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2. No Strong Association between the Apolipoprotein E E4 Allele and Glaucoma: A Multicohort Study

Author

Mullany, Sean, Diaz-Torres, Santiago, Schmidt, Joshua M., Thomson, Daniel, Qassim, Ayub, Marshall, Henry N., Knight, Lachlan S.W., Berry, Ella C., Kolovos, Antonia, Dimasi, David, Lake, Stewart, Mills, Richard A., Landers, John, Mitchell, Paul, Healey, Paul R., Commerford, Toby, Klebe, Sonja, Souzeau, Emmanuelle, Hassall, Mark M., MacGregor, Stuart, Gharahkhani, Puya, Siggs, Owen M., and Craig, Jamie E.

Published
2023
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6. Retinal ganglion cell-specific genetic regulation in primary open-angle glaucoma

Author

Daniszewski, Maciej, Senabouth, Anne, Liang, Helena H., Han, Xikun, Lidgerwood, Grace E., Hernández, Damián, Sivakumaran, Priyadharshini, Clarke, Jordan E., Lim, Shiang Y., Lees, Jarmon G., Rooney, Louise, Gulluyan, Lerna, Souzeau, Emmanuelle, Graham, Stuart L., Chan, Chia-Ling, Nguyen, Uyen, Farbehi, Nona, Gnanasambandapillai, Vikkitharan, McCloy, Rachael A., Clarke, Linda, Kearns, Lisa S., Mackey, David A., Craig, Jamie E., MacGregor, Stuart, Powell, Joseph E., Pébay, Alice, and Hewitt, Alex W.

Published
2022
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7. The APOE E4 Allele Is Associated with Faster Rates of Neuroretinal Thinning in a Prospective Cohort Study of Suspect and Early Glaucoma

Author

Mullany, Sean, Marshall, Henry, Diaz-Torres, Santiago, Berry, Ella C., Schmidt, Joshua M., Thomson, Daniel, Qassim, Ayub, To, Minh-Son, Dimasi, David, Kuot, Abraham, Knight, Lachlan S.W., Hollitt, Georgina, Kolovos, Antonia, Schulz, Angela, Lake, Stewart, Mills, Richard A., Agar, Ashish, Galanopoulos, Anna, Landers, John, Mitchell, Paul, Healey, Paul R., Graham, Stuart L., Hewitt, Alex W., Souzeau, Emmanuelle, Hassall, Mark M., Klebe, Sonja, MacGregor, Stuart, Gharahkhani, Puya, Casson, Robert J., Siggs, Owen M., and Craig, Jamie E.

Published
2022
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8. Development and evaluation of patient-centred polygenic risk score reports for glaucoma screening.

Author

Hollitt, Georgina L, Hassall, Mark M, Siggs, Owen M, Craig, Jamie E, and Souzeau, Emmanuelle

Abstract

Background: Polygenic risk scores (PRS), which provide an individual probabilistic estimate of genetic susceptibility to develop a disease, have shown effective risk stratification for glaucoma onset. However, there is limited best practice evidence for reporting PRS and patient-friendly reports for communicating PRS effectively are lacking. Here we developed patient-centred PRS reports for glaucoma screening based on the literature, and evaluated them with participants using a qualitative research approach. Methods: We first reviewed existing PRS reports and literature on probabilistic risk communication. This informed the development of a draft glaucoma screening PRS report for a hypothetical high risk individual from the general population. We designed three versions of the report to illustrate risk using a pictograph, a pie chart and a bell curve. We then conducted semi-structured interviews to assess preference of visual risk communication aids, understanding of risk, content, format and structure of the reports. Participants were invited from an existing study, which aims to evaluate the clinical validity of glaucoma PRS among individuals > 50 years from the general population. Numeracy and literacy levels were assessed. Results: We interviewed 12 individuals. The cohort was highly educated (42% university education), all were European and 50% were female. Numeracy (mean 2.1 ± 0.9, range 0 to 3), graph literacy (mean 2.8 ± 0.8, range 0 to 4) and genetic literacy (mean 24.2 ± 6.2, range − 20 to + 46) showed a range of levels. We analysed the reports under three main themes: visual preferences, understanding risk and reports formatting. The visual component was deemed important to understanding risk, with the pictograph being the preferred visual risk representation, followed by the pie chart and the bell curve. Participants expressed preference for absolute risk in understanding risk, along with the written content explaining the results. The importance of follow-up recommendations and time to glaucoma onset were deemed important. Participants expressed varied opinions in the level of information and the colours used, which informed revisions of the report. Conclusions: Our study revealed preferences for reporting PRS information in the context of glaucoma screening, to support the development of clinical PRS reporting. Further research is needed to assess PRS communication in other groups representative of target populations and with other target audiences (e.g. referring clinicians), and its potential psychosocial impact in the wider community. [ABSTRACT FROM AUTHOR]

Published
2025
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9. Impact of polygeNic risk score for glaucoma on psycHosocial ouTcomes (INSiGHT) study protocol.

Author

Maxwell, Giorgina, Allen, Robert, Kelley, Simone, Hodge, Lucinda, Hollitt, Georgina L., Seviiri, Mathias, Thomson, Daniel, Schmidt, Joshua, Craig, Jamie E., Cohen-Woods, Sarah, and Souzeau, Emmanuelle

Subjects
GENETIC risk score, HEALTH Belief Model, MONOGENIC & polygenic inheritance (Genetics), EYE diseases, PSYCHOLOGICAL factors
Abstract

Glaucoma is the leading cause of irreversible blindness with early detection and intervention critical to slowing disease progression. However, half of those affected are undiagnosed. This is largely due to the early stages of disease being asymptomatic; current population-based screening measures being unsupported; and a lack of current efficient prediction models. Research investigating polygenic risk scores (PRS) for glaucoma have shown predictive ability to identify individuals at higher risk. Potential clinical applications include identification of high-risk individuals, resulting in earlier diagnosis and treatment to prevent glaucoma blindness, and adjusted monitoring for low-risk individuals. However, the psychological impact of receiving glaucoma PRS is unknown. There is a critical need to evaluate risk information communication and assess the impact of receiving results, to support clinical implementation of glaucoma PRS testing. In this prospective study, 300 individuals from the GRADE (Genetic Risk Assessment of Degenerative Eye disease) study will be recruited to investigate the psychosocial impact of disclosing polygenic risk results for glaucoma. GRADE aimed to apply PRS testing on 1,000 unexamined individuals aged 50 years or older from the general population and examine a subset of these individuals to assess the clinical validity of PRS to detect glaucoma. In this study, individuals each from the bottom decile (10%), top decile (10%), and middle (45–55%) of the PRS distributions will be invited to receive research glaucoma PRS results. Participants who choose to receive their results will complete up to four questionnaires (prior to receiving their results, and subsequently two-weeks, six- and 12-months after receiving their result). The questionnaires will include health belief model measures and assess glaucoma anxiety, general anxiety and depression, test-related distress, decisional regret, and recall and understanding of results. This research will provide guidance for the implementation of polygenic risk testing into clinical practice and inform delivery strategies. [ABSTRACT FROM AUTHOR]

Published
2024
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10. Healthcare professionals' knowledge and attitudes towards polygenic risk testing for glaucoma.

Author

Hollitt, Georgina L., Keane, Miriam C., Nguyen, Thi T., Hassall, Mark M., Siggs, Owen M., Craig, Jamie E., and Souzeau, Emmanuelle

Subjects
MEDICAL personnel, MONOGENIC & polygenic inheritance (Genetics), PROFESSIONALISM, GENERAL practitioners, GENETIC testing
Abstract

Background: Effective clinical implementation of polygenic risk testing for glaucoma relies on healthcare professionals' attitudes and knowledge of the test. Given the emerging applications of the test, it will likely impact a range of healthcare professionals and will require competency in polygenic risk scores concepts for all those involved in patient care. To our knowledge, this is the first study to assess healthcare professionals' views towards polygenic testing for glaucoma. Methods: An online cross‐sectional questionnaire was distributed to healthcare professionals via relevant professional organisations in Australia. The questionnaire assessed experience and confidence with genetic testing, glaucoma and genetic knowledge, recommendations for the tests, and factors affecting the decision. Results: A total of 94 participants completed the questionnaire. The sample was composed of ophthalmologists (36%), optometrists (21%), orthoptists (17%), general practitioners (16%) and clinical geneticists/genetic counsellors (10%). Although familiarity with polygenic risk scores for glaucoma was low overall (11%), the majority reported a positive attitude towards recommending testing based on known risk factors such as family history (91%) and older age (57%). Over 95% indicated that ophthalmologists would be the most appropriate group to order polygenic risk testing and communicate results. The majority felt they would benefit from more training on polygenic risk scores (93%). Conclusions: Our findings indicated that multiple groups of healthcare professionals were neither familiar nor confident with the concept of glaucoma polygenic risk testing, and identified training and education needs to support the implementation of testing into clinical practice. [ABSTRACT FROM AUTHOR]

Published
2024
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12. Author Correction: Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases.

Author

Iglesias, Adriana I, Mishra, Aniket, Vitart, Veronique, Bykhovskaya, Yelena, Höhn, René, Springelkamp, Henriët, Cuellar-Partida, Gabriel, Gharahkhani, Puya, Bailey, Jessica N Cooke, Willoughby, Colin E, Li, Xiaohui, Yazar, Seyhan, Nag, Abhishek, Khawaja, Anthony P, Polašek, Ozren, Siscovick, David, Mitchell, Paul, Tham, Yih Chung, Haines, Jonathan L, Kearns, Lisa S, Hayward, Caroline, Shi, Yuan, van Leeuwen, Elisabeth M, Taylor, Kent D, Blue Mountains Eye Study - GWAS group, Bonnemaijer, Pieter, Rotter, Jerome I, Martin, Nicholas G, Zeller, Tanja, Mills, Richard A, Souzeau, Emmanuelle, Staffieri, Sandra E, Jonas, Jost B, Schmidtmann, Irene, Boutin, Thibaud, Kang, Jae H, Lucas, Sionne EM, Wong, Tien Yin, Beutel, Manfred E, Wilson, James F, Wellcome Trust Case Control Consortium 2 (WTCCC2), NEIGHBORHOOD consortium, Uitterlinden, André G, Vithana, Eranga N, Foster, Paul J, Hysi, Pirro G, Hewitt, Alex W, Khor, Chiea Chuen, Pasquale, Louis R, Montgomery, Grant W, Klaver, Caroline CW, Aung, Tin, Pfeiffer, Norbert, Mackey, David A, Hammond, Christopher J, Cheng, Ching-Yu, Craig, Jamie E, Rabinowitz, Yaron S, Wiggs, Janey L, Burdon, Kathryn P, van Duijn, Cornelia M, and MacGregor, Stuart

Subjects
Blue Mountains Eye Study - GWAS group, Wellcome Trust Case Control Consortium 2, NEIGHBORHOOD consortium, Eye Disease and Disorders of Vision
Abstract

Emmanuelle Souzeau, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this Article. This has now been corrected in both the PDF and HTML versions of the Article.

Published
2019

13. Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases.

Author

Iglesias, Adriana I, Mishra, Aniket, Vitart, Veronique, Bykhovskaya, Yelena, Höhn, René, Springelkamp, Henriët, Cuellar-Partida, Gabriel, Gharahkhani, Puya, Bailey, Jessica N Cooke, Willoughby, Colin E, Li, Xiaohui, Yazar, Seyhan, Nag, Abhishek, Khawaja, Anthony P, Polašek, Ozren, Siscovick, David, Mitchell, Paul, Tham, Yih Chung, Haines, Jonathan L, Kearns, Lisa S, Hayward, Caroline, Shi, Yuan, van Leeuwen, Elisabeth M, Taylor, Kent D, Blue Mountains Eye Study—GWAS group, Bonnemaijer, Pieter, Rotter, Jerome I, Martin, Nicholas G, Zeller, Tanja, Mills, Richard A, Souzeau, Emmanuelle, Staffieri, Sandra E, Jonas, Jost B, Schmidtmann, Irene, Boutin, Thibaud, Kang, Jae H, Lucas, Sionne EM, Wong, Tien Yin, Beutel, Manfred E, Wilson, James F, NEIGHBORHOOD Consortium, Wellcome Trust Case Control Consortium 2 (WTCCC2), Uitterlinden, André G, Vithana, Eranga N, Foster, Paul J, Hysi, Pirro G, Hewitt, Alex W, Khor, Chiea Chuen, Pasquale, Louis R, Montgomery, Grant W, Klaver, Caroline CW, Aung, Tin, Pfeiffer, Norbert, Mackey, David A, Hammond, Christopher J, Cheng, Ching-Yu, Craig, Jamie E, Rabinowitz, Yaron S, Wiggs, Janey L, Burdon, Kathryn P, van Duijn, Cornelia M, and MacGregor, Stuart

Subjects
Blue Mountains Eye Study—GWAS group, NEIGHBORHOOD Consortium, Wellcome Trust Case Control Consortium 2, Cornea, Humans, Marfan Syndrome, Corneal Diseases, Corneal Dystrophies, Hereditary, Keratoconus, Eye Diseases, Hereditary, Glaucoma, Open-Angle, Myopia, Ehlers-Danlos Syndrome, Proteoglycans, Gene Expression, Quantitative Trait, Heritable, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome, Human, Asian Continental Ancestry Group, European Continental Ancestry Group, Transforming Growth Factor beta2, Genome-Wide Association Study, Loeys-Dietz Syndrome, Mendelian Randomization Analysis, Decorin, Lumican, Fibrillin-1, ADAMTS Proteins, Corneal Dystrophies, Hereditary, Eye Diseases, Glaucoma, Open-Angle, Quantitative Trait, Heritable, Polymorphism, Single Nucleotide, Genome, Human
Abstract

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = -0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r = -0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.

Published
2018

14. Childhood and Early Onset Glaucoma Classification and Genetic Profile in a Large Australasian Disease Registry

Author

Knight, Lachlan S.W., Ruddle, Jonathan B., Taranath, Deepa A., Goldberg, Ivan, Smith, James E.H., Gole, Glen, Chiang, Mark Y., Willett, Faren, D’Mellow, Guy, Breen, James, Qassim, Ayub, Mullany, Sean, Elder, James E., Vincent, Andrea L., Staffieri, Sandra E., Kearns, Lisa S., Mackey, David A., Luu, Susie, Siggs, Owen M., Souzeau, Emmanuelle, and Craig, Jamie E.

Published
2021
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15. A Polygenic Risk Score Predicts Intraocular Pressure Readings Outside Office Hours and Early Morning Spikes as Measured by Home Tonometry

Author

Qassim, Ayub, Mullany, Sean, Awadalla, Mona S., Hassall, Mark M., Nguyen, Thi, Marshall, Henry, Kolovos, Antonia, Schulz, Angela M., Han, Xikun, Gharahkhani, Puya, Galanopoulos, Anna, Agar, Ashish, Healey, Paul R., Hewitt, Alex W., Landers, John, Casson, Robert J., Graham, Stuart L., MacGregor, Stuart, Souzeau, Emmanuelle, Siggs, Owen M., and Craig, Jamie E.

Published
2021
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16. Childhood glaucoma: Implications for genetic counselling.

Author

Maxwell, Giorgina and Souzeau, Emmanuelle

Subjects
*CONGENITAL glaucoma, *GENETIC counseling, *GENETIC testing, *AGE of onset, *GLAUCOMA
Abstract

Childhood glaucoma is a heterogeneous group of ocular disorders defined by an age of onset from birth to 18 years. These vision‐threatening disorders require early diagnosis, timely treatment, and lifelong management to maintain vision and minimise irreversible blindness. The genetics of childhood glaucoma is complex with both phenotypic and genetic heterogeneity. The purpose of this review is to summarise the different types of childhood glaucoma and their genetic architecture to aid in the genetic counselling process with patients and their families. We provide an overview of associated syndromes and discuss implications for genetic counselling, including genetic testing strategies, cascade genetic testing, and reproductive options. [ABSTRACT FROM AUTHOR]

Published
2024
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17. An Intraocular Pressure Polygenic Risk Score Stratifies Multiple Primary Open-Angle Glaucoma Parameters Including Treatment Intensity

Author

Qassim, Ayub, Souzeau, Emmanuelle, Siggs, Owen M., Hassall, Mark M., Han, Xikun, Griffiths, Helen L., Frost, N. Andrew, Vallabh, Neeru A., Kirwan, James F., Menon, Geeta, Cree, Angela J., Galanopoulos, Anna, Agar, Ashish, Healey, Paul R., Graham, Stuart L., Landers, John, Casson, Robert J., Gharahkhani, Puya, Willoughby, Colin E., Hewitt, Alex W., Lotery, Andrew J., MacGregor, Stuart, and Craig, Jamie E.

Published
2020
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20. Macular Ganglion Cell–Inner Plexiform Layer Loss Precedes Peripapillary Retinal Nerve Fiber Layer Loss in Glaucoma with Lower Intraocular Pressure

Author

Marshall, Henry N., Andrew, Nicholas H., Hassall, Mark, Qassim, Ayub, Souzeau, Emmanuelle, Ridge, Bronwyn, Nguyen, Thi, Fitzgerald, Jude, Awadalla, Mona S., Burdon, Kathryn P., Healey, Paul R., Agar, Ashish, Galanopoulos, Anna, Hewitt, Alex W., Graham, Stuart L., Landers, John, Casson, Robert J., and Craig, Jamie E.

Published
2019
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22. 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

25. Genome-wide association study of intraocular pressure uncovers new pathways to glaucoma

Author

MacGregor, Stuart, Ong, Jue-Sheng, An, Jiyuan, Han, Xikun, Zhou, Tiger, Siggs, Owen M., Law, Matthew H., Souzeau, Emmanuelle, Sharma, Shiwani, Lynn, David J., Beesley, Jonathan, Sheldrick, Bronwyn, Mills, Richard A., Landers, John, Ruddle, Jonathan B., Graham, Stuart L., Healey, Paul R., White, Andrew J. R., Casson, Robert J., Best, Stephen, Grigg, John R, Goldberg, Ivan, Powell, Joseph E., Whiteman, David C., Radford-Smith, Graham L., Martin, Nicholas G., Montgomery, Grant W., Burdon, Kathryn P., Mackey, David A., Gharahkhani, Puya, Craig, Jamie E., and Hewitt, Alex W.

Published
2018
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26. Angiopoietin-1 is required for Schlemm's canal development in mice and humans

Author

Thomson, Benjamin R., Souma, Tomokazu, Tompson, Stuart W., Onay, Tuncer, Kizhatil, Krishnakumar, Siggs, Owen M., Feng, Liang, Whisenhunt, Kristina N., Yanovitch, Tammy L., Kalaydjieva, Luba, Azmanov, Dimitar N., Finzi, Simone, Tanna, Christine E., Hewit, Alex W., Mackey, David A., Bradfield, Yasmin S., Souzeau, Emmanuelle, Javadiyan, Shari, Wiggs, Janey L., Pasutto, Francesca, Liu, Xiaorong, John, Simon W.M., Craig, Jamie E., Jin, Jing, Young, Terri L., and Quaggin, Susan E.

Subjects
Research, Risk factors, Hypertension -- Risk factors, Vascular endothelial growth factor -- Research, Glaucoma -- Analysis -- Risk factors
Abstract

Introduction Afflicting more than 60 million individuals worldwide and leaving 8 million blind, glaucoma is a devastating disease with no cure (1). Current therapy slows disease progression but cannot repair [...], Primary congenital glaucoma (PCG) is a leading cause of blindness in children worldwide and is caused by developmental defects in 2 aqueous humor outflow structures, Schlemm's canal (SC) and the trabecular meshwork. We previously identified loss-of-function mutations in the angiopoietin (ANGPT) receptor TEK in families with PCG and showed that ANGPT/TEK signaling is essential for SC development. Here, we describe roles for the major ANGPT ligands in the development of the aqueous outflow pathway. We determined that ANGPT1 is essential for SC development, and that Angpt1-knockout mice form a severely hypomorphic canal with elevated intraocular pressure. By contrast, ANGPT2 was dispensable, although mice deficient in both Angpt1 and Angpt2 completely lacked SC, indicating that ANGPT2 compensates for the loss of ANGPT1. In addition, we identified 3 human subjects with rare ANGPT1 variants within an international cohort of 284 PCG patients. Loss of function in 2 of the 3 patient alleles was observed by functional analysis of ANGPT1 variants in a combined in silico, in vitro, and in vivo approach, supporting a causative role for ANGPT1 in disease. By linking ANGPT1 with PCG, these results highlight the importance of ANGPT/TEK signaling in glaucoma pathogenesis and identify a candidate target for therapeutic development.

Published
2017
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28. Association of High Polygenic Risk With Visual Field Worsening Despite Treatment in Early Primary Open-Angle Glaucoma

Author

Siggs, Owen M., primary, Qassim, Ayub, additional, Han, Xikun, additional, Marshall, Henry N., additional, Mullany, Sean, additional, He, Weixiong, additional, Souzeau, Emmanuelle, additional, Galanopoulos, Anna, additional, Agar, Ashish, additional, Landers, John, additional, Casson, Robert J., additional, Hewitt, Alex W., additional, Healey, Paul R., additional, Graham, Stuart L., additional, MacGregor, Stuart, additional, and Craig, Jamie E., additional

Published
2023
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31. Specifications of the ACMG/AMP variant curation guidelines for myocilin: Recommendations from the clingen glaucoma expert panel

Author

Burdon, Kathryn P., primary, Graham, Patricia, additional, Hadler, Johanna, additional, Hulleman, John D., additional, Pasutto, Francesca, additional, Boese, Erin A., additional, Craig, Jamie E., additional, Fingert, John H., additional, Hewitt, Alex W., additional, Siggs, Owen M., additional, Whisenhunt, Kristina, additional, Young, Terri L., additional, Mackey, David A., additional, Dubowsky, Andrew, additional, and Souzeau, Emmanuelle, additional

Published
2022
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33. Diagnostic yield of candidate genes in an Australian corneal dystrophy cohort

Author

Souzeau, Emmanuelle, primary, Siggs, Owen M., additional, Mullany, Sean, additional, Schmidt, Joshua M., additional, Hassall, Mark M., additional, Dubowsky, Andrew, additional, Chappell, Angela, additional, Breen, James, additional, Bae, Haae, additional, Nicholl, Jillian, additional, Hadler, Johanna, additional, Kearns, Lisa S., additional, Staffieri, Sandra E., additional, Hewitt, Alex W., additional, Mackey, David A., additional, Gupta, Aanchal, additional, Burdon, Kathryn P., additional, Klebe, Sonja, additional, Craig, Jamie E., additional, and Mills, Richard A., additional

Published
2022
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34. Pathogenic genetic variants identified in Australian families with paediatric cataract

Author

Jones, Johanna L, primary, McComish, Bennet J, additional, Staffieri, Sandra E, additional, Souzeau, Emmanuelle, additional, Kearns, Lisa S, additional, Elder, James E, additional, Charlesworth, Jac C, additional, Mackey, David A, additional, Ruddle, Jonathan B, additional, Taranath, Deepa, additional, Pater, John, additional, Casey, Theresa, additional, Craig, Jamie E, additional, and Burdon, Kathryn P, additional

Published
2022
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37. RNA Sequencing of Lens Capsular Epithelium Implicates Novel Pathways in Pseudoexfoliation Syndrome

Author

Mullany, Sean, primary, Marshall, Henry, additional, Zhou, Tiger, additional, Thomson, Daniel, additional, Schmidt, Joshua M., additional, Qassim, Ayub, additional, Knight, Lachlan S. W., additional, Hollitt, Georgina, additional, Berry, Ella C., additional, Nguyen, Thi, additional, To, Minh-Son, additional, Dimasi, David, additional, Kuot, Abraham, additional, Dubowsky, Joshua, additional, Fogarty, Rhys, additional, Sun, Michelle, additional, Chehade, Luke, additional, Kuruvilla, Shilpa, additional, Supramaniam, Devaraj, additional, Breen, James, additional, Sharma, Shiwani, additional, Landers, John, additional, Lake, Stewart, additional, Mills, Richard A., additional, Hassall, Mark M., additional, Chan, Weng O., additional, Klebe, Sonja, additional, Souzeau, Emmanuelle, additional, Siggs, Owen M., additional, and Craig, Jamie E., additional

Published
2022
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38. New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics

Author

Springelkamp, Henriët, Iglesias, Adriana I., Mishra, Aniket, Höhn, René, Wojciechowski, Robert, Khawaja, Anthony P., Nag, Abhishek, Wang, Ya Xing, Wang, Jie Jin, Cuellar-Partida, Gabriel, Gibson, Jane, Bailey, Jessica N. Cooke, Vithana, Eranga N., Gharahkhani, Puya, Boutin, Thibaud, Ramdas, Wishal D., Zeller, Tanja, Luben, Robert N., Yonova-Doing, Ekaterina, Viswanathan, Ananth C., Yazar, Seyhan, Cree, Angela J., Haines, Jonathan L., Koh, Jia Yu, Souzeau, Emmanuelle, Wilson, James F., Amin, Najaf, Müller, Christian, Venturini, Cristina, Kearns, Lisa S., Kang, Jae Hee, Tham, Yih Chung, Zhou, Tiger, van Leeuwen, Elisabeth M., Nickels, Stefan, Sanfilippo, Paul, Liao, Jiemin, van der Linde, Herma, Zhao, Wanting, van Koolwijk, Leonieke M.E., Zheng, Li, Rivadeneira, Fernando, Baskaran, Mani, van der Lee, Sven J., Perera, Shamira, de Jong, Paulus T.V.M., Oostra, Ben A., Uitterlinden, André G., Fan, Qiao, Hofman, Albert, Tai, E-Shyong, Vingerling, Johannes R., Sim, Xueling, Wolfs, Roger C.W., Teo, Yik Ying, Lemij, Hans G., Khor, Chiea Chuen, Willemsen, Rob, Lackner, Karl J., Aung, Tin, Jansonius, Nomdo M., Montgomery, Grant, Wild, Philipp S., Young, Terri L., Burdon, Kathryn P., Hysi, Pirro G., Pasquale, Louis R., Wong, Tien Yin, Klaver, Caroline C.W., Hewitt, Alex W., Jonas, Jost B., Mitchell, Paul, Lotery, Andrew J., Foster, Paul J., Vitart, Veronique, Pfeiffer, Norbert, Craig, Jamie E., Mackey, David A., Hammond, Christopher J., Wiggs, Janey L., Cheng, Ching-Yu, van Duijn, Cornelia M., and MacGregor, Stuart

Published
2017
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39. SPECIFICATIONS OF THE ACMG/AMP VARIANT CURATION GUIDELINES FOR MYOCILIN: RECOMMENDATIONS FROM THE CLINGEN GLAUCOMA EXPERT PANEL

Author

Burdon, Kathryn P, primary, Graham, Patricia, additional, Hadler, Johanna, additional, Hulleman, John D, additional, Pasutto, Francesca, additional, Boese, Erin A, additional, Craig, Jamie E, additional, Fingert, John H, additional, Hewitt, Alex W, additional, Siggs, Owen M, additional, Whisenhunt, Kristina, additional, Young, Terri L, additional, Mackey, David A, additional, Dubowsky, Andrew, additional, and Souzeau, Emmanuelle, additional

Published
2022
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40. A transcriptome-wide association study based on 27 tissues identifies 106 genes potentially relevant for disease pathology in age-related macular degeneration

Author

Strunz, Tobias, Lauwen, Susette, Kiel, Christina, Fritsche, Lars G., Igl, Wilmar, Bailey, Jessica N.Cooke, Grassmann, Felix, Sengupta, Sebanti, Bragg-Gresham, Jennifer L., Burdon, Kathryn P., Hebbring, Scott J., Wen, Cindy, Gorski, Mathias, Kim, Ivana K., Cho, David, Zack, Donald, Souied, Eric, Scholl, Hendrik P.N., Bala, Elisa, Lee, Kristine E., Hunter, David J., Sardell, Rebecca J., Mitchell, Paul, Merriam, Joanna E., Cipriani, Valentina, Hoffman, Joshua D., Schick, Tina, Lechanteur, Yara T.E., Guymer, Robyn H., Johnson, Matthew P., Jiang, Yingda, Stanton, Chloe M., Buitendijk, Gabriëlle H.S., Zhan, Xiaowei, Kwong, Alan M., Boleda, Alexis, Brooks, Matthew, Gieser, Linn, Ratnapriya, Rinki, Branham, Kari E., Foerster, Johanna R., Heckenlively, John R., Othman, Mohammad I., Vote, Brendan J., Liang, Helena Hai, Souzeau, Emmanuelle, Cree, Angela J., Goverdhan, Srinivas V., Moore, Emily L., Lotery, Andrew J., Epidemiology, Ophthalmology, Public Health, and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, genetic structures, Gene regulatory network, lcsh:Medicine, Genome-wide association study, Pathogenesis, Disease, Biology, Quantitative trait, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Article, Transcriptome, Macular Degeneration, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, medicine, Humans, Gene Regulatory Networks, Genetic Predisposition to Disease, lcsh:Science, Gene, Genetic association study, Genetic association, Multidisciplinary, Molecular medicine, Gene Expression Profiling, lcsh:R, eye diseases, Computational biology and bioinformatics, Gene regulation, Gene expression profiling, 030104 developmental biology, Genes, Human genome, lcsh:Q, Gene expression, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Contains fulltext : 218949.pdf (Publisher’s version ) (Open Access) Genome-wide association studies (GWAS) for late stage age-related macular degeneration (AMD) have identified 52 independent genetic variants with genome-wide significance at 34 genomic loci. Typically, such an approach rarely results in the identification of functional variants implicating a defined gene in the disease process. We now performed a transcriptome-wide association study (TWAS) allowing the prediction of effects of AMD-associated genetic variants on gene expression. The TWAS was based on the genotypes of 16,144 late-stage AMD cases and 17,832 healthy controls, and gene expression was imputed for 27 different human tissues which were obtained from 134 to 421 individuals. A linear regression model including each individuals imputed gene expression data and the respective AMD status identified 106 genes significantly associated to AMD variants in at least one tissue (Q-value < 0.001). Gene enrichment analysis highlighted rather systemic than tissue- or cell-specific processes. Remarkably, 31 of the 106 genes overlapped with significant GWAS signals of other complex traits and diseases, such as neurological or autoimmune conditions. Taken together, our study highlights the fact that expression of genes associated with AMD is not restricted to retinal tissue as could be expected for an eye disease of the posterior pole, but instead is rather ubiquitous suggesting processes underlying AMD pathology to be of systemic nature.

Published
2020
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46. 6. GENOME WIDE ASSOCIATION STUDY IN THE AUSTRALIAN AND NEW ZEALAND REGISTRY OF ADVANCED GLAUCOMA IDENTIFIES COMMON SEQUENCE VARIANTS IN ABCA1, AFAP1 AND GMDS WHICH CONFER RISK OF PRIMARY OPEN-ANGLE GLAUCOMA, AND REPLICATE IN MULTIPLE INDEPENDENT COHORTS: P0506

Author

Craig, Jamie, Burdon, Kathryn, Gharahkhani, Puya, Hewitt, Alex, Mackey, David, Mitchell, Paul, Graham, Stuart, Goldberg, Ivan, White, Andrew, Pasquale, Lou, Landers, John, Casson, Robert, Ruddle, Jon, Sharma, Shiwani, Brown, Matthew, Zhou, Tiger, Souzeau, Emmanuelle, Mills, Richard, and Macgregor, Stuart

Published
2014

49. Retinal ganglion cell-specific genetic regulation in primary open angle glaucoma

Author

Daniszewski, Maciej S., primary, Senabouth, Anne, additional, Liang, Helena H., additional, Han, Xikun, additional, Lidgerwood, Grace E., additional, Hernández, Damián, additional, Sivakumaran, Priyadharshini, additional, Clarke, Jordan E., additional, Lim, Shiang Y., additional, Lees, Jarmon G., additional, Rooney, Louise, additional, Gulluyan, Lerna, additional, Souzeau, Emmanuelle, additional, Graham, Stuart L., additional, Chan, Chia-Ling, additional, Nguyen, Uyen, additional, Farbehi, Nona, additional, Gnanasambandapillai, Vikkitharan, additional, McCloy, Rachael A., additional, Clarke, Linda, additional, Kearns, Lisa, additional, Mackey, David A, additional, Craig, Jamie E., additional, MacGregor, Stuart, additional, Powell, Joseph E., additional, Pébay, Alice, additional, and Hewitt, Alex W., additional

Published
2021
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50. PAX6 molecular analysis and genotype–phenotype correlations in families with aniridia from Australasia and Southeast Asia

Author

Souzeau, Emmanuelle, Rudkin, Adam K., Dubowsky, Andrew, Casson, Robert J., Muecke, James S., Mancel, Erica, Whiting, Mark, Mills, Richard A.D., Burdon, Kathryn P., and Craig, Jamie E.

Subjects
parasitic diseases, sense organs, eye diseases, Research Article
Abstract

Purpose Aniridia is a congenital disorder caused by variants in the PAX6 gene. In this study, we assessed the involvement of PAX6 in patients with aniridia from Australasia and Southeast Asia. Methods Twenty-nine individuals with aniridia from 18 families originating from Australia, New Caledonia, Cambodia, Sri Lanka, and Bhutan were included. The PAX6 gene was investigated for sequence variants and analyzed for deletions with multiplex ligation-dependent probe amplification. Results We identified 11 sequence variants and six chromosomal deletions, including one in mosaic. Four deleterious sequence variants were novel: p.(Pro81HisfsTer12), p.(Gln274Ter), p.(Ile29Thr), and p.(Met1?). Ocular complications were associated with a progressive loss of visual function as shown by a visual acuity ≤ 1.00 logMAR reported in 65% of eyes. The prevalence of keratopathy was statistically significantly higher in the Australasian cohort (78.6%) compared with the Southeast Asian cohort (9.1%, p=0.002). Variants resulting in protein truncating codons displayed limited genotype–phenotype correlations compared with other variants. Conclusions PAX6 variants and deletions were identified in 94% of patients with aniridia from Australasia and Southeast Asia. This study is the first report of aniridia and variations in PAX6 in individuals from Cambodia, Sri Lanka, Bhutan, and New Caledonia, and the largest cohort from Australia.

Published
2018

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