Development of a Genotype Assay for Age-Related Macular Degeneration: The EYE-RISK Consortium

Anita de Breuk; Ilhan E. Acar; Eveline Kersten; Mascha M.V.A.P. Schijvenaars; Johanna M. Colijn; Lonneke Haer-Wigman; Bjorn Bakker; Sarah de Jong; Magda Meester-Smoor; Timo Verzijden; Tom O.A.R. Missotten; Jordi Monés; Marc Biarnés; Daniel Pauleikhoff; Hans W. Hense; Rufino Silva; Sandrina Nunes; Joana B. Melo; Sascha Fauser; Carel B. Hoyng; Marius Ueffing; Marieke J.H. Coenen; Caroline C.W. Klaver; Anneke I. den Hollander; Soufiane Ajana; Blanca Arango-Gonzalez; Franz Badura; Berta De la Cerda; Marc Biarnés; Anna Borrell; Johanna M. Colijn; Audrey Cougnard-Grégoire; Sascha Dammeier; Eiko K. de Jong; Cécile Delcourt; Anneke I. den Hollander; Sigrid Diether; Eszter Emri; Tanja Endermann; Lucia L. Ferraro; Míriam Garcia; Thomas J. Heesterbeek; Sabina Honisch; A. Ikram; Eveline Kersten; Ellen Kilger; Caroline C.W. Klaver; Hanno Langen; Imre Lengyel; Phil Luthert; Magda Meester-Smoor; Bénédicte M.J. Merle; Jordi Monés; Everson Nogoceke; Tunde Peto; Frances M. Pool; Eduardo Rodríguez; Marius Ueffing; Timo Verzijden; Johannes Vingerling; Markus Zumbansen

doi:10.1016/j.ophtha.2020.07.037

Development of a Genotype Assay for Age-Related Macular Degeneration: The EYE-RISK Consortium

Anita de Breuk, Ilhan E. Acar, Eveline Kersten, Mascha M.V.A.P. Schijvenaars, Johanna M. Colijn, Lonneke Haer-Wigman, Bjorn Bakker, Sarah de Jong, Magda Meester-Smoor, Timo Verzijden, Tom O.A.R. Missotten, Jordi Monés, Marc Biarnés, Daniel Pauleikhoff, Hans W. Hense, Rufino Silva, Sandrina Nunes, Joana B. Melo, Sascha Fauser, Carel B. HoyngMarius Ueffing, Marieke J.H. Coenen, Caroline C.W. Klaver, Anneke I. den Hollander, Soufiane Ajana, Blanca Arango-Gonzalez, Franz Badura, Berta De la Cerda, Marc Biarnés, Anna Borrell, Johanna M. Colijn, Audrey Cougnard-Grégoire, Sascha Dammeier, Eiko K. de Jong, Cécile Delcourt, Anneke I. den Hollander, Sigrid Diether, Eszter Emri, Tanja Endermann, Lucia L. Ferraro, Míriam Garcia, Thomas J. Heesterbeek, Sabina Honisch, A. Ikram, Eveline Kersten, Ellen Kilger, Caroline C.W. Klaver, Hanno Langen, Imre Lengyel, Phil Luthert, Magda Meester-Smoor, Bénédicte M.J. Merle, Jordi Monés, Everson Nogoceke, Tunde Peto, Frances M. Pool, Eduardo Rodríguez, Marius Ueffing, Timo Verzijden, Johannes Vingerling, Markus Zumbansen

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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.

Original language	English
Pages (from-to)	1604-1617
Journal	Ophthalmology
Volume	128
Issue number	11
Early online date	25 Jul 2020
DOIs	https://doi.org/10.1016/j.ophtha.2020.07.037
Publication status	Published - Nov 2021

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Development of a Genotype Assay for Age-Related Macular Degeneration: The EYE-RISK Consortium
© 2020 The Authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 2.32 MBLicence: CC BY

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de Breuk, A., Acar, I. E., Kersten, E., Schijvenaars, M. M. V. A. P., Colijn, J. M., Haer-Wigman, L., Bakker, B., de Jong, S., Meester-Smoor, M., Verzijden, T., Missotten, T. O. A. R., Monés, J., Biarnés, M., Pauleikhoff, D., Hense, H. W., Silva, R., Nunes, S., Melo, J. B., Fauser, S., ... Zumbansen, M. (2021). Development of a Genotype Assay for Age-Related Macular Degeneration: The EYE-RISK Consortium. Ophthalmology, 128(11), 1604-1617. https://doi.org/10.1016/j.ophtha.2020.07.037

@article{07e4ac17e5964d92b33793246941cb7a,

title = "Development of a Genotype Assay for Age-Related Macular Degeneration: The EYE-RISK Consortium",

abstract = "PurposeTo 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.DesignCase-control study.ParticipantsIndividuals (n = 4740) from 5 European cohorts.MethodsWe 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 MeasuresGenetic risk score, association of genetic variants with AMD, and genotype–phenotype correlations.ResultsWe 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.ConclusionsThis 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.",

author = "{de Breuk}, Anita and Acar, {Ilhan E.} and Eveline Kersten and Schijvenaars, {Mascha M.V.A.P.} and Colijn, {Johanna M.} and Lonneke Haer-Wigman and Bjorn Bakker and {de Jong}, Sarah and Magda Meester-Smoor and Timo Verzijden and Missotten, {Tom O.A.R.} and Jordi Mon{\'e}s and Marc Biarn{\'e}s and Daniel Pauleikhoff and Hense, {Hans W.} and Rufino Silva and Sandrina Nunes and Melo, {Joana B.} and Sascha Fauser and Hoyng, {Carel B.} and Marius Ueffing and Coenen, {Marieke J.H.} and Klaver, {Caroline C.W.} and {den Hollander}, {Anneke I.} and Soufiane Ajana and Blanca Arango-Gonzalez and Franz Badura and {De la Cerda}, Berta and Marc Biarn{\'e}s and Anna Borrell and Colijn, {Johanna M.} and Audrey Cougnard-Gr{\'e}goire and Sascha Dammeier and {de Jong}, {Eiko K.} and C{\'e}cile Delcourt and {den Hollander}, {Anneke I.} and Sigrid Diether and Eszter Emri and Tanja Endermann and Ferraro, {Lucia L.} and M{\'i}riam Garcia and Heesterbeek, {Thomas J.} and Sabina Honisch and A. Ikram and Eveline Kersten and Ellen Kilger and Klaver, {Caroline C.W.} and Hanno Langen and Imre Lengyel and Phil Luthert and Magda Meester-Smoor and Merle, {B{\'e}n{\'e}dicte M.J.} and Jordi Mon{\'e}s and Everson Nogoceke and Tunde Peto and Pool, {Frances M.} and Eduardo Rodr{\'i}guez and Marius Ueffing and Timo Verzijden and Johannes Vingerling and Markus Zumbansen",

year = "2021",

month = nov,

doi = "10.1016/j.ophtha.2020.07.037",

language = "English",

volume = "128",

pages = " 1604--1617",

journal = "Ophthalmology",

issn = "0161-6420",

publisher = "Elsevier Inc.",

number = "11",

}

de Breuk, A, Acar, IE, Kersten, E, Schijvenaars, MMVAP, Colijn, JM, Haer-Wigman, L, Bakker, B, de Jong, S, Meester-Smoor, M, Verzijden, T, Missotten, TOAR, Monés, J, Biarnés, M, Pauleikhoff, D, Hense, HW, Silva, R, Nunes, S, Melo, JB, Fauser, S, Hoyng, CB, Ueffing, M, Coenen, MJH, Klaver, CCW, den Hollander, AI, Ajana, S, Arango-Gonzalez, B, Badura, F, De la Cerda, B, Biarnés, M, Borrell, A, Colijn, JM, Cougnard-Grégoire, A, Dammeier, S, de Jong, EK, Delcourt, C, den Hollander, AI, Diether, S, Emri, E, Endermann, T, Ferraro, LL, Garcia, M, Heesterbeek, TJ, Honisch, S, Ikram, A, Kersten, E, Kilger, E, Klaver, CCW, Langen, H, Lengyel, I, Luthert, P, Meester-Smoor, M, Merle, BMJ, Monés, J, Nogoceke, E, Peto, T, Pool, FM, Rodríguez, E, Ueffing, M, Verzijden, T, Vingerling, J & Zumbansen, M 2021, 'Development of a Genotype Assay for Age-Related Macular Degeneration: The EYE-RISK Consortium', Ophthalmology, vol. 128, no. 11, pp. 1604-1617. https://doi.org/10.1016/j.ophtha.2020.07.037

TY - JOUR

T1 - Development of a Genotype Assay for Age-Related Macular Degeneration: 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

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 - Ajana, Soufiane

AU - Arango-Gonzalez, Blanca

AU - Badura, Franz

AU - De la Cerda, Berta

AU - Biarnés, Marc

AU - Borrell, Anna

AU - Colijn, Johanna M.

AU - Cougnard-Grégoire, Audrey

AU - Dammeier, Sascha

AU - de Jong, Eiko K.

AU - Delcourt, Cécile

AU - den Hollander, Anneke I.

AU - Diether, Sigrid

AU - Emri, Eszter

AU - Endermann, Tanja

AU - Ferraro, Lucia L.

AU - Garcia, Míriam

AU - Heesterbeek, Thomas J.

AU - Honisch, Sabina

AU - Ikram, A.

AU - Kersten, Eveline

AU - Kilger, Ellen

AU - Klaver, Caroline C.W.

AU - Langen, Hanno

AU - Lengyel, Imre

AU - Luthert, Phil

AU - Meester-Smoor, Magda

AU - Merle, Bénédicte M.J.

AU - Monés, Jordi

AU - Nogoceke, Everson

AU - Peto, Tunde

AU - Pool, Frances M.

AU - Rodríguez, Eduardo

AU - Ueffing, Marius

AU - Verzijden, Timo

AU - Vingerling, Johannes

AU - Zumbansen, Markus

PY - 2021/11

Y1 - 2021/11

N2 - PurposeTo 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.DesignCase-control study.ParticipantsIndividuals (n = 4740) from 5 European cohorts.MethodsWe 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 MeasuresGenetic risk score, association of genetic variants with AMD, and genotype–phenotype correlations.ResultsWe 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.ConclusionsThis 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 - PurposeTo 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.DesignCase-control study.ParticipantsIndividuals (n = 4740) from 5 European cohorts.MethodsWe 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 MeasuresGenetic risk score, association of genetic variants with AMD, and genotype–phenotype correlations.ResultsWe 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.ConclusionsThis 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.

U2 - 10.1016/j.ophtha.2020.07.037

DO - 10.1016/j.ophtha.2020.07.037

M3 - Article

SN - 0161-6420

VL - 128

SP - 1604

EP - 1617

JO - Ophthalmology

JF - Ophthalmology

IS - 11

ER -

Development of a Genotype Assay for Age-Related Macular Degeneration: The EYE-RISK Consortium

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