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1. Exome sequencing in Asian populations identifies low-frequency and rare coding variation influencing Parkinson’s disease risk

Author

Chew, Elaine GY, Liu, Zhehao, Li, Zheng, Chung, Sun Ju, Lian, Michelle M., Tandiono, Moses, Heng, Yue Jing, Ng, Ebonne Y., Tan, Louis CS, Chng, Wee Ling, Tan, Tiak Ju, Peh, Esther KL, Ho, Ying Swan, Chen, Xiao Yin, Lim, Erin YT, Chang, Chu Hua, Leong, Jonavan J., Peh, Ting Xuan, Chan, Ling Ling, Chao, Yinxia, Au, Wing-Lok, Prakash, Kumar M., Lim, Jia Lun, Tay, Yi Wen, Mok, Vincent, Chan, Anne YY, Lin, Juei-Jueng, Jeon, Beom S., Song, Kyuyoung, Tham, Clement C., Pang, Chi Pui, Ahn, Jeeyun, Park, Kyu Hyung, Wiggs, Janey L., Aung, Tin, Tan, Ai Huey, Ahmad Annuar, Azlina, Makarious, Mary B., Blauwendraat, Cornelis, Nalls, Mike A., Robak, Laurie A., Alcalay, Roy N., Gan-Or, Ziv, Reynolds, Richard, Lim, Shen-Yang, Xia, Yun, Khor, Chiea Chuen, Tan, Eng-King, Wang, Zhenxun, and Foo, Jia Nee

Published
2024
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2. Genome-wide meta-analysis identifies 22 loci for normal tension glaucoma with significant overlap with high tension glaucoma

Author

Diaz-Torres, Santiago, He, Weixiong, Yu, Regina, Khawaja, Anthony P., Hammond, Christopher J., Hysi, Pirro G., Pasquale, Louis R., Wu, Yeda, Kubo, Michiaki, Akiyama, Masato, Aung, Tin, Cheng, Ching-Yu, Khor, Chiea Chuen, Kraft, Peter, Kang, Jae H., Hewitt, Alex W., Mackey, David A., Craig, Jamie E., Wiggs, Janey L., Ong, Jue-Sheng, MacGregor, Stuart, and Gharahkhani, Puya

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

Author

Hamel, Andrew R., Yan, Wenjun, Rouhana, John M., Monovarfeshani, Aboozar, Jiang, Xinyi, Mehta, Puja A., Advani, Jayshree, Luo, Yuyang, Liang, Qingnan, Rajasundaram, Skanda, Shrivastava, Arushi, Duchinski, Katherine, Mantena, Sreekar, Wang, Jiali, van Zyl, Tavé, Pasquale, Louis R., Swaroop, Anand, Gharahkhani, Puya, Khawaja, Anthony P., MacGregor, Stuart, Chen, Rui, Vitart, Veronique, Sanes, Joshua R., Wiggs, Janey L., and Segrè, Ayellet V.

Published
2024
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5. The Association of Urinary Sodium Excretion with Glaucoma and Related Traits in a Large United Kingdom Population

Author

Aschard, Hugues, Chia, Mark, Chua, Sharon, Do, Ron, Foster, Paul, Kang, Jae, Kastner, Alan, Khawaja, Anthony, Kim, Jihye, Lentjes, Marleen, Luben, Robert, Madjedi, Kian, Montesano, Giovanni, Pasquale, Louis, Stuart, Kelsey, Warwick, Alasdair, Wiggs, Janey, Allen, Naomi, Aslam, Tariq, Atan, Denize, Barman, Sarah, Barrett, Jenny, Bishop, Paul, Black, Graeme, Braithwaite, Tasanee, Carare, Roxana, Chakravarthy, Usha, Chan, Michelle, Day, Alexander, Desai, Parul, Dhillon, Bal, Dick, Andrew, Doney, Alexander, Egan, Cathy, Ennis, Sarah, Fruttiger, Marcus, Garway-Heath, David (Ted), Gibson, Jane, Guggenheim, Jeremy, Hammond, Chris, Hardcastle, Alison, Harding, Simon, Hogg, Ruth, Hysi, Pirro, Keane, Pearse, Khaw, Peng Tee, Lascaratos, Gerassimos, Littlejohns, Thomas, Lotery, Andrew, Luthert, Phil, MacGillivray, Tom, Mackie, Sarah, McGuinness, Bernadette, McKay, Gareth, McKibbin, Martin, Moore, Tony, Morgan, James, O'Sullivan, Eoin, Oram, Richard, Owen, Chris, Patel, Praveen, Paterson, Euan, Peto, Tunde, Petzold, Axel, Pontikos, Nikolas, Rahi, Jugnoo, Rudnicka, Alicja, Sattar, Naveed, Self, Jay, Sergouniotis, Panagiotis, Sivaprasad, Sobha, Steel, David, Stratton, Irene, Strouthidis, Nicholas, Sudlow, Cathie, Sun, Zihan, Tapp, Robyn, Thomas, Dhanes, Trucco, Emanuele, Tufail, Adnan, Viswanathan, Ananth, Vitart, Veronique, Weedon, Mike, Williams, Katie, Williams, Cathy, Woodside, Jayne, Yates, Max, Yip, Jennifer, Zheng, Yalin, Aung, Tin, Burdon, Kathryn, Chen, Li, Cheng, Ching-Yu, Craig, Jamie, Cree, Angela, de Vries, Victor, Driessen, Sjoerd, Fingert, John, Gharahkhani, Puya, Hammond, Christopher, Hayward, Caroline, Hewitt, Alex, Jansonius, Nomdo, Jonansson, Fridbert, Jonas, Jost, Kass, Michael, Khor, Chiea, Klaver, Caroline, Koh, Jacyline, MacGregor, Stuart, Mackey, David, Mitchell, Paul, Pang, Calvin, Pasutto, Francesca, Pfeiffer, Norbert, Polašek, Ozren, Ramdas, Wishal, Schuster, Alexander, Segrè, Ayellet, Stefansson, Einer, Stefánsson, Kári, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, van Duijn, Cornelia, Vergroesen, Joëlle, Vithana, Eranga, Wilson, James, Wojciechowski, Robert, Wong, Tien, Young, Terri, Stuart, Kelsey V., Biradar, Mahantesh I., Luben, Robert N., Dhaun, Neeraj, Wagner, Siegfried K., Warwick, Alasdair N., Madjedi, Kian M., Pasquale, Louis R., Wiggs, Janey L., Kang, Jae H., Lentjes, Marleen A.H., Foster, Paul J., and Khawaja, Anthony P.

Published
2024
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6. The Clinical Usefulness of a Glaucoma Polygenic Risk Score in 4 Population-Based European Ancestry Cohorts

Author

de Vries, Victor A., Hanyuda, Akiko, Vergroesen, Joëlle E., Do, Ron, Friedman, David S., Kraft, Peter, Turman, Constance, Luo, Yuyang (Leo), Tran, Jessica H., Liefers, Bart, Wong, Sze H., Lee, Rachel H., Zebardast, Nazlee, Klaver, Caroline C.W., Segrè, Ayellet V., Pasquale, Louis R., Wiggs, Janey L., Kang, Jae H., and Ramdas, Wishal D.

Published
2025
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10. The Association of Alcohol Consumption with Glaucoma and Related Traits: Findings from the UK Biobank

Author

Aschard, Hugues, Chia, Mark, Chua, Sharon, Do, Ron, Foster, Paul, Kang, Jae, Kastner, Alan, Khawaja, Anthony, Kim, Jihye, Lentjes, Marleen, Luben, Robert, Madjedi, Kian, Montesano, Giovanni, Pasquale, Louis, Stuart, Kelsey, Warwick, Alasdair, Wiggs, Janey, Allen, Naomi, Aslam, Tariq, Atan, Denize, Barman, Sarah, Barrett, Jenny, Bishop, Paul, Black, Graeme, Braithwaite, Tasanee, Carare, Roxana, Chakravarthy, Usha, Chan, Michelle, Day, Alexander, Desai, Parul, Dhillon, Bal, Dick, Andrew, Doney, Alexander, Egan, Cathy, Ennis, Sarah, Fruttiger, Marcus, Gallacher, John, Garway-Heath, David (Ted), Gibson, Jane, Guggenheim, Jeremy, Hammond, Chris, Hardcastle, Alison, Harding, Simon, Hogg, Ruth, Hysi, Pirro, Keane, Pearse, Khaw, Peng Tee, Lascaratos, Gerassimos, Littlejohns, Thomas, Lotery, Andrew, Luthert, Phil, MacGillivray, Tom, Mackie, Sarah, McGuinness, Bernadette, McKay, Gareth, McKibbin, Martin, Moore, Tony, Morgan, James, O'Sullivan, Eoin, Oram, Richard, Owen, Chris, Patel, Praveen, Paterson, Euan, Peto, Tunde, Petzold, Axel, Pontikos, Nikolas, Rahi, Jugnoo, Rudnicka, Alicja, Sattar, Naveed, Self, Jay, Sergouniotis, Panagiotis, Sivaprasad, Sobha, Steel, David, Stratton, Irene, Strouthidis, Nicholas, Sudlow, Cathie, Sun, Zihan, Tapp, Robyn, Thomas, Dhanes, Trucco, Emanuele, Tufail, Adnan, Viswanathan, Ananth, Vitart, Veronique, Weedon, Mike, Williams, Katie, Williams, Cathy, Woodside, Jayne, Yates, Max, Yip, Jennifer, Zheng, Yalin, Aung, Tin, Burdon, Kathryn, Chen, Li, Cheng, Ching-Yu, Craig, Jamie, Cree, Angela, de Vries, Victor, Driessen, Sjoerd, Fingert, John, Gharahkhani, Puya, Hammond, Christopher, Hayward, Caroline, Hewitt, Alex, Jansonius, Nomdo, Jonansson, Fridbert, Jonas, Jost, Kass, Michael, Khor, Chiea, Klaver, Caroline, Koh, Jacyline, MacGregor, Stuart, Mackey, David, Mitchell, Paul, Pang, Calvin, Pasutto, Francesca, Pfeiffer, Norbert, Polašek, Ozren, Ramdas, Wishal, Schuster, Alexander, Segrè, Ayellet, Stefansson, Einer, Stefánsson, Kári, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, van Duijn, Cornelia, Vergroesen, Joëlle, Vithana, Eranga, Wilson, James, Wojciechowski, Robert, Wong, Tien, Young, Terri, Stuart, Kelsey V., Luben, Robert N., Warwick, Alasdair N., Madjedi, Kian M., Patel, Praveen J., Biradar, Mahantesh I., Chia, Mark A., Pasquale, Louis R., Wiggs, Janey L., Kang, Jae H., Tran, Jessica H., Lentjes, Marleen A.H., Foster, Paul J., and Khawaja, Anthony P.

Published
2023
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12. Large-scale multitrait genome-wide association analyses identify hundreds of glaucoma risk loci

Author

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

Published
2023
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16. A multi-cohort genome-wide association study in African ancestry individuals reveals risk loci for primary open-angle glaucoma

Author

Verma, Shefali S., Gudiseva, Harini V., Chavali, Venkata R.M., Salowe, Rebecca J., Bradford, Yuki, Guare, Lindsay, Lucas, Anastasia, Collins, David W., Vrathasha, Vrathasha, Nair, Rohini M., Rathi, Sonika, Zhao, Bingxin, He, Jie, Lee, Roy, Zenebe-Gete, Selam, Bowman, Anita S., McHugh, Caitlin P., Zody, Michael C., Pistilli, Maxwell, Khachatryan, Naira, Daniel, Ebenezer, Murphy, Windell, Henderer, Jeffrey, Kinzy, Tyler G., Iyengar, Sudha K., Peachey, Neal S., Taylor, Kent D., Guo, Xiuqing, Chen, Yii-Der Ida, Zangwill, Linda, Girkin, Christopher, Ayyagari, Radha, Liebmann, Jeffrey, Chuka-Okosa, Chimd M., Williams, Susan E., Akafo, Stephen, Budenz, Donald L., Olawoye, Olusola O., Ramsay, Michele, Ashaye, Adeyinka, Akpa, Onoja M., Aung, Tin, Wiggs, Janey L., Ross, Ahmara G., Cui, Qi N., Addis, Victoria, Lehman, Amanda, Miller-Ellis, Eydie, Sankar, Prithvi S., Williams, Scott M., Ying, Gui-shuang, Cooke Bailey, Jessica, Rotter, Jerome I., Weinreb, Robert, Khor, Chiea Chuen, Hauser, Michael A., Ritchie, Marylyn D., and O’Brien, Joan M.

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

Author

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

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

Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.

Published
2021

20. Mitochondrial TXNRD2 and ME3 Genetic Risk Scores Are Associated with Specific Primary Open-Angle Glaucoma Phenotypes

Author

Allingham, R. Rand, Brilliant, Murray, Budenz, Donald L., Cooke Bailey, Jessica N., Fingert, John H., Gaasterland, Douglas, Gaasterland, Teresa, Haines, Jonathan L., Hauser, Michael A., Lee, Richard K., Lichter, Paul R., Liu, Yutao, Moroi, Syoko, Myers, Jonathan, Pasquale, Louis R., Pericak-Vance, Margaret, Realini, Anthony, Rhee, Doug, Richards, Julia E., Ritch, Robert, Schuman, Joel S., Scott, William K., Singh, Kuldev, Sit, Arthur J., Vollrath, Douglas, Weinreb, Robert N., Wiggs, Janey L., Wollstein, Gadi, Zack, Donald J., Aboobakar, Inas F., Kinzy, Tyler G., Zhao, Yan, Fan, Baojian, Qassim, Ayub, Kolovos, Antonia, Schmidt, Joshua M., and Craig, Jamie E.

Published
2023
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21. Disentangling the genetic overlap and causal relationships between primary open-angle glaucoma, brain morphology and four major neurodegenerative disorders

Author

Diaz-Torres, Santiago, He, Weixiong, Thorp, Jackson, Seddighi, Sahba, Mullany, Sean, Hammond, Christopher J., Hysi, Pirro G., Pasquale, Louis R., Khawaja, Anthony P., Hewitt, Alex W., Craig, Jamie E., Mackey, David A., Wiggs, Janey L., van Duijn, Cornelia, Lupton, Michelle K., Ong, Jue-Sheng, MacGregor, Stuart, and Gharahkhani, Puya

Published
2023
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23. The Genetics of Common, Complex Diseases

Author

Cooke Bailey, Jessica N., Sobrin, Lucia, Wiggs, Janey L., Comander, Jason, Section editor, Vandenberghe, Luk, Section editor, Albert, Daniel M., editor, Miller, Joan W., editor, Azar, Dimitri T., editor, and Young, Lucy H., editor

Published
2022
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24. Genetic Testing

Author

Wiggs, Janey L., Place, Emily M., Comander, Jason, Section editor, Vandenberghe, Luk, Section editor, Albert, Daniel M., editor, Miller, Joan W., editor, Azar, Dimitri T., editor, and Young, Lucy H., editor

Published
2022
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25. Genetics of Glaucoma

Author

Wiggs, Janey L., Tsai, James C., Section editor, Sun, Yang, Section editor, Albert, Daniel M., editor, Miller, Joan W., editor, Azar, Dimitri T., editor, and Young, Lucy H., editor

Published
2022
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28. List of contributors

Author

Ahmad, Hanif, primary, Alany, Raid G., additional, Alió, Jorge L., additional, Anderson, Andrew J., additional, Arora, Anmol, additional, Azuara-Blanco, Augusto, additional, Barrio, Jorge Alio del, additional, Baudouin, Christophe, additional, Bou Said, Reeda, additional, Bourne, Rupert R.A., additional, Butt, Fatima, additional, Calkins, David J., additional, Chan, Geoffrey Z.P., additional, Cheng, Ching-Yu, additional, Chong, Rachel S., additional, Cordeiro, Maria Francesca, additional, Crowston, Jonathan G., additional, Daka, Qëndresë, additional, Daneshvar, Ramin, additional, Denniss, Jonathan, additional, Deol, Sundeep Singh, additional, Epstein, Rebecca, additional, Ertel, Monica, additional, Fam, Jonathan M., additional, Fellman, Ronald L., additional, Garway-Heath, Ted, additional, Gazzard, Gus, additional, Gilbert, Clare, additional, Gillmann, Kevin, additional, Goldberg, Ivan, additional, Goldberg, Jeffrey L., additional, Grover, Sumit, additional, Heatley, Gregg A., additional, Hoffmann M., Esther, additional, Huang, Alex S., additional, Jin, Zi-Bing, additional, Johnstone, Murray, additional, Kahook, Malik, additional, Katz, L. Jay, additional, Kaufman, Paul L., additional, Keane, Pearse A., additional, Khawaja, Anthony P., additional, Khoueir, Ziad, additional, Lawlor, Mitchell, additional, Leung, Christopher, additional, Malyugin, Boris, additional, Mansberger, Steven L., additional, Mansouri, Kaweh, additional, Martin, Keith R., additional, Martinez, Christine E., additional, McKendrick, Allison M., additional, Mermoud, André, additional, Nickells, Robert W., additional, Nouri-Mahdavi, Kouros, additional, Oostra, Tyler D., additional, Palko, Joel, additional, Patel, Radhika Pooja, additional, Pradhan, Zia S., additional, Priyanka, Ramesh, additional, Rao, Harsha L., additional, Razeghinejad, Reza, additional, Realini, Tony, additional, Ritch, Robert, additional, Roy, Sylvain, additional, Sailer, Kerstin, additional, Sanchez, Facundo G., additional, Schlötzer-Schrehardt, Ursula, additional, Schuman, Joel S., additional, Scott, Andrew, additional, Seibold, Leonard, additional, Sharma, Anant, additional, Spaeth, George, additional, Strohmaier, Clemens A., additional, Szymanska, Maja, additional, Tanna, Angelo P., additional, Tanuj, Dada, additional, Tapply, Ian H., additional, Tatham, Andrew J., additional, Toris, Carol B., additional, Tsasousis, Konstantinos T., additional, Wang, Ningli, additional, Weinreb, Robert N., additional, Wiggs, Janey L., additional, Wo, Yu Jun, additional, Wollstein, Gadi, additional, Wu, Shen, additional, Wu, Zhichao, additional, Xin, Chen, additional, Yoo, Chungkwon, additional, Young, Cara Capitena, additional, and Zhang, Jingxue, additional

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

Author

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

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

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

Published
2019

30. Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry

Author

Consortium, The Genetics of Glaucoma in People of African Descent, Hauser, Michael A, Allingham, R Rand, Aung, Tin, Van Der Heide, Carly J, Taylor, Kent D, Rotter, Jerome I, Wang, Shih-Hsiu J, Bonnemaijer, Pieter WM, Williams, Susan E, Abdullahi, Sadiq M, Abu-Amero, Khaled K, Anderson, Michael G, Akafo, Stephen, Alhassan, Mahmoud B, Asimadu, Ifeoma, Ayyagari, Radha, Bakayoko, Saydou, Nyamsi, Prisca Biangoup, Bowden, Donald W, Bromley, William C, Budenz, Donald L, Carmichael, Trevor R, Challa, Pratap, Chen, Yii-Der Ida, Chuka-Okosa, Chimdi M, Bailey, Jessica N Cooke, Costa, Vital Paulino, Cruz, Dianne A, DuBiner, Harvey, Ervin, John F, Feldman, Robert M, Flamme-Wiese, Miles, Gaasterland, Douglas E, Garnai, Sarah J, Girkin, Christopher A, Guirou, Nouhoum, Guo, Xiuqing, Haines, Jonathan L, Hammond, Christopher J, Herndon, Leon, Hoffmann, Thomas J, Hulette, Christine M, Hydara, Abba, Igo, Robert P, Jorgenson, Eric, Kabwe, Joyce, Kilangalanga, Ngoy Janvier, Kizor-Akaraiwe, Nkiru, Kuchtey, Rachel W, Lamari, Hasnaa, Li, Zheng, Liebmann, Jeffrey M, Liu, Yutao, Loos, Ruth JF, Melo, Monica B, Moroi, Sayoko E, Msosa, Joseph M, Mullins, Robert F, Nadkarni, Girish, Napo, Abdoulaye, Ng, Maggie CY, Nunes, Hugo Freire, Obeng-Nyarkoh, Ebenezer, Okeke, Anthony, Okeke, Suhanya, Olaniyi, Olusegun, Olawoye, Olusola, Oliveira, Mariana Borges, Pasquale, Louise R, Perez-Grossmann, Rodolfo A, Pericak-Vance, Margaret A, Qin, Xue, Ramsay, Michele, Resnikoff, Serge, Richards, Julia E, Schimiti, Rui Barroso, Sim, Kar Seng, Sponsel, William E, Svidnicki, Paulo Vinicius, Thiadens, Alberta AHJ, Uche, Nkechinyere J, van Duijn, Cornelia M, de Vasconcellos, José Paulo Cabral, Wiggs, Janey L, Zangwill, Linda M, Risch, Neil, Milea, Dan, Ashaye, Adeyinka, Klaver, Caroline CW, Weinreb, Robert N, Koch, Allison E Ashley, Fingert, John H, and Khor, Chiea Chuen

Subjects
Biomedical and Clinical Sciences, Ophthalmology and Optometry, Human Genome, Genetics, Neurodegenerative, Clinical Research, Aging, Neurosciences, Eye Disease and Disorders of Vision, 2.1 Biological and endogenous factors, 2.4 Surveillance and distribution, Eye, Adaptor Proteins, Signal Transducing, Aged, Amyloid beta-Peptides, Black People, Case-Control Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Glaucoma, Open-Angle, Humans, Immunohistochemistry, Male, Meta-Analysis as Topic, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors, Genetics of Glaucoma in People of African Descent (GGLAD) Consortium, Medical and Health Sciences, General & Internal Medicine, Biomedical and clinical sciences, Health sciences
Abstract

ImportancePrimary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders.ObjectivesTo perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma.Design, settings, and participantsA 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma.ExposuresGenetic variants associated with primary open-angle glaucoma.Main outcomes and measuresPresence of primary open-angle glaucoma. Genome-wide significance was defined as P C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10-8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P

Published
2019

31. Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry.

Author

Genetics of Glaucoma in People of African Descent (GGLAD) Consortium, Hauser, Michael A, Allingham, R Rand, Aung, Tin, Van Der Heide, Carly J, Taylor, Kent D, Rotter, Jerome I, Wang, Shih-Hsiu J, Bonnemaijer, Pieter WM, Williams, Susan E, Abdullahi, Sadiq M, Abu-Amero, Khaled K, Anderson, Michael G, Akafo, Stephen, Alhassan, Mahmoud B, Asimadu, Ifeoma, Ayyagari, Radha, Bakayoko, Saydou, Nyamsi, Prisca Biangoup, Bowden, Donald W, Bromley, William C, Budenz, Donald L, Carmichael, Trevor R, Challa, Pratap, Chen, Yii-Der Ida, Chuka-Okosa, Chimdi M, Cooke Bailey, Jessica N, Costa, Vital Paulino, Cruz, Dianne A, DuBiner, Harvey, Ervin, John F, Feldman, Robert M, Flamme-Wiese, Miles, Gaasterland, Douglas E, Garnai, Sarah J, Girkin, Christopher A, Guirou, Nouhoum, Guo, Xiuqing, Haines, Jonathan L, Hammond, Christopher J, Herndon, Leon, Hoffmann, Thomas J, Hulette, Christine M, Hydara, Abba, Igo, Robert P, Jorgenson, Eric, Kabwe, Joyce, Kilangalanga, Ngoy Janvier, Kizor-Akaraiwe, Nkiru, Kuchtey, Rachel W, Lamari, Hasnaa, Li, Zheng, Liebmann, Jeffrey M, Liu, Yutao, Loos, Ruth JF, Melo, Monica B, Moroi, Sayoko E, Msosa, Joseph M, Mullins, Robert F, Nadkarni, Girish, Napo, Abdoulaye, Ng, Maggie CY, Nunes, Hugo Freire, Obeng-Nyarkoh, Ebenezer, Okeke, Anthony, Okeke, Suhanya, Olaniyi, Olusegun, Olawoye, Olusola, Oliveira, Mariana Borges, Pasquale, Louise R, Perez-Grossmann, Rodolfo A, Pericak-Vance, Margaret A, Qin, Xue, Ramsay, Michele, Resnikoff, Serge, Richards, Julia E, Schimiti, Rui Barroso, Sim, Kar Seng, Sponsel, William E, Svidnicki, Paulo Vinicius, Thiadens, Alberta AHJ, Uche, Nkechinyere J, van Duijn, Cornelia M, de Vasconcellos, José Paulo Cabral, Wiggs, Janey L, Zangwill, Linda M, Risch, Neil, Milea, Dan, Ashaye, Adeyinka, Klaver, Caroline CW, Weinreb, Robert N, Ashley Koch, Allison E, Fingert, John H, and Khor, Chiea Chuen

Subjects
Genetics of Glaucoma in People of African Descent (GGLAD) Consortium, Humans, Glaucoma, Open-Angle, Genetic Predisposition to Disease, Adaptor Proteins, Signal Transducing, Immunohistochemistry, Risk Factors, Case-Control Studies, Genotype, Polymorphism, Single Nucleotide, Aged, Middle Aged, African Continental Ancestry Group, Female, Male, Meta-Analysis as Topic, Genome-Wide Association Study, Amyloid beta-Peptides, Eye Disease and Disorders of Vision, Clinical Research, Human Genome, Aging, Neurodegenerative, Genetics, Neurosciences, 2.1 Biological and endogenous factors, General & Internal Medicine, Medical and Health Sciences
Abstract

Importance:Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders. Objectives:To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma. Design, Settings, and Participants:A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma. Exposures:Genetic variants associated with primary open-angle glaucoma. Main Outcomes and Measures:Presence of primary open-angle glaucoma. Genome-wide significance was defined as P C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10-8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P

Published
2019

32. Association of a Primary Open-Angle Glaucoma Genetic Risk Score With Earlier Age at Diagnosis

Author

Fan, Bao Jian, Bailey, Jessica Cooke, Igo, Rob P, Kang, Jae H, Boumenna, Tahani, Brilliant, Murray H, Budenz, Donald L, Fingert, John H, Gaasterland, Terry, Gaasterland, Douglas, Hauser, Michael A, Kraft, Peter, Lee, Richard K, Lichter, Paul R, Liu, Yutao, Moroi, Syoko E, Myers, Jonathan S, Pericak-Vance, Margaret A, Realini, Anthony, Rhee, Douglas J, Richards, Julia E, Ritch, Robert, Schuman, Joel S, Scott, William K, Singh, Kuldev, Sit, Arthur J, Vollrath, Douglas, Weinreb, Robert N, Wollstein, Gadi, Zack, Donald J, Haines, Jonathan L, Pasquale, Louis R, and Wiggs, Janey L

Subjects
Neurosciences, Clinical Research, Human Genome, Eye Disease and Disorders of Vision, Neurodegenerative, Genetics, Aging, Prevention, 2.1 Biological and endogenous factors, Aetiology, Opthalmology and Optometry, Ophthalmology & Optometry
Abstract

ImportanceGenetic variants associated with primary open-angle glaucoma (POAG) are known to influence disease risk. However, the clinical effect of associated variants individually or in aggregate is not known. Genetic risk scores (GRS) examine the cumulative genetic load by combining individual genetic variants into a single measure, which is assumed to have a larger effect and increased power to detect relevant disease-related associations.ObjectiveTo investigate if a GRS that comprised 12 POAG genetic risk variants is associated with age at disease diagnosis.Design, setting, and participantsA cross-sectional study included individuals with POAG and controls from the Glaucoma Genes and Environment (GLAUGEN) study and the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) study. A GRS was formulated using 12 variants known to be associated with POAG, and the alleles associated with increasing risk of POAG were aligned in the case-control sets. In case-only analyses, the association of the GRS with age at diagnosis was analyzed as an estimate of disease onset. Results from cohort-specific analyses were combined with meta-analysis. Data collection started in August 2012 for the NEIGHBOR cohort and in July 2008 for the GLAUGEN cohort and were analyzed starting in March 2018.Main outcomes and measuresAssociation of a 12 single-nucleotide polymorphism POAG GRS with age at diagnosis in individuals with POAG using linear regression.ResultsThe GLAUGEN study included 976 individuals with POAG and 1140 controls. The NEIGHBOR study included 2132 individuals with POAG and 2290 controls. For individuals with POAG, the mean (SD) age at diagnosis was 63.6 (9.8) years in the GLAUGEN cohort and 66.0 (13.7) years in the NEIGHBOR cohort. For controls, the mean (SD) age at enrollment was 65.5 (9.2) years in the GLAUGEN cohort and 68.9 (11.4) years in the NEIGHBOR cohort. All study participants were European white. The GRS was strongly associated with POAG risk in case-control analysis (odds ratio per 1-point increase in score = 1.24; 95% CI, 1.21-1.27; P = 3.4 × 10-66). In case-only analyses, each higher GRS unit was associated with a 0.36-year earlier age at diagnosis (β = -0.36; 95% CI, -0.56 to -0.16; P = 4.0 × 10-4). Individuals in the top 5% of the GRS had a mean (SD) age at diagnosis of 5.2 (12.8) years earlier than those in the bottom 5% GRS (61.4 [12.7] vs 66.6 [12.9] years; P = 5.0 × 10-4).Conclusions and relevanceA higher dose of POAG risk alleles was associated with an earlier age at glaucoma diagnosis. On average, individuals with POAG with the highest GRS had 5.2-year earlier age at diagnosis of disease. These results suggest that a GRS that comprised genetic variants associated with POAG could help identify patients with risk of earlier disease onset impacting screening and therapeutic strategies.

Published
2019

33. Myocilin Mutations in Patients With Normal-Tension Glaucoma

Author

Alward, Wallace LM, van der Heide, Carly, Khanna, Cheryl L, Roos, Ben R, Sivaprasad, Sobha, Kam, Jason, Ritch, Robert, Lotery, Andrew, Igo, Robert P, Bailey, Jessica N Cooke, Stone, Edwin M, Scheetz, Todd E, Kwon, Young H, Pasquale, Louis R, Wiggs, Janey L, and Fingert, John H

Subjects
Neurosciences, Clinical Research, Neurodegenerative, Eye Disease and Disorders of Vision, Aging, 2.1 Biological and endogenous factors, Aetiology, Eye, Aged, Case-Control Studies, Cytoskeletal Proteins, Eye Proteins, Female, Glycoproteins, Humans, Intraocular Pressure, Low Tension Glaucoma, Male, Middle Aged, Mutation, NEIGHBORHOOD Consortium, Opthalmology and Optometry, Ophthalmology & Optometry
Abstract

Importance:Mutations in the myocilin (MYOC) gene are the most common molecularly defined cause of primary open-angle glaucoma that typically occurs in patients with high intraocular pressures (IOP). One MYOC mutation, p.Gln368Ter, has been associated with as many as 1.6% of primary open-angle glaucoma cases that had a mean maximum recorded IOP of 30 mm Hg. However, to our knowledge, the role of the p.Gln368Ter mutation in patients with normal-tension glaucoma (NTG) with an IOP of 21 mm Hg or lower has not been investigated. Objective:To evaluate the role of the p.Gln368Ter MYOC mutation in patients with NTG. Design, Setting, and Participants:In this case-control study of the prevalence of the p.Gln368Ter mutation in patients with NTG, cohort 1 was composed of 772 patients with NTG and 2152 controls from the United States (Iowa, Minnesota, and New York) and England and cohort 2 was composed of 561 patients with NTG and 2606 controls from the Massachusetts Eye and Ear Infirmary and the NEIGHBORHOOD consortium. Genotyping was conducted using real-time polymerase chain reaction that was confirmed with Sanger sequencing, the imputation of genome-wide association study data, or an analysis of whole-exome sequence data. Data analysis occurred between April 2007 and April 2018. Main Outcomes and Measures:Comparison of the frequency of the p.Gln368Ter MYOC mutation between NTG cases and controls with the Fisher exact test. Results:Of 6091 total participants, 3346 (54.9%) were women and 5799 (95.2%) were white. We detected the p.Gln368Ter mutation in 7 of 772 patients with NTG (0.91%) and 7 of 2152 controls (0.33%) in cohort 1 (P = .03). In cohort 2, we detected the p.Gln368Ter mutation in 4 of 561 patients with NTG (0.71%) and 10 of 2606 controls (0.38%; P = .15). When the cohorts were analyzed as a group, the p.Gln368Ter mutation was associated with NTG (odds ratio, 2.3; 95% CI, 0.98-5.3; P = .04). Conclusions and Relevance:In cohorts 1 and 2, the p.Gln368Ter mutation in MYOC was found in patients with IOPs that were 21 mm Hg or lower (NTG), although at a frequency that is lower than previously detected in patients with higher IOP. These data suggest that the p.Gln368Ter mutation may be associated with glaucoma in patients with normal IOPs as well as in patients with IOPs that are greater than 21 mm Hg.

Published
2019

37. The Association between Serum Lipids and Intraocular Pressure in 2 Large United Kingdom Cohorts

Author

Chia, Mark, Do, Ron, Kastner, Alan, Kim, Jihye, Montesano, Giovanni, Atan, Denize, Aslam, Tariq, Barman, Sarah A., Barrett, Jenny H., Bishop, Paul, Blows, Peter, Bunce, Catey, Carare, Roxana O., Chakravarthy, Usha, Chan, Michelle, Chua, Sharon Y.L., Crabb, David P., Cumberland, Philippa M., Day, Alexander, Desai, Parul, Dhillon, Bal, Dick, Andrew D., Egan, Cathy, Ennis, Sarah, Foster, Paul, Fruttiger, Marcus, Gallacher, John E.J., Garway-Heath, David F., Gibson, Jane, Gore, Dan, Guggenheim, Jeremy A., Hammond, Chris J., Hardcastle, Alison, Harding, Simon P., Hogg, Ruth E., Hysi, Pirro, Keane, Pearse A., Khaw, Sir Peng T., Khawaja, Anthony P., Lascaratos, Gerassimos, Lotery, Andrew J., Macgillivray, Tom, Mackie, Sarah, Martin, Keith, McGaughey, Michelle, McGuinness, Bernadette, McKay, Gareth J., McKibbin, Martin, Mitry, Danny, Moore, Tony, Morgan, James E., Muthy, Zaynah A., O’Sullivan, Eoin, Owen, Chris G., Patel, Praveen, Paterson, Euan, Peto, Tunde, Petzold, Axel, Rahi, Jugnoo S., Rudnikca, Alicja R., Self, Jay, Sivaprasad, Sobha, Steel, David, Stratton, Irene, Strouthidis, Nicholas, Sudlow, Cathie, Thomas, Dhanes, Trucco, Emanuele, Tufail, Adnan, Vitart, Veronique, Vernon, Stephen A., Viswanathan, Ananth C., Williams, Cathy, Williams, Katie, Woodside, Jayne V., Yates, MaxM., Yip, Jennifer, Zheng, Yalin, Madjedi, Kian M., Stuart, Kelsey V., Luben, Robert N., Warwick, Alasdair, Pasquale, Louis R., Kang, Jae H., Wiggs, Janey L., Lentjes, Marleen A.H., Aschard, Hugues, Sattar, Naveed, and Foster, Paul J.

Published
2022
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40. Genome-Wide Association Study Identifies Two Common Loci Associated with Pigment Dispersion Syndrome/Pigmentary Glaucoma and Implicates Myopia in its Development

Author

Simcoe, Mark J., Shah, Ameet, Fan, Baojian, Choquet, Hélène, Weisschuh, Nicole, Waseem, Naushin H., Jiang, Chen, Melles, Ronald B., Ritch, Robert, Mahroo, Omar A., Wissinger, Bernd, Jorgenson, Eric, Wiggs, Janey L., Garway-Heath, David F., Hysi, Pirro G., and Hammond, Christopher J.

Published
2022
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43. 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

44. Genome-wide association study of primary open-angle glaucoma in continental and admixed African populations.

Author

Bonnemaijer, Pieter WM, Iglesias, Adriana I, Nadkarni, Girish N, Sanyiwa, Anna J, Hassan, Hassan G, Cook, Colin, GIGA Study Group, Simcoe, Mark, Taylor, Kent D, Schurmann, Claudia, Belbin, Gillian M, Kenny, Eimear E, Bottinger, Erwin P, van de Laar, Suzanne, Wiliams, Susan EI, Akafo, Stephen K, Ashaye, Adeyinka O, Zangwill, Linda M, Girkin, Christopher A, Ng, Maggie CY, Rotter, Jerome I, Weinreb, Robert N, Li, Zheng, Allingham, R Rand, Eyes of Africa Genetics Consortium, Nag, Abhishek, Hysi, Pirro G, Meester-Smoor, Magda A, Wiggs, Janey L, NEIGHBORHOOD Consortium, Hauser, Michael A, Hammond, Christopher J, Lemij, Hans G, Loos, Ruth JF, van Duijn, Cornelia M, Thiadens, Alberta AHJ, and Klaver, Caroline CW

Subjects
GIGA Study Group, Eyes of Africa Genetics Consortium, NEIGHBORHOOD Consortium, Humans, Glaucoma, Open-Angle, Vesicular Transport Proteins, Aged, Aged, 80 and over, Middle Aged, African Continental Ancestry Group, Female, Male, Thioredoxin Reductase 2, Genome-Wide Association Study, Genetic Loci, Neurodegenerative, Human Genome, Aging, Eye Disease and Disorders of Vision, Genetics, Neurosciences, 2.1 Biological and endogenous factors, Genetics & Heredity, Complementary and Alternative Medicine, Paediatrics and Reproductive Medicine
Abstract

Primary open angle glaucoma (POAG) is a complex disease with a major genetic contribution. Its prevalence varies greatly among ethnic groups, and is up to five times more frequent in black African populations compared to Europeans. So far, worldwide efforts to elucidate the genetic complexity of POAG in African populations has been limited. We conducted a genome-wide association study in 1113 POAG cases and 1826 controls from Tanzanian, South African and African American study samples. Apart from confirming evidence of association at TXNRD2 (rs16984299; OR[T] 1.20; P = 0.003), we found that a genetic risk score combining the effects of the 15 previously reported POAG loci was significantly associated with POAG in our samples (OR 1.56; 95% CI 1.26-1.93; P = 4.79 × 10-5). By genome-wide association testing we identified a novel candidate locus, rs141186647, harboring EXOC4 (OR[A] 0.48; P = 3.75 × 10-8), a gene transcribing a component of the exocyst complex involved in vesicle transport. The low frequency and high degree of genetic heterogeneity at this region hampered validation of this finding in predominantly West-African replication sets. Our results suggest that established genetic risk factors play a role in African POAG, however, they do not explain the higher disease load. The high heterogeneity within Africans remains a challenge to identify the genetic commonalities for POAG in this ethnicity, and demands studies of extremely large size.

Published
2018

45. 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

46. The Association of Urinary Sodium Excretion with Glaucoma and Related Traits in a Large United Kingdom Population

Author

Stuart, Kelsey V., primary, Biradar, Mahantesh I., additional, Luben, Robert N., additional, Dhaun, Neeraj, additional, Wagner, Siegfried K., additional, Warwick, Alasdair N., additional, Sun, Zihan, additional, Madjedi, Kian M., additional, Pasquale, Louis R., additional, Wiggs, Janey L., additional, Kang, Jae H., additional, Lentjes, Marleen A.H., additional, Aschard, Hugues, additional, Kim, Jihye, additional, Foster, Paul J., additional, Khawaja, Anthony P., additional, Chia, Mark, additional, Chua, Sharon, additional, Do, Ron, additional, Foster, Paul, additional, Kang, Jae, additional, Kastner, Alan, additional, Khawaja, Anthony, additional, Lentjes, Marleen, additional, Luben, Robert, additional, Madjedi, Kian, additional, Montesano, Giovanni, additional, Pasquale, Louis, additional, Stuart, Kelsey, additional, Warwick, Alasdair, additional, Wiggs, Janey, additional, Allen, Naomi, additional, Aslam, Tariq, additional, Atan, Denize, additional, Barman, Sarah, additional, Barrett, Jenny, additional, Bishop, Paul, additional, Black, Graeme, additional, Braithwaite, Tasanee, additional, Carare, Roxana, additional, Chakravarthy, Usha, additional, Chan, Michelle, additional, Day, Alexander, additional, Desai, Parul, additional, Dhillon, Bal, additional, Dick, Andrew, additional, Doney, Alexander, additional, Egan, Cathy, additional, Ennis, Sarah, additional, Fruttiger, Marcus, additional, Garway-Heath, David (Ted), additional, Gibson, Jane, additional, Guggenheim, Jeremy, additional, Hammond, Chris, additional, Hardcastle, Alison, additional, Harding, Simon, additional, Hogg, Ruth, additional, Hysi, Pirro, additional, Keane, Pearse, additional, Khaw, Peng Tee, 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, Moore, Tony, additional, Morgan, James, additional, O'Sullivan, Eoin, additional, Oram, Richard, 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, Sattar, Naveed, 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, Thomas, Dhanes, additional, Trucco, Emanuele, additional, Tufail, Adnan, additional, Viswanathan, Ananth, additional, Vitart, Veronique, additional, Weedon, Mike, additional, Williams, Katie, additional, Williams, Cathy, additional, Woodside, Jayne, additional, Yates, Max, additional, Yip, Jennifer, additional, Zheng, Yalin, additional, Aung, Tin, additional, Burdon, Kathryn, additional, Chen, Li, additional, Cheng, Ching-Yu, additional, Craig, Jamie, additional, Cree, Angela, additional, de Vries, Victor, additional, Driessen, Sjoerd, additional, Fingert, John, additional, Gharahkhani, Puya, additional, Hammond, Christopher, additional, Hayward, Caroline, additional, Hewitt, Alex, additional, Jansonius, Nomdo, additional, Jonansson, Fridbert, additional, Jonas, Jost, additional, Kass, Michael, additional, Khor, Chiea, additional, Klaver, Caroline, additional, Koh, Jacyline, additional, MacGregor, Stuart, additional, Mackey, David, additional, Mitchell, Paul, additional, Pang, Calvin, additional, Pasutto, Francesca, additional, Pfeiffer, Norbert, additional, Polašek, Ozren, additional, Ramdas, Wishal, additional, Schuster, Alexander, additional, Segrè, Ayellet, additional, Stefansson, Einer, additional, Stefánsson, Kári, additional, Thorleifsson, Gudmar, additional, Thorsteinsdottir, Unnur, additional, van Duijn, Cornelia, additional, Vergroesen, Joëlle, additional, Vithana, Eranga, additional, Wilson, James, additional, Wojciechowski, Robert, additional, Wong, Tien, additional, and Young, Terri, additional

Published
2024
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48. Characteristics of p.Gln368Ter Myocilin Variant and Influence of Polygenic Risk on Glaucoma Penetrance in the UK Biobank

Author

Aung, Tin, Craig, Jamie E., Cheng, Ching-Yu, Cooke Bailey, Jessica N., Cree, Angela J., Foster, Paul J., Gharahkhani, Puya, Hammond, Christopher J., Hewitt, Alex W., Höhn, René, Hysi, Pirro G., Iglesias, Adriana I., Jonas, Jost B., Klaver, Caroline C.W., Khawaja, Anthony P., Khor, Chiea Chuen, Lotery, Andrew J., MacGregor, Stuart, Mackey, David A., Ong, Jue Sheng, Mitchell, Paul, Pasquale, Louis R., Pang, ChiPui, Pasutto, Francesca, Pfeiffer, Norbert, Segre, Ayellet V., van Duijn, Cornelia M., Viswanathan, Ananth C., Vitart, Veronique, Vithana, Eranga N., Wiggs, Janey L., Wojciechowski, Robert, Young, Terri L., Wong, Tien Yin, Yazar, Seyhan, Zebardast, Nazlee, Sekimitsu, Sayuri, Wang, Jiali, Elze, Tobias, Cole, Brian S., Lin, Michael M., and Segrè, Ayellet V.

Published
2021
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49. Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: An Analysis in Two Large Datasets

Author

Cooke Bailey, Jessica N, Gharahkhani, Puya, Kang, Jae H, Butkiewicz, Mariusz, Sullivan, David A, Weinreb, Robert N, Aschard, Hugues, Allingham, R Rand, Ashley-Koch, Allison, Lee, Richard K, Moroi, Sayoko E, Brilliant, Murray H, Wollstein, Gadi, Schuman, Joel S, Fingert, John H, Budenz, Donald L, Realini, Tony, Gaasterland, Terry, Scott, William K, Singh, Kuldev, Sit, Arthur J, Igo, Robert P, Song, Yeunjoo E, Hark, Lisa, Ritch, Robert, Rhee, Douglas J, Vollrath, Douglas, Zack, Donald J, Medeiros, Felipe, Vajaranant, Thasarat S, Chasman, Daniel I, Christen, William G, Pericak-Vance, Margaret A, Liu, Yutao, Kraft, Peter, Richards, Julia E, Rosner, Bernard A, Hauser, Michael A, Craig, Jamie E, Burdon, Kathryn P, Hewitt, Alex W, Mackey, David A, Haines, Jonathan L, MacGregor, Stuart, Wiggs, Janey L, and Pasquale, Louis R

Subjects
Genetics, Neurodegenerative, Aging, 2.1 Biological and endogenous factors, Aetiology, Datasets as Topic, Female, Gene Frequency, Genome-Wide Association Study, Genotype, Glaucoma, Open-Angle, Humans, Intraocular Pressure, Low Tension Glaucoma, Male, Metabolic Networks and Pathways, Middle Aged, Polymorphism, Single Nucleotide, Testosterone, primary open-angle glaucoma, testosterone, genetics, pathway analysis, Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG) Consortium, Biological Sciences, Medical and Health Sciences, Ophthalmology & Optometry
Abstract

Purpose:Sex hormones may be associated with primary open-angle glaucoma (POAG), although the mechanisms are unclear. We previously observed that gene variants involved with estrogen metabolism were collectively associated with POAG in women but not men; here we assessed gene variants related to testosterone metabolism collectively and POAG risk. Methods:We used two datasets: one from the United States (3853 cases and 33,480 controls) and another from Australia (1155 cases and 1992 controls). Both datasets contained densely called genotypes imputed to the 1000 Genomes reference panel. We used pathway- and gene-based approaches with Pathway Analysis by Randomization Incorporating Structure (PARIS) software to assess the overall association between a panel of single nucleotide polymorphisms (SNPs) in testosterone metabolism genes and POAG. In sex-stratified analyses, we evaluated POAG overall and POAG subtypes defined by maximum IOP (high-tension [HTG] or normal tension glaucoma [NTG]). Results:In the US dataset, the SNP panel was not associated with POAG (permuted P = 0.77), although there was an association in the Australian sample (permuted P = 0.018). In both datasets, the SNP panel was associated with POAG in men (permuted P ≤ 0.033) and not women (permuted P ≥ 0.42), but in gene-based analyses, there was no consistency on the main genes responsible for these findings. In both datasets, the testosterone pathway association with HTG was significant (permuted P ≤ 0.011), but again, gene-based analyses showed no consistent driver gene associations. Conclusions:Collectively, testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets.

Published
2018

50. Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: An Analysis in Two Large Datasets.

Author

Bailey, Jessica N Cooke, Gharahkhani, Puya, Kang, Jae H, Butkiewicz, Mariusz, Sullivan, David A, Weinreb, Robert N, Aschard, Hugues, Allingham, R Rand, Ashley-Koch, Allison, Lee, Richard K, Moroi, Sayoko E, Brilliant, Murray H, Wollstein, Gadi, Schuman, Joel S, Fingert, John H, Budenz, Donald L, Realini, Tony, Gaasterland, Terry, Scott, William K, Singh, Kuldev, Sit, Arthur J, Igo, Robert P, Song, Yeunjoo E, Hark, Lisa, Ritch, Robert, Rhee, Douglas J, Vollrath, Douglas, Zack, Donald J, Medeiros, Felipe, Vajaranant, Thasarat S, Chasman, Daniel I, Christen, William G, Pericak-Vance, Margaret A, Liu, Yutao, Kraft, Peter, Richards, Julia E, Rosner, Bernard A, Hauser, Michael A, Craig, Jamie E, Burdon, Kathryn P, Hewitt, Alex W, Mackey, David A, Haines, Jonathan L, MacGregor, Stuart, Wiggs, Janey L, Pasquale, Louis R, and Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG) Consortium

Subjects
Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG) Consortium, Humans, Glaucoma, Open-Angle, Testosterone, Intraocular Pressure, Gene Frequency, Genotype, Polymorphism, Single Nucleotide, Middle Aged, Female, Male, Metabolic Networks and Pathways, Genome-Wide Association Study, Low Tension Glaucoma, Datasets as Topic, primary open-angle glaucoma, testosterone, genetics, pathway analysis, Glaucoma, Open-Angle, Polymorphism, Single Nucleotide, Biological Sciences, Medical and Health Sciences, Ophthalmology & Optometry
Abstract

Purpose:Sex hormones may be associated with primary open-angle glaucoma (POAG), although the mechanisms are unclear. We previously observed that gene variants involved with estrogen metabolism were collectively associated with POAG in women but not men; here we assessed gene variants related to testosterone metabolism collectively and POAG risk. Methods:We used two datasets: one from the United States (3853 cases and 33,480 controls) and another from Australia (1155 cases and 1992 controls). Both datasets contained densely called genotypes imputed to the 1000 Genomes reference panel. We used pathway- and gene-based approaches with Pathway Analysis by Randomization Incorporating Structure (PARIS) software to assess the overall association between a panel of single nucleotide polymorphisms (SNPs) in testosterone metabolism genes and POAG. In sex-stratified analyses, we evaluated POAG overall and POAG subtypes defined by maximum IOP (high-tension [HTG] or normal tension glaucoma [NTG]). Results:In the US dataset, the SNP panel was not associated with POAG (permuted P = 0.77), although there was an association in the Australian sample (permuted P = 0.018). In both datasets, the SNP panel was associated with POAG in men (permuted P ≤ 0.033) and not women (permuted P ≥ 0.42), but in gene-based analyses, there was no consistency on the main genes responsible for these findings. In both datasets, the testosterone pathway association with HTG was significant (permuted P ≤ 0.011), but again, gene-based analyses showed no consistent driver gene associations. Conclusions:Collectively, testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets.

Published
2018

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