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 - EYE-RISK Consortium
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.
AU - Ikram, A.
AU - Vingerling, Johannes
N1 - Funding Information:
Supported by the Dutch Organization for Scientific Research (grant no.: 016.Vici.170.024 [A.I.d.H.]); the European Union Horizon 2020 Research and Innovation Programme (grant no.: 634479 [EYE-RISK]); F. Hoffmann-La Roche, Ltd., Basel, Switzerland. The sponsor or funding organizations had no role in the design or conduct of this research.
Publisher Copyright: © 2020 American Academy of Ophthalmology
PY - 2021/11/1
Y1 - 2021/11/1
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 - http://www.scopus.com/inward/record.url?scp=85090061789&partnerID=8YFLogxK
U2 - 10.1016/j.ophtha.2020.07.037
DO - 10.1016/j.ophtha.2020.07.037
M3 - Article
C2 - 32717343
AN - SCOPUS:85090061789
SN - 0161-6420
VL - 128
SP - 1604
EP - 1617
JO - Ophthalmology
JF - Ophthalmology
IS - 11
ER -