Nazlee Zebardast1, Sayuri Sekimitsu2, Jiali Wang3, Tobias Elze4, Puya Gharahkhani5, Brian S Cole3, Michael M Lin6, Ayellet V Segrè3, Janey L Wiggs3. 1. Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts. Electronic address: Nazlee_Zebardast@meei.harvard.edu. 2. Tufts University School of Medicine, Boston, Massachusetts. 3. Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts; Ocular Genomics Institute, Harvard Medical School, Boston, Massachusetts. 4. Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts. 5. Statistical Genetics Group, Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia. 6. Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts.
Abstract
PURPOSE: MYOC (myocilin) mutations account for 3% to 5% of primary open-angle glaucoma (POAG) cases. We aimed to understand the true population-wide penetrance and characteristics of glaucoma among individuals with the most common MYOC variant (p.Gln368Ter) and the impact of a POAG polygenic risk score (PRS) in this population. DESIGN: Cross-sectional population-based study. PARTICIPANTS: Individuals with the p.Gln368Ter variant among 77 959 UK Biobank participants with fundus photographs (FPs). METHODS: A genome-wide POAG PRS was computed, and 2 masked graders reviewed FPs for disc-defined glaucoma (DDG). MAIN OUTCOME MEASURES: Penetrance of glaucoma. RESULTS: Two hundred individuals carried the p.Gln368Ter heterozygous genotype, and 177 had gradable FPs. One hundred thirty-two showed no evidence of glaucoma, 45 (25.4%) had probable/definite glaucoma in at least 1 eye, and 19 (10.7%) had bilateral glaucoma. No differences were found in age, race/ethnicity, or gender among groups (P > 0.05). Of those with DDG, 31% self-reported or had International Classification of Diseases codes for glaucoma, whereas 69% were undiagnosed. Those with DDG had higher medication-adjusted cornea-corrected intraocular pressure (IOPcc) (P < 0.001) vs. those without glaucoma. This difference in IOPcc was larger in those with DDG with a prior glaucoma diagnosis versus those not diagnosed (P < 0.001). Most p.Gln368Ter carriers showed IOP in the normal range (≤21 mmHg), although this proportion was lower in those with DDG (P < 0.02) and those with prior glaucoma diagnosis (P < 0.03). Prevalence of DDG increased with each decile of POAG PRS. Individuals with DDG demonstrated significantly higher PRS compared with those without glaucoma (0.37 ± 0.97 vs. 0.01 ± 0.90; P = 0.03). Of those with DDG, individuals with a prior diagnosis of glaucoma had higher PRS compared with undiagnosed individuals (1.31 ± 0.64 vs. 0.00 ± 0.81; P < 0.001) and 27.5 times (95% confidence interval, 2.5-306.6) adjusted odds of being in the top decile of PRS for POAG. CONCLUSIONS: One in 4 individuals with the MYOC p.Gln368Ter mutation demonstrated evidence of glaucoma, a substantially higher penetrance than previously estimated, with 69% of cases undetected. A large portion of p.Gln368Ter carriers, including those with DDG, have IOP in the normal range, despite similar age. Polygenic risk score increases disease penetrance and severity, supporting the usefulness of PRS in risk stratification among MYOC p.Gln368Ter carriers.
PURPOSE: MYOC (myocilin) mutations account for 3% to 5% of primary open-angle glaucoma (POAG) cases. We aimed to understand the true population-wide penetrance and characteristics of glaucoma among individuals with the most common MYOC variant (p.Gln368Ter) and the impact of a POAG polygenic risk score (PRS) in this population. DESIGN: Cross-sectional population-based study. PARTICIPANTS: Individuals with the p.Gln368Ter variant among 77 959 UK Biobank participants with fundus photographs (FPs). METHODS: A genome-wide POAG PRS was computed, and 2 masked graders reviewed FPs for disc-defined glaucoma (DDG). MAIN OUTCOME MEASURES: Penetrance of glaucoma. RESULTS: Two hundred individuals carried the p.Gln368Ter heterozygous genotype, and 177 had gradable FPs. One hundred thirty-two showed no evidence of glaucoma, 45 (25.4%) had probable/definite glaucoma in at least 1 eye, and 19 (10.7%) had bilateral glaucoma. No differences were found in age, race/ethnicity, or gender among groups (P > 0.05). Of those with DDG, 31% self-reported or had International Classification of Diseases codes for glaucoma, whereas 69% were undiagnosed. Those with DDG had higher medication-adjusted cornea-corrected intraocular pressure (IOPcc) (P < 0.001) vs. those without glaucoma. This difference in IOPcc was larger in those with DDG with a prior glaucoma diagnosis versus those not diagnosed (P < 0.001). Most p.Gln368Ter carriers showed IOP in the normal range (≤21 mmHg), although this proportion was lower in those with DDG (P < 0.02) and those with prior glaucoma diagnosis (P < 0.03). Prevalence of DDG increased with each decile of POAG PRS. Individuals with DDG demonstrated significantly higher PRS compared with those without glaucoma (0.37 ± 0.97 vs. 0.01 ± 0.90; P = 0.03). Of those with DDG, individuals with a prior diagnosis of glaucoma had higher PRS compared with undiagnosed individuals (1.31 ± 0.64 vs. 0.00 ± 0.81; P < 0.001) and 27.5 times (95% confidence interval, 2.5-306.6) adjusted odds of being in the top decile of PRS for POAG. CONCLUSIONS: One in 4 individuals with the MYOC p.Gln368Ter mutation demonstrated evidence of glaucoma, a substantially higher penetrance than previously estimated, with 69% of cases undetected. A large portion of p.Gln368Ter carriers, including those with DDG, have IOP in the normal range, despite similar age. Polygenic risk score increases disease penetrance and severity, supporting the usefulness of PRS in risk stratification among MYOC p.Gln368Ter carriers.
Authors: Ursula Schmidt-Erfurth; Sebastian M Waldstein; Sophie Klimscha; Amir Sadeghipour; Xiaofeng Hu; Bianca S Gerendas; Aaron Osborne; Hrvoje Bogunovic Journal: Invest Ophthalmol Vis Sci Date: 2018-07-02 Impact factor: 4.799
Authors: Xikun Han; Emmanuelle Souzeau; Jue-Sheng Ong; Jiyuan An; Owen M Siggs; Kathryn P Burdon; Stephen Best; Ivan Goldberg; Paul R Healey; Stuart L Graham; Jonathan B Ruddle; Richard A Mills; John Landers; Anna Galanopoulos; Andrew J R White; Robert Casson; David A Mackey; Alex W Hewitt; Puya Gharahkhani; Jamie E Craig; Stuart MacGregor Journal: JAMA Ophthalmol Date: 2019-01-01 Impact factor: 7.389
Authors: W L Alward; J H Fingert; M A Coote; A T Johnson; S F Lerner; D Junqua; F J Durcan; P J McCartney; D A Mackey; V C Sheffield; E M Stone Journal: N Engl J Med Date: 1998-04-09 Impact factor: 91.245
Authors: J L Wiggs; R R Allingham; D Vollrath; K H Jones; M De La Paz; J Kern; K Patterson; V L Babb; E A Del Bono; B W Broomer; M A Pericak-Vance; J L Haines Journal: Am J Hum Genet Date: 1998-11 Impact factor: 11.025
Authors: Julie Lecarpentier; Valentina Silvestri; Karoline B Kuchenbaecker; Daniel Barrowdale; Joe Dennis; Lesley McGuffog; Penny Soucy; Goska Leslie; Piera Rizzolo; Anna Sara Navazio; Virginia Valentini; Veronica Zelli; Andrew Lee; Ali Amin Al Olama; Jonathan P Tyrer; Melissa Southey; Esther M John; Thomas A Conner; David E Goldgar; Saundra S Buys; Ramunas Janavicius; Linda Steele; Yuan Chun Ding; Susan L Neuhausen; Thomas V O Hansen; Ana Osorio; Jeffrey N Weitzel; Angela Toss; Veronica Medici; Laura Cortesi; Ines Zanna; Domenico Palli; Paolo Radice; Siranoush Manoukian; Bernard Peissel; Jacopo Azzollini; Alessandra Viel; Giulia Cini; Giuseppe Damante; Stefania Tommasi; Paolo Peterlongo; Florentia Fostira; Ute Hamann; D Gareth Evans; Alex Henderson; Carole Brewer; Diana Eccles; Jackie Cook; Kai-Ren Ong; Lisa Walker; Lucy E Side; Mary E Porteous; Rosemarie Davidson; Shirley Hodgson; Debra Frost; Julian Adlard; Louise Izatt; Ros Eeles; Steve Ellis; Marc Tischkowitz; Andrew K Godwin; Alfons Meindl; Andrea Gehrig; Bernd Dworniczak; Christian Sutter; Christoph Engel; Dieter Niederacher; Doris Steinemann; Eric Hahnen; Jan Hauke; Kerstin Rhiem; Karin Kast; Norbert Arnold; Nina Ditsch; Shan Wang-Gohrke; Barbara Wappenschmidt; Dorothea Wand; Christine Lasset; Dominique Stoppa-Lyonnet; Muriel Belotti; Francesca Damiola; Laure Barjhoux; Sylvie Mazoyer; Mattias Van Heetvelde; Bruce Poppe; Kim De Leeneer; Kathleen B M Claes; Miguel de la Hoya; Vanesa Garcia-Barberan; Trinidad Caldes; Pedro Perez Segura; Johanna I Kiiski; Kristiina Aittomäki; Sofia Khan; Heli Nevanlinna; Christi J van Asperen; Tibor Vaszko; Miklos Kasler; Edith Olah; Judith Balmaña; Sara Gutiérrez-Enríquez; Orland Diez; Alex Teulé; Angel Izquierdo; Esther Darder; Joan Brunet; Jesús Del Valle; Lidia Feliubadalo; Miquel Angel Pujana; Conxi Lazaro; Adalgeir Arason; Bjarni A Agnarsson; Oskar Th Johannsson; Rosa B Barkardottir; Elisa Alducci; Silvia Tognazzo; Marco Montagna; Manuel R Teixeira; Pedro Pinto; Amanda B Spurdle; Helene Holland; Jong Won Lee; Min Hyuk Lee; Jihyoun Lee; Sung-Won Kim; Eunyoung Kang; Zisun Kim; Priyanka Sharma; Timothy R Rebbeck; Joseph Vijai; Mark Robson; Anne Lincoln; Jacob Musinsky; Pragna Gaddam; Yen Y Tan; Andreas Berger; Christian F Singer; Jennifer T Loud; Mark H Greene; Anna Marie Mulligan; Gord Glendon; Irene L Andrulis; Amanda Ewart Toland; Leigha Senter; Anders Bojesen; Henriette Roed Nielsen; Anne-Bine Skytte; Lone Sunde; Uffe Birk Jensen; Inge Sokilde Pedersen; Lotte Krogh; Torben A Kruse; Maria A Caligo; Sook-Yee Yoon; Soo-Hwang Teo; Anna von Wachenfeldt; Dezheng Huo; Sarah M Nielsen; Olufunmilayo I Olopade; Katherine L Nathanson; Susan M Domchek; Christa Lorenchick; Rachel C Jankowitz; Ian Campbell; Paul James; Gillian Mitchell; Nick Orr; Sue Kyung Park; Mads Thomassen; Kenneth Offit; Fergus J Couch; Jacques Simard; Douglas F Easton; Georgia Chenevix-Trench; Rita K Schmutzler; Antonis C Antoniou; Laura Ottini Journal: J Clin Oncol Date: 2017-04-27 Impact factor: 44.544
Authors: Anthony P Khawaja; Jessica N Cooke Bailey; Nicholas J Wareham; Robert A Scott; Mark Simcoe; Robert P Igo; Yeunjoo E Song; Robert Wojciechowski; Ching-Yu Cheng; Peng T Khaw; Louis R Pasquale; Jonathan L Haines; Paul J Foster; Janey L Wiggs; Chris J Hammond; Pirro G Hysi Journal: Nat Genet Date: 2018-05-21 Impact factor: 38.330
Authors: Jamie E Craig; Xikun Han; Ayub Qassim; Alex W Hewitt; Stuart MacGregor; Mark Hassall; Jessica N Cooke Bailey; Tyler G Kinzy; Anthony P Khawaja; Jiyuan An; Henry Marshall; Puya Gharahkhani; Robert P Igo; Stuart L Graham; Paul R Healey; Jue-Sheng Ong; Tiger Zhou; Owen Siggs; Matthew H Law; Emmanuelle Souzeau; Bronwyn Ridge; Pirro G Hysi; Kathryn P Burdon; Richard A Mills; John Landers; Jonathan B Ruddle; Ashish Agar; Anna Galanopoulos; Andrew J R White; Colin E Willoughby; Nicholas H Andrew; Stephen Best; Andrea L Vincent; Ivan Goldberg; Graham Radford-Smith; Nicholas G Martin; Grant W Montgomery; Veronique Vitart; Rene Hoehn; Robert Wojciechowski; Jost B Jonas; Tin Aung; Louis R Pasquale; Angela Jane Cree; Sobha Sivaprasad; Neeru A Vallabh; Ananth C Viswanathan; Francesca Pasutto; Jonathan L Haines; Caroline C W Klaver; Cornelia M van Duijn; Robert J Casson; Paul J Foster; Peng Tee Khaw; Christopher J Hammond; David A Mackey; Paul Mitchell; Andrew J Lotery; Janey L Wiggs Journal: Nat Genet Date: 2020-01-20 Impact factor: 38.330
Authors: Amit V Khera; Mark Chaffin; Krishna G Aragam; Mary E Haas; Carolina Roselli; Seung Hoan Choi; Pradeep Natarajan; Eric S Lander; Steven A Lubitz; Patrick T Ellinor; Sekar Kathiresan Journal: Nat Genet Date: 2018-08-13 Impact factor: 38.330