert F, Orozco, Luz D, Voigt, Andrew P, Chen, Hsu-Hsin, Strunz, Tobias, Grassmann, Felix, Haines, Jonathan L, Kuiper, Jonas JW, Tumminia, Santa J, Allikmets, Rando, Hageman, Gregory S, Stambolian, Dwight, Klaver, Caroline CW, Boeke, Jef D, Chen, Hao, Honigberg, Lee, Katti, Suresh, Frazer, Kelly A, Weber, Bernhard HF, and Gorin, Michael B

Abstract

Genomic studies in age-related macular degeneration (AMD) have identified genetic variants that account for the majority of AMD risk. An important next step is to understand the functional consequences and downstream effects of the identified AMD-associated genetic variants. Instrumental for this next step are 'omics' technologies, which enable high-throughput characterization and quantification of biological molecules, and subsequent integration of genomics with these omics datasets, a field referred to as systems genomics. Single cell sequencing studies of the retina and choroid demonstrated that the majority of candidate AMD genes identified through genomic studies are expressed in non-neuronal cells, such as the retinal pigment epithelium (RPE), glia, myeloid and choroidal cells, highlighting that many different retinal and choroidal cell types contribute to the pathogenesis of AMD. Expression quantitative trait locus (eQTL) studies in retinal tissue have identified putative causal genes by demonstrating a genetic overlap between gene regulation and AMD risk. Linking genetic data to complement measurements in the systemic circulation has aided in understanding the effect of AMD-associated genetic variants in the complement system, and supports that protein QTL (pQTL) studies in plasma or serum samples may aid in understanding the effect of genetic variants and pinpointing causal genes in AMD. A recent epigenomic study fine-mapped AMD causal variants by determing regulatory regions in RPE cells differentiated from induced pluripotent stem cells (iPSC-RPE). Another approach that is being employed to pinpoint causal AMD genes is to produce synthetic DNA assemblons representing risk and protective haplotypes, which are then delivered to cellular or animal model systems. Pinpointing causal genes and understanding disease mechanisms is crucial for the next step towards clinical translation. Clinical trials targeting proteins encoded by the AMD-associated genomic loci

Published
2022

49. Systems genomics in age-related macular degeneration

Author

den Hollander, Anneke I., Mullins, Robert F., Orozco, Luz D., Voigt, Andrew P., Chen, Hsu Hsin, Strunz, Tobias, Grassmann, Felix, Haines, Jonathan L., Kuiper, Jonas J.W., Tumminia, Santa J., Allikmets, Rando, Hageman, Gregory S., Stambolian, Dwight, Klaver, Caroline C.W., Boeke, Jef D., Chen, Hao, Honigberg, Lee, Katti, Suresh, Frazer, Kelly A., Weber, Bernhard H.F., Gorin, Michael B., den Hollander, Anneke I., Mullins, Robert F., Orozco, Luz D., Voigt, Andrew P., Chen, Hsu Hsin, Strunz, Tobias, Grassmann, Felix, Haines, Jonathan L., Kuiper, Jonas J.W., Tumminia, Santa J., Allikmets, Rando, Hageman, Gregory S., Stambolian, Dwight, Klaver, Caroline C.W., Boeke, Jef D., Chen, Hao, Honigberg, Lee, Katti, Suresh, Frazer, Kelly A., Weber, Bernhard H.F., and Gorin, Michael B.

Abstract

Genomic studies in age-related macular degeneration (AMD) have identified genetic variants that account for the majority of AMD risk. An important next step is to understand the functional consequences and downstream effects of the identified AMD-associated genetic variants. Instrumental for this next step are ‘omics’ technologies, which enable high-throughput characterization and quantification of biological molecules, and subsequent integration of genomics with these omics datasets, a field referred to as systems genomics. Single cell sequencing studies of the retina and choroid demonstrated that the majority of candidate AMD genes identified through genomic studies are expressed in non-neuronal cells, such as the retinal pigment epithelium (RPE), glia, myeloid and choroidal cells, highlighting that many different retinal and choroidal cell types contribute to the pathogenesis of AMD. Expression quantitative trait locus (eQTL) studies in retinal tissue have identified putative causal genes by demonstrating a genetic overlap between gene regulation and AMD risk. Linking genetic data to complement measurements in the systemic circulation has aided in understanding the effect of AMD-associated genetic variants in the complement system, and supports that protein QTL (pQTL) studies in plasma or serum samples may aid in understanding the effect of genetic variants and pinpointing causal genes in AMD. A recent epigenomic study fine-mapped AMD causal variants by determing regulatory regions in RPE cells differentiated from induced pluripotent stem cells (iPSC-RPE). Another approach that is being employed to pinpoint causal AMD genes is to produce synthetic DNA assemblons representing risk and protective haplotypes, which are then delivered to cellular or animal model systems. Pinpointing causal genes and understanding disease mechanisms is crucial for the next step towards clinical translation. Clinical trials targeting proteins encoded by the AMD-associated genomic lo

Published
2022

50. Systems genomics in age-related macular degeneration

Author

MS Oogheelkunde, Infection & Immunity, den Hollander, Anneke I, Mullins, Robert F, Orozco, Luz D, Voigt, Andrew P, Chen, Hsu-Hsin, Strunz, Tobias, Grassmann, Felix, Haines, Jonathan L, Kuiper, Jonas J W, Tumminia, Santa J, Allikmets, Rando, Hageman, Gregory S, Stambolian, Dwight, Klaver, Caroline C W, Boeke, Jef D, Chen, Hao, Honigberg, Lee, Katti, Suresh, Frazer, Kelly A, Weber, Bernhard H F, Gorin, Michael B, MS Oogheelkunde, Infection & Immunity, den Hollander, Anneke I, Mullins, Robert F, Orozco, Luz D, Voigt, Andrew P, Chen, Hsu-Hsin, Strunz, Tobias, Grassmann, Felix, Haines, Jonathan L, Kuiper, Jonas J W, Tumminia, Santa J, Allikmets, Rando, Hageman, Gregory S, Stambolian, Dwight, Klaver, Caroline C W, Boeke, Jef D, Chen, Hao, Honigberg, Lee, Katti, Suresh, Frazer, Kelly A, Weber, Bernhard H F, and Gorin, Michael B

Published
2022

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