Bennet J McComish1, Srujana Sahebjada2,3, Yelena Bykhovskaya4,5,6, Colin E Willoughby7,8, Andrea J Richardson2, Abi Tenen9,10,11, Jac C Charlesworth1, Stuart MacGregor12, Paul Mitchell13, Sionne E M Lucas1, Richard A Mills14, David A Mackey15, Xiaohui Li16,17, Jie Jin Wang13, Richard A Jensen18, Jerome I Rotter16,17, Kent D Taylor16,17, Alex W Hewitt1,2, Yaron S Rabinowitz4,5,6, Paul N Baird2,3, Jamie E Craig1,14, Kathryn P Burdon1,14. 1. Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia. 2. Centre for Eye Research Australia, Melbourne, Victoria, Australia. 3. Department of Surgery (Ophthalmology), Royal Victorian Eye and Ear Hospital, University of Melbourne, Melbourne, Victoria, Australia. 4. Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California. 5. Cornea Genetic Eye Institute, Beverly Hills, California. 6. Board of the Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California. 7. Biomedical Sciences Research Institute, Ulster University, Coleraine, Northern Ireland, United Kingdom. 8. Belfast Health and Social Care Trust, Belfast, Northern Ireland, United Kingdom. 9. Vision Eye Institute, Melbourne, Victoria, Australia. 10. School of Primary and Allied Health Care, Monash University, Melbourne, Victoria, Australia. 11. Melbourne Stem Cell Centre, Melbourne, Victoria, Australia. 12. QIMR Berghofer Medical Research Institute, Brisbane, Australia. 13. Centre for Vision Research, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia. 14. Department of Ophthalmology, Flinders University, Adelaide, South Australia, Australia. 15. Lions Eye Institute, University of Western Australia, Perth, Western Australia, Australia. 16. Institute for Translational Genomics and Population Science, Los Angeles Biomedical Research Institute, Los Angeles, California. 17. Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California. 18. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle.
Abstract
Importance: Keratoconus is a condition in which the cornea progressively thins and protrudes in a conical shape, severely affecting refraction and vision. It is a major indication for corneal transplant. To discover new genetic loci associated with keratoconus and better understand the causative mechanism of this disease, we performed a genome-wide association study on patients with keratoconus. Objective: To identify genetic susceptibility regions for keratoconus in the human genome. Design, Setting, and Participants: This study was conducted with data from eye clinics in Australia, the United States, and Northern Ireland. The discovery cohort of individuals with keratoconus and control participants from Australia was genotyped using the Illumina HumanCoreExome single-nucleotide polymorphism array. After quality control and data cleaning, genotypes were imputed against the 1000 Genomes Project reference panel (phase III; version 5), and association analyses were completed using PLINK version 1.90. Single-nucleotide polymorphisms with P < 1.00 × 10-6 were assessed for replication in 3 additional cohorts. Control participants were drawn from the cohorts of the Blue Mountains Eye Study and a previous study of glaucoma. Replication cohorts were from a previous keratoconus genome-wide association study data set from the United States, a cohort of affected and control participants from Australia and Northern Ireland, and a case-control cohort from Victoria, Australia. Data were collected from January 2006 to March 2019. Main Outcomes and Measures: Associations between keratoconus and 6 252 612 genetic variants were estimated using logistic regression after adjusting for ancestry using the first 3 principal components. Results: The discovery cohort included 522 affected individuals and 655 control participants, while the replication cohorts included 818 affected individuals (222 from the United States, 331 from Australia and Northern Ireland, and 265 from Victoria, Australia) and 3858 control participants (2927 from the United States, 229 from Australia and Northern Ireland, and 702 from Victoria, Australia). Two novel loci reached genome-wide significance (defined as P < 5.00 × 10-8), with a P value of 7.46 × 10-9 at rs61876744 in patatin-like phospholipase domain-containing 2 gene (PNPLA2) on chromosome 11 and a P value of 6.35 × 10-12 at rs138380, 2.2 kb upstream of casein kinase I isoform epsilon gene (CSNK1E) on chromosome 22. One additional locus was identified with a P value less than 1.00 × 10-6 in mastermind-like transcriptional coactivator 2 (MAML2) on chromosome 11 (P = 3.91 × 10-7). The novel locus in PNPLA2 reached genome-wide significance in an analysis of all 4 cohorts (P = 2.45 × 10-8). Conclusions and Relevance: In this relatively large keratoconus genome-wide association study, we identified a genome-wide significant locus for keratoconus in the region of PNPLA2 on chromosome 11.
Importance: Keratoconus is a condition in which the cornea progressively thins and protrudes in a conical shape, severely affecting refraction and vision. It is a major indication for corneal transplant. To discover new genetic loci associated with keratoconus and better understand the causative mechanism of this disease, we performed a genome-wide association study on patients with keratoconus. Objective: To identify genetic susceptibility regions for keratoconus in the human genome. Design, Setting, and Participants: This study was conducted with data from eye clinics in Australia, the United States, and Northern Ireland. The discovery cohort of individuals with keratoconus and control participants from Australia was genotyped using the Illumina HumanCoreExome single-nucleotide polymorphism array. After quality control and data cleaning, genotypes were imputed against the 1000 Genomes Project reference panel (phase III; version 5), and association analyses were completed using PLINK version 1.90. Single-nucleotide polymorphisms with P < 1.00 × 10-6 were assessed for replication in 3 additional cohorts. Control participants were drawn from the cohorts of the Blue Mountains Eye Study and a previous study of glaucoma. Replication cohorts were from a previous keratoconus genome-wide association study data set from the United States, a cohort of affected and control participants from Australia and Northern Ireland, and a case-control cohort from Victoria, Australia. Data were collected from January 2006 to March 2019. Main Outcomes and Measures: Associations between keratoconus and 6 252 612 genetic variants were estimated using logistic regression after adjusting for ancestry using the first 3 principal components. Results: The discovery cohort included 522 affected individuals and 655 control participants, while the replication cohorts included 818 affected individuals (222 from the United States, 331 from Australia and Northern Ireland, and 265 from Victoria, Australia) and 3858 control participants (2927 from the United States, 229 from Australia and Northern Ireland, and 702 from Victoria, Australia). Two novel loci reached genome-wide significance (defined as P < 5.00 × 10-8), with a P value of 7.46 × 10-9 at rs61876744 in patatin-like phospholipase domain-containing 2 gene (PNPLA2) on chromosome 11 and a P value of 6.35 × 10-12 at rs138380, 2.2 kb upstream of casein kinase I isoform epsilon gene (CSNK1E) on chromosome 22. One additional locus was identified with a P value less than 1.00 × 10-6 in mastermind-like transcriptional coactivator 2 (MAML2) on chromosome 11 (P = 3.91 × 10-7). The novel locus in PNPLA2 reached genome-wide significance in an analysis of all 4 cohorts (P = 2.45 × 10-8). Conclusions and Relevance: In this relatively large keratoconus genome-wide association study, we identified a genome-wide significant locus for keratoconus in the region of PNPLA2 on chromosome 11.
Authors: Dimitrios Karamichos; Paulina Escandon; Brenda Vasini; Sarah E Nicholas; Lyly Van; Deanna H Dang; Rebecca L Cunningham; Kamran M Riaz Journal: Prog Retin Eye Res Date: 2021-11-02 Impact factor: 19.704
Authors: Erik Fransen; Hanne Valgaeren; Katleen Janssens; Manou Sommen; Raphael De Ridder; Geert Vandeweyer; Luigi Bisceglia; Vincent Soler; Alexander Hoischen; Geert Mortier; François Malecaze; Carina Koppen; Guy Van Camp Journal: Eur J Hum Genet Date: 2021-03-19 Impact factor: 4.246
Authors: Petra Liskova; Yelena Bykhovskaya; Bennet J McComish; Alice E Davidson; Chris F Inglehearn; Alison J Hardcastle; Xiaohui Li; Hélène Choquet; Mahmoud Habeeb; Sionne E M Lucas; Srujana Sahebjada; Nikolas Pontikos; Karla E Rojas Lopez; Anthony P Khawaja; Manir Ali; Lubica Dudakova; Pavlina Skalicka; Bart T H Van Dooren; Annette J M Geerards; Christoph W Haudum; Valeria Lo Faro; Abi Tenen; Mark J Simcoe; Karina Patasova; Darioush Yarrand; Jie Yin; Salina Siddiqui; Aine Rice; Layal Abi Farraj; Yii-Der Ida Chen; Jugnoo S Rahi; Ronald M Krauss; Elisabeth Theusch; Jac C Charlesworth; Loretta Szczotka-Flynn; Carmel Toomes; Magda A Meester-Smoor; Andrea J Richardson; Paul A Mitchell; Kent D Taylor; Ronald B Melles; Anthony J Aldave; Richard A Mills; Ke Cao; Elsie Chan; Mark D Daniell; Jie Jin Wang; Jerome I Rotter; Alex W Hewitt; Stuart MacGregor; Caroline C W Klaver; Wishal D Ramdas; Jamie E Craig; Sudha K Iyengar; David O'Brart; Eric Jorgenson; Paul N Baird; Yaron S Rabinowitz; Kathryn P Burdon; Chris J Hammond; Stephen J Tuft; Pirro G Hysi Journal: Commun Biol Date: 2021-03-01
Authors: Liubov O Skorodumova; Alexandra V Belodedova; Elena I Sharova; Elena S Zakharova; Liliia N Iulmetova; Mukharram M Bikbov; Emin L Usubov; Olga P Antonova; Oksana V Selezneva; Anastasia Levchenko; Olga Yu Fedorenko; Svetlana A Ivanova; Raul R Gainetdinov; Boris E Malyugin Journal: BMC Ophthalmol Date: 2021-10-08 Impact factor: 2.209