Anita de Breuk1, Ilhan E Acar1, Eveline Kersten1, Mascha M V A P Schijvenaars2, Johanna M Colijn3, Lonneke Haer-Wigman4, Bjorn Bakker1, Sarah de Jong1, Magda A Meester-Smoor3, Timo Verzijden3, Tom O A R Missotten5, Jordi Monés6, Marc Biarnés6, Daniel Pauleikhoff7, Hans W Hense8, Rufino Silva9, Sandrina Nunes10, Joana B Melo11, Sascha Fauser12, Carel B Hoyng1, Marius Ueffing13, Marieke J H Coenen2, Caroline C W Klaver14, Anneke I den Hollander15. 1. Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands. 2. Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands. 3. Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. 4. Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. 5. The Rotterdam Eye Hospital, Rotterdam, The Netherlands. 6. Barcelona Macula Foundation, Barcelona, Spain; Institut de la Màcula, Barcelona, Spain. 7. Department of Ophthalmology, St. Franziskus Hospital, Münster, Germany. 8. Institute of Epidemiology and Social Medicine, Westfälische Wilhelms University, Münster, Germany. 9. Department of Ophthalmology, Centro Hospitalar e Universitário de Coimbra (CHUC), Coimbra, Portugal; Coimbra Institute for Clinical and Biomedical Research, Faculty of Medicine, University of Coimbra (iCBR-FMUC), Coimbra, Portugal; Association for Innovation and Biomedical Research on Light and Image (AIBILI), Coimbra, Portugal. 10. Association for Innovation and Biomedical Research on Light and Image (AIBILI), Coimbra, Portugal. 11. Cytogenetics and Genomics Laboratory, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; iCBR-CIMAGO, Center of Investigation on Environment, Genetics and Oncobiology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal. 12. Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany. 13. Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany. 14. Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands; Institute of Molecular and Clinical Ophthalmology, Basel, Switzerland. 15. Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: Anneke.denHollander@radboudumc.nl.
Abstract
PURPOSE: To develop a genotype assay to assess associations with common and rare age-related macular degeneration (AMD) risk variants, to calculate an overall genetic risk score (GRS), and to identify potential misdiagnoses with inherited macular dystrophies that mimic AMD. DESIGN: Case-control study. PARTICIPANTS: Individuals (n = 4740) from 5 European cohorts. METHODS: We designed single-molecule molecular inversion probes for target selection and used next generation sequencing to sequence 87 single nucleotide polymorphisms (SNPs), coding and splice-site regions of 10 AMD-(related) genes (ARMS2, C3, C9, CD46, CFB, CFH, CFI, HTRA1, TIMP3, and SLC16A8), and 3 genes that cause inherited macular dystrophies (ABCA4, CTNNA1, and PRPH2). Genetic risk scores for common AMD risk variants were calculated based on effect size and genotype of 52 AMD-associated variants. Frequency of rare variants was compared between late AMD patients and control individuals with logistic regression analysis. MAIN OUTCOME MEASURES: Genetic risk score, association of genetic variants with AMD, and genotype-phenotype correlations. RESULTS: We observed high concordance rates between our platform and other genotyping platforms for the 69 successfully genotyped SNPs (>96%) and for the rare variants (>99%). We observed a higher GRS for patients with late AMD compared with patients with early/intermediate AMD (P < 0.001) and individuals without AMD (P < 0.001). A higher proportion of pathogenic variants in the CFH (odds ratio [OR] = 2.88; P = 0.006), CFI (OR = 4.45; P = 0.005), and C3 (OR = 6.56; P = 0.0003) genes was observed in late AMD patients compared with control individuals. In 9 patients, we identified pathogenic variants in the PRPH2, ABCA4, and CTNNA1 genes, which allowed reclassification of these patients as having inherited macular dystrophy. CONCLUSIONS: This study reports a genotype assay for common and rare AMD genetic variants, which can identify individuals at intermediate to high genetic risk of late AMD and enables differential diagnosis of AMD-mimicking dystrophies. Our study supports sequencing of CFH, CFI, and C3 genes because they harbor rare high-risk variants. Carriers of these variants could be amendable for new treatments for AMD that currently are under development.
PURPOSE: To develop a genotype assay to assess associations with common and rare age-related macular degeneration (AMD) risk variants, to calculate an overall genetic risk score (GRS), and to identify potential misdiagnoses with inherited macular dystrophies that mimic AMD. DESIGN: Case-control study. PARTICIPANTS: Individuals (n = 4740) from 5 European cohorts. METHODS: We designed single-molecule molecular inversion probes for target selection and used next generation sequencing to sequence 87 single nucleotide polymorphisms (SNPs), coding and splice-site regions of 10 AMD-(related) genes (ARMS2, C3, C9, CD46, CFB, CFH, CFI, HTRA1, TIMP3, and SLC16A8), and 3 genes that cause inherited macular dystrophies (ABCA4, CTNNA1, and PRPH2). Genetic risk scores for common AMD risk variants were calculated based on effect size and genotype of 52 AMD-associated variants. Frequency of rare variants was compared between late AMDpatients and control individuals with logistic regression analysis. MAIN OUTCOME MEASURES: Genetic risk score, association of genetic variants with AMD, and genotype-phenotype correlations. RESULTS: We observed high concordance rates between our platform and other genotyping platforms for the 69 successfully genotyped SNPs (>96%) and for the rare variants (>99%). We observed a higher GRS for patients with late AMD compared with patients with early/intermediate AMD (P < 0.001) and individuals without AMD (P < 0.001). A higher proportion of pathogenic variants in the CFH (odds ratio [OR] = 2.88; P = 0.006), CFI (OR = 4.45; P = 0.005), and C3 (OR = 6.56; P = 0.0003) genes was observed in late AMDpatients compared with control individuals. In 9 patients, we identified pathogenic variants in the PRPH2, ABCA4, and CTNNA1 genes, which allowed reclassification of these patients as having inherited macular dystrophy. CONCLUSIONS: This study reports a genotype assay for common and rare AMD genetic variants, which can identify individuals at intermediate to high genetic risk of late AMD and enables differential diagnosis of AMD-mimicking dystrophies. Our study supports sequencing of CFH, CFI, and C3 genes because they harbor rare high-risk variants. Carriers of these variants could be amendable for new treatments for AMD that currently are under development.
Authors: Amy V Jones; Darin Curtiss; Claire Harris; Tom Southerington; Marco Hautalahti; Pauli Wihuri; Johanna Mäkelä; Roosa E Kallionpää; Enni Makkonen; Theresa Knopp; Arto Mannermaa; Erna Mäkinen; Anne-Mari Moilanen; Tongalp H Tezel; Nadia K Waheed Journal: PLoS One Date: 2022-09-06 Impact factor: 3.752
Authors: Manon H C A Peeters; Mubeen Khan; Anoek A M B Rooijakkers; Timo Mulders; Lonneke Haer-Wigman; Camiel J F Boon; Caroline C W Klaver; L Ingeborgh van den Born; Carel B Hoyng; Frans P M Cremers; Anneke I den Hollander; Claire-Marie Dhaenens; Rob W J Collin Journal: Hum Mutat Date: 2021-09-20 Impact factor: 4.700
Authors: Yiming Li; Jaro Karppinen; Kathryn S E Cheah; Danny Chan; Pak C Sham; Dino Samartzis Journal: Eur Spine J Date: 2021-09-25 Impact factor: 3.134
Authors: Sarah de Jong; Anita de Breuk; Elena B Volokhina; Bjorn Bakker; Alejandro Garanto; Sascha Fauser; Suresh Katti; Carel B Hoyng; Yara T E Lechanteur; Lambert P van den Heuvel; Anneke I den Hollander Journal: Hum Mol Genet Date: 2022-02-03 Impact factor: 6.150
Authors: Eszter Emri; Elod Kortvely; Sascha Dammeier; Franziska Klose; David Simpson; Eye-Risk Consortium; Anneke I Den Hollander; Marius Ueffing; Imre Lengyel Journal: Nutrients Date: 2020-10-06 Impact factor: 5.717
Authors: Esther Willems; Laura Lorés-Motta; Andrea Zanichelli; Chiara Suffritti; Michiel van der Flier; Renate G van der Molen; Jeroen D Langereis; Joris van Drongelen; Lambert P van den Heuvel; Elena Volokhina; Nicole Caj van de Kar; Jenneke Keizer-Garritsen; Michael Levin; Jethro A Herberg; Federico Martinon-Torres; Hans Jtc Wessels; Anita de Breuk; Sascha Fauser; Carel B Hoyng; Anneke I den Hollander; Ronald de Groot; Alain J van Gool; Jolein Gloerich; Marien I de Jonge Journal: Clin Transl Immunology Date: 2020-12-09
Authors: Thomas J Heesterbeek; Mansour Rouhi-Parkouhi; Stephanie J Church; Yara T Lechanteur; Laura Lorés-Motta; Nikolaos Kouvatsos; Simon J Clark; Paul N Bishop; Carel B Hoyng; Anneke I den Hollander; Richard D Unwin; Anthony J Day Journal: Exp Eye Res Date: 2020-10-21 Impact factor: 3.467