Development of a Genotype Assay for Age-Related Macular Degeneration : The EYE-RISK Consortium
Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved..
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.
| Errataetall: |
CommentIn: Ophthalmology. 2021 Nov;128(11):1618-1619. - PMID 34688431 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:128 |
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| Enthalten in: |
Ophthalmology - 128(2021), 11 vom: 25. Nov., Seite 1604-1617 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
de Breuk, Anita [VerfasserIn] |
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| Links: |
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| Themen: |
9007-49-2 |
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| Anmerkungen: |
Date Completed 22.11.2021 Date Revised 22.11.2021 published: Print-Electronic CommentIn: Ophthalmology. 2021 Nov;128(11):1618-1619. - PMID 34688431 Citation Status MEDLINE |
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| doi: |
10.1016/j.ophtha.2020.07.037 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Development of a Genotype Assay for Age-Related Macular Degeneration |b The EYE-RISK Consortium |
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| 500 | |a Date Completed 22.11.2021 | ||
| 500 | |a Date Revised 22.11.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a CommentIn: Ophthalmology. 2021 Nov;128(11):1618-1619. - PMID 34688431 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a 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 | ||
| 520 | |a DESIGN: Case-control study | ||
| 520 | |a PARTICIPANTS: Individuals (n = 4740) from 5 European cohorts | ||
| 520 | |a 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 | ||
| 520 | |a MAIN OUTCOME MEASURES: Genetic risk score, association of genetic variants with AMD, and genotype-phenotype correlations | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Multicenter Study | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Age-related macular degeneration | |
| 650 | 4 | |a Genetic counseling | |
| 650 | 4 | |a Genetic testing | |
| 650 | 4 | |a Genetics | |
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| 700 | 1 | |a Verzijden, Timo |e verfasserin |4 aut | |
| 700 | 1 | |a Missotten, Tom O A R |e verfasserin |4 aut | |
| 700 | 1 | |a Monés, Jordi |e verfasserin |4 aut | |
| 700 | 1 | |a Biarnés, Marc |e verfasserin |4 aut | |
| 700 | 1 | |a Pauleikhoff, Daniel |e verfasserin |4 aut | |
| 700 | 1 | |a Hense, Hans W |e verfasserin |4 aut | |
| 700 | 1 | |a Silva, Rufino |e verfasserin |4 aut | |
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| 700 | 1 | |a Ueffing, Marius |e verfasserin |4 aut | |
| 700 | 1 | |a Coenen, Marieke J H |e verfasserin |4 aut | |
| 700 | 1 | |a Klaver, Caroline C W |e verfasserin |4 aut | |
| 700 | 1 | |a den Hollander, Anneke I |e verfasserin |4 aut | |
| 700 | 0 | |a EYE-RISK Consortium |e verfasserin |4 aut | |
| 700 | 1 | |a Ajana, Soufiane |e investigator |4 oth | |
| 700 | 1 | |a Cougnard-Grégoire, Audrey |e investigator |4 oth | |
| 700 | 1 | |a Delcourt, Cécile |e investigator |4 oth | |
| 700 | 1 | |a Merle, Bénédicte M J |e investigator |4 oth | |
| 700 | 1 | |a Arango-Gonzalez, Blanca |e investigator |4 oth | |
| 700 | 1 | |a Dammeier, Sascha |e investigator |4 oth | |
| 700 | 1 | |a Diether, Sigrid |e investigator |4 oth | |
| 700 | 1 | |a Honisch, Sabina |e investigator |4 oth | |
| 700 | 1 | |a Kilger, Ellen |e investigator |4 oth | |
| 700 | 1 | |a Ueffing, Marius |e investigator |4 oth | |
| 700 | 1 | |a Endermann, Tanja |e investigator |4 oth | |
| 700 | 1 | |a Zumbansen, Markus |e investigator |4 oth | |
| 700 | 1 | |a Badura, Franz |e investigator |4 oth | |
| 700 | 1 | |a De la Cerda, Berta |e investigator |4 oth | |
| 700 | 1 | |a Biarnés, Marc |e investigator |4 oth | |
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| 700 | 1 | |a Ferraro, Lucia L |e investigator |4 oth | |
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