TY - JOUR
T1 - Development of a Genotype Assay for Age-Related Macular Degeneration
T2 - The EYE-RISK Consortium
AU - de Breuk, Anita
AU - Acar, Ilhan E
AU - Kersten, Eveline
AU - Schijvenaars, Mascha M V A P
AU - Colijn, Johanna M
AU - Haer-Wigman, Lonneke
AU - Bakker, Bjorn
AU - de Jong, Sarah
AU - Meester-Smoor, Magda A
AU - Verzijden, Timo
AU - Missotten, Tom O A R
AU - Monés, Jordi
AU - Biarnés, Marc
AU - Pauleikhoff, Daniel
AU - Hense, Hans W
AU - Silva, Rufino
AU - Nunes, Sandrina
AU - Melo, Joana B
AU - Fauser, Sascha
AU - Hoyng, Carel B
AU - Ueffing, Marius
AU - Coenen, Marieke J H
AU - Klaver, Caroline C W
AU - den Hollander, Anneke I
N1 - Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.
PY - 2021/11
Y1 - 2021/11
N2 - 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.
AB - 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.
UR - https://www.mendeley.com/catalogue/41058295-9b40-3e76-90ae-876449178d5a/
U2 - 10.1016/j.ophtha.2020.07.037
DO - 10.1016/j.ophtha.2020.07.037
M3 - Article
C2 - 32717343
SN - 0161-6420
VL - 128
SP - 1604
EP - 1617
JO - Ophthalmology
JF - Ophthalmology
IS - 11
ER -