Universität zu Köln

de Breuk, Anita ORCID: 0000-0001-7072-1928, Acar, Ilhan E., Kersten, Eveline, Schijvenaars, Mascha M. V. A. P., Colijn, Johanna M., Haer-Wigman, Lonneke, Bakker, Bjorn, de Jong, Sarah ORCID: 0000-0002-3705-3371, Meester-Smoor, Magda A., Verzijden, Timo, Missotten, Tom O. A. R., Mones, Jordi, Biarnes, Marc, Pauleikhoff, Daniel, Hense, Hans W., Silva, Rufino ORCID: 0000-0001-8676-0833, Nunes, Sandrina, Melo, Joana B., Fauser, Sascha, Hoyng, Carel B., Ueffing, Marius, Coenen, Marieke J. H., Klaver, Caroline C. W. and den Hollander, Anneke, I (2021). Development of a Genotype Assay for Age-Related Macular Degeneration The EYE-RISK Consortium. Ophthalmology, 128 (11). S. 1604 - 1618. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1549-4713

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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. (C) 2020 by the American Academy of Ophthalmology.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code de Breuk, Anita UNSPECIFIED orcid.org/0000-0001-7072-1928 UNSPECIFIED Acar, Ilhan E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kersten, Eveline UNSPECIFIED UNSPECIFIED UNSPECIFIED Schijvenaars, Mascha M. V. A. P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Colijn, Johanna M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Haer-Wigman, Lonneke UNSPECIFIED UNSPECIFIED UNSPECIFIED Bakker, Bjorn UNSPECIFIED UNSPECIFIED UNSPECIFIED de Jong, Sarah UNSPECIFIED orcid.org/0000-0002-3705-3371 UNSPECIFIED Meester-Smoor, Magda A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Verzijden, Timo UNSPECIFIED UNSPECIFIED UNSPECIFIED Missotten, Tom O. A. R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mones, Jordi UNSPECIFIED UNSPECIFIED UNSPECIFIED Biarnes, Marc UNSPECIFIED UNSPECIFIED UNSPECIFIED Pauleikhoff, Daniel UNSPECIFIED UNSPECIFIED UNSPECIFIED Hense, Hans W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Silva, Rufino UNSPECIFIED orcid.org/0000-0001-8676-0833 UNSPECIFIED Nunes, Sandrina UNSPECIFIED UNSPECIFIED UNSPECIFIED Melo, Joana B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fauser, Sascha UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoyng, Carel B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ueffing, Marius UNSPECIFIED UNSPECIFIED UNSPECIFIED Coenen, Marieke J. H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Klaver, Caroline C. W. UNSPECIFIED UNSPECIFIED UNSPECIFIED den Hollander, Anneke, I UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-601736
DOI:	10.1016/j.ophtha.2020.07.037
Journal or Publication Title:	Ophthalmology
Volume:	128
Number:	11
Page Range:	S. 1604 - 1618
Date:	2021
Publisher:	ELSEVIER SCIENCE INC
Place of Publication:	NEW YORK
ISSN:	1549-4713
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language RARE GENETIC-VARIANTS; STARGARDT-DISEASE; CFI GENE; MUTATIONS; DYSTROPHY; ABCR; ASSOCIATION; PREVALENCE; FAMILIES; DRUSEN Multiple languages Ophthalmology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/60173