A DNA analysis of nearly 400,000 people identified 127 locations on chromosomes containing genes that raise the risk of glaucoma, including 44 that had not been previously connected to the blinding eye disease. The findings could improve prevention measures and the search for drug treatments.
Publishing their results Feb. 24 in a paper in Nature Communications, an international team of researchers was the first to study genomic data from people of European descent in addition to those of Asian and African ancestries, who experience relatively higher rates of glaucoma but are researched less often. The meta-analysis is the largest-ever genetic study of glaucoma and included 10 times as many subjects as a 2016 paper by a similar group.
Glaucoma, found in more than 75 million people worldwide and 3 million people in the U.S., is a condition that damages optic nerves through high internal eye pressure and is a leading cause of blindness.
Primary open-angle glaucoma, the focus of the new study, is the most common form of the disease in the U.S. and is usually not accompanied by symptoms or pain at early stages. It is a highly genetic disease, but the known genes don’t explain most of the genetic risk, said Puya Gharahkhani, an assistant professor of statistical genetics at the QIMR Berghofer Medical Research Institute in Australia and a co-first author of the study.
“The problem is the majority of risk genes which contribute to glaucoma still are not known,” Gharahkhani said. “That's why we wanted to look at a large sample size and see what genes are contributing to glaucoma.”
The meta-analysis spanned 21 previous studies that covered the full genomes of about 34,000 subjects with primary open-angle glaucoma and 350,000 control subjects. Groups of people of European, Asian and African descent were studied separately before the results were cross-analyzed. People with Asian and African heritage suffer from glaucoma more frequently and are not often studied, according to Gharahkhani, though European ancestry was still overrepresented in the study, with nearly 16,700 cases and 200,000 controls.
Due to limitations in the analysis, the researchers identified only gene loci, focusing on locations or “genetic street addresses” on a chromosome that may contain multiple genes.
The analysis surfaced 44 newly identified gene loci with a link to glaucoma, in addition to the 83 previously known loci. Some of the new associated genes are highly expressed in eye tissues, nerves and arteries, according to the paper.
From the 127 identified gene loci, cross-ancestry analysis allowed the research team to pick out a gene most likely causing the glaucoma risk from 57 of them. Nearly all of the loci were found in all three lineages, however.
"These new findings come out of the highest-powered genome-wide association study of glaucoma to date, and show the power of team science and using big data to answer questions when research groups around the world join forces," said co-senior study author Janey L. Wiggs, a professor of ophthalmology at Harvard Medical School and the associate chief of ophthalmology clinical research at Mass Eye and Ear.
The associated gene loci were tested in an independent genetic database from 23andMe, a company that provides consumer genetic testing. It analyzed about 43,000 participants with self-reported primary open-angle glaucoma and another 1.5 million in a control group and found that most associations were replicated in these new subjects, largely ruling out false positives.
“It was very interesting because they found a very high concordance,” Gharahkhani said. “It's very assuring that what we find is not a false discovery.”
The 23andMe testing also found that the 127 gene loci collectively explained 9.4% of the glaucoma familial risk, with 1.9% being explained by the 44 newly reported loci.
The researchers noted in the paper that their meta-analysis also covered some studies that did not match glaucoma cases and controls by age, possibly obscuring genes that are expressed differently at different ages. They also said there is room for more research to learn on a molecular level how the new gene loci function to cause glaucoma.
Understanding which genes are associated with a risk of glaucoma can improve early detection and treatment before the worst effects set in, said Gharahkhani. He said it can also guide the development of new medications to treat the eye disease and even the search for preexisting drugs that target these new gene loci. A few are floated as potential candidates by the researchers, such as dipyridamole, which is being tested in clinical trials for diseases such as stroke and coronary heart disease.
The professor is involved in current and upcoming research on both bettering genetic risk detection models and identifying drug candidates. He is additionally collaborating with other scientists around the world who are recruiting more subjects to eventually run another analysis with an even larger sample pool.
The study, “Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries,” published Feb. 24 in Nature Communications, was authored by Puya Gharahkhani, Xikun Han, Jue Sheng Ong, Michelle Lupton, Nicholas Martin and Stuart MacGregor, QIMR Berghofer Medical Research Institute; Eric Jorgenson, Helene Choquet and Ronald Melles, Kaiser Permanente Northern California; Pirro Hysi and Chris Hammond, King’s College London; Anthony Khawaja, NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust, UCL Institute of Ophthalmology and University of Cambridge School of Clinical Medicine; Sarah Pendergrass and Navya Josyula, Biomedical and Translational Informatics Institute; Alex Hewitt, University of Tasmania and University of Melbourne; Ayellet Segrè, John Rouhana, Andrew Hamel and Janey Wiggs, Harvard Medical School; Robert Igo Jr., Jessica Cooke Bailey and Jonathan Haines, Case Western Reserve University School of Medicine; Ayub Qassim, Owen Siggs and Jamie Craig, Flinders University; Pieter Bonnemaijer, Erasmus University Medical Center and Rotterdam Eye Hospital; Adriana Iglesias and Alberta Thiadens, Erasmus University Medical Center; Terri Young, University of Wisconsin-Madison; Veronique Vitart, Institute of Genetics and Molecular Medicine; Juha Karjalainen, University of Helsinki, Broad Institute and Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School; Steffen Uebe and Francesca Pasutto, University of Erlangen-Nuremberg; K. Saidas Nair, University of California, San Francisco; Robert Luben, University of Cambridge School of Clinical Medicine; Mark Simcoe, King’s College London and University College London; Nishani Amersinghe, University Hospital Southampton NHS Foundation Trust; Angela Cree, University of Southampton; Rene Hohn, University of Bern and University Medical Center Mainz; Alicia Poplawski, University Medical Center Mainz; Li Jia Chen and Chi Pui Pang, The Chinese University of Hong Kong; Shi-Song Rong, Harvard Medical School and The Chinese University of Hong Kong; Tin Aung and Ching-Yu Cheng, Singapore National Eye Centre, Duke-NUS Medical School and National University of Singapore; Eranga Vithana, Singapore National Eye Centre and Duke-NUS Medical School; NEIGHBORHOOD consortium; ANZRAG consortium; Biobank Japan project; FinnGen study; UK Biobank Eye and Vision Consortium; GIGA study group; 23andMe Research Team; Gen Tamiya, Tohoku University and RIKEN Center for Advanced Intelligence Project; Yukihiro Shiga, Masayuki Yamamoto, Toru Nakazawa and Kazuki Hashimoto, Tohoku University; Hannah Currant and Ewan Birney, European Bioinformatics Institute; Xin Wang and Adam Auton, 23andMe; Adeyinka Ashaye and Olusola Olawoye, University of Ibadan; Susan Williams and Michele Ramsay, University of the Witwatersrand; Stephen Akafo, University of Ghana Medical School; Yoichiro Kamatani, RIKEN Center for Integrative Medical Sciences and The University of Tokyo; Masato Akiyama, RIKEN Center for Integrative Medical Sciences and Kyushu University; Yukihide Momozawa and Michiaki Kubo, RIKEN Center for Integrative Medical Sciences; Paul Foster and Peng Khaw, NIHR Biomedical Research Centre at Moorfields Eye Hospital, National Health Service Foundation Trust and UCL Institute of Ophthalmology; James Morgan, Cardiff University; Nicholas Strouthidis, National Institute for Health Research NIHR Biomedical Research Centre at Moorfields Eye Hospital National Health Service Foundation Trust & UCL Institute of Ophthalmology and University College London; Peter Kraft, Harvard T.H. Chan School of Public Health; Jae Kang, Brigham and Women’s Hospital and Harvard Medical School; Paul Mitchell, University of Sydney; Andrew Lotery, University Hospital Southampton NHS Foundation Trust and University of Southampton; Aarno Palotie, University of Helsinki, Massachusetts General Hospital and Broad Institute; Cornelia van Duijn, Erasmus University Medical Center and University of Oxford; Louis Pasquale, Icahn School of Medicine at Mount Sinai; Caroline Klaver, Erasmus University Medical Center, Radboud University Medical Center and Institute for Molecular and Clinical Ophthalmology; Michael Hauser, Duke University, Singapore Eye Research Institute and Duke-NUS Medical School; Chiea Chuen Khor, Genome Institute of Singapore; and David Mackey, University of Tasmania, University of Melbourne and Lion’s Eye Institute, University of Western Australia.
Correction: A previously published version of this article incorrectly stated Puya Gharahkani's title. The error has been corrected.