AustralieFrV1, Main, Exploration, bibRecord, 005357

Heritability and Genome-wide Association Study To Assess Genetic Differences Between Advanced Age-Related Macular Degeneration Subtypes

Identifieur interne : 005357 ( Main/Exploration ); précédent : 005356; suivant : 005358

Heritability and Genome-wide Association Study To Assess Genetic Differences Between Advanced Age-Related Macular Degeneration Subtypes

Auteurs : Lucia Sobrin [États-Unis] ; Stephan Ripke [États-Unis] ; Yi Yu [États-Unis] ; Jesen Fagerness [États-Unis] ; Tushar R. Bhangale [États-Unis] ; Perciliz L. Tan [États-Unis] ; Eric H. Souied [France] ; Gabriëlle H. S. Buitendijk [Pays-Bas] ; Joanna E. Merriam [États-Unis] ; Andrea J. Richardson [Australie] ; Soumya Raychaudhuri [États-Unis] ; Robyn Reynolds [États-Unis] ; Kimberly A. Chin [États-Unis] ; Aaron Y. Lee [États-Unis] ; Nicolas Leveziel [France] ; Donald J. Zack [États-Unis, France] ; Peter Campochiaro [États-Unis] ; R. Theodore Smith [États-Unis] ; Gaetano R. Barile [États-Unis] ; Ruth E. Hogg ; Usha Chakravarthy ; Timothy W. Behrens [États-Unis] ; André G. Uitterlinden [Pays-Bas] ; Cornelia M. Van Duijn [Pays-Bas] ; Johannes R. Vingerling [Pays-Bas] ; Milam A. Brantley [États-Unis] ; Paul N. Baird [Australie] ; Caroline C. W. Klaver [Pays-Bas] ; Rando Allikmets [États-Unis] ; Nicholas Katsanis [États-Unis] ; Robert R. Graham [États-Unis] ; John P. A. Ioannidis [Grèce, États-Unis] ; Mark J. Daly [États-Unis] ; Johanna M. Seddon [États-Unis]

Source :

Ophthalmology [ 0161-6420 ] ; 2012.

RBID : PMC:3899891

Abstract

Purpose

To investigate whether the two subtypes of advanced age-related macular degeneration (AMD), choroidal neovascularization (CNV) and geographic atrophy (GA), segregate separately in families and to identify which genetic variants are associated with these two subtypes.

Design

Sibling correlation study and genome-wide association study (GWAS)

Participants

For the sibling correlation study, we included 209 sibling pairs with advanced AMD. For the GWAS, we included 2594 participants with advanced AMD subtypes and 4134 controls. Replication cohorts included 5383 advanced AMD participants and 15,240 controls.

Methods

Participants had AMD grade assigned based on fundus photography and/or examination. To determine heritability of advanced AMD subtypes, we performed a sibling correlation study. For the GWAS, we conducted genome-wide genotyping and imputed 6,036,699 single nucleotide polymorphism (SNPs). We then analyzed SNPs with a generalized linear model controlling for genotyping platform and genetic ancestry. The most significant associations were evaluated in independent cohorts.

Main Outcome Measures

Concordance of advanced AMD subtypes in sibling pairs and associations between SNPs with GA and CNV advanced AMD subtypes.

Results

The difference between the observed and expected proportion of siblings concordant for the same subtype of advanced AMD was different to a statistically significant degree (P=4.2 x 10⁻⁵) meaning that siblings of probands with CNV or GA are more likely to develop CNV or GA, respectively. In the analysis comparing participants with CNV to those with GA, we observed a statistically significant association at the ARMS2/HTRA1 locus [rs10490924, odds ratio (OR)=1.47, P=4.3 ×10⁻⁹] which was confirmed in the replication samples (OR=1.38, P=7.4 x 10⁻¹⁴ for combined discovery and replication analysis).

Conclusions

Whether a patient with AMD develops CNV vs. GA is determined in part by genetic variation. In this large GWAS meta-analysis and replication analysis, the ARMS2/HTRA1 locus confers increased risk for both advanced AMD subtypes but imparts greater risk for CNV than for GA. This locus explains a small proportion of the excess sibling correlation for advanced AMD subtype. Other loci were detected with suggestive associations which differ for advanced AMD subtypes and deserve follow-up in additional studies.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3899891

DOI: 10.1016/j.ophtha.2012.03.014
PubMed: 22705344
PubMed Central: 3899891

Affiliations:

Le document en format XML

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<author><name sortKey="Raychaudhuri, Soumya" sort="Raychaudhuri, Soumya" uniqKey="Raychaudhuri S" first="Soumya" last="Raychaudhuri">Soumya Raychaudhuri</name>
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<author><name sortKey="Chin, Kimberly A" sort="Chin, Kimberly A" uniqKey="Chin K" first="Kimberly A." last="Chin">Kimberly A. Chin</name>
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<author><name sortKey="Lee, Aaron Y" sort="Lee, Aaron Y" uniqKey="Lee A" first="Aaron Y." last="Lee">Aaron Y. Lee</name>
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<author><name sortKey="Leveziel, Nicolas" sort="Leveziel, Nicolas" uniqKey="Leveziel N" first="Nicolas" last="Leveziel">Nicolas Leveziel</name>
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<country xml:lang="fr">France</country>
<wicri:regionArea>Department of Ophthalmology, University Paris Est Creteil, Hopital Intercommunal de Creteil, Creteil, 94000</wicri:regionArea>
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</placeName>
</affiliation>
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<affiliation wicri:level="2"><nlm:aff id="A14">Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205</nlm:aff>
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<placeName><region type="state">Maryland</region>
</placeName>
<wicri:cityArea>Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore</wicri:cityArea>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="A15">Department of Molecular Biology and Genetics and Institut de la Vision, UPMC, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Department of Molecular Biology and Genetics and Institut de la Vision, UPMC, Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
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</affiliation>
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<author><name sortKey="Campochiaro, Peter" sort="Campochiaro, Peter" uniqKey="Campochiaro P" first="Peter" last="Campochiaro">Peter Campochiaro</name>
<affiliation wicri:level="2"><nlm:aff id="A13">McKusick-Nathans Institute of Genetic Medicine, Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Maryland</region>
</placeName>
<wicri:cityArea>McKusick-Nathans Institute of Genetic Medicine, Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore</wicri:cityArea>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="A14">Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Maryland</region>
</placeName>
<wicri:cityArea>Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Smith, R Theodore" sort="Smith, R Theodore" uniqKey="Smith R" first="R. Theodore" last="Smith">R. Theodore Smith</name>
<affiliation wicri:level="4"><nlm:aff id="A9">Department of Ophthalmology, Columbia University, New York, NY, 10032</nlm:aff>
<orgName type="university">Université Columbia</orgName>
<country>États-Unis</country>
<placeName><settlement type="city">New York</settlement>
<region type="state">État de New York</region>
</placeName>
</affiliation>
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<author><name sortKey="Barile, Gaetano R" sort="Barile, Gaetano R" uniqKey="Barile G" first="Gaetano R." last="Barile">Gaetano R. Barile</name>
<affiliation wicri:level="4"><nlm:aff id="A9">Department of Ophthalmology, Columbia University, New York, NY, 10032</nlm:aff>
<orgName type="university">Université Columbia</orgName>
<country>États-Unis</country>
<placeName><settlement type="city">New York</settlement>
<region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Hogg, Ruth E" sort="Hogg, Ruth E" uniqKey="Hogg R" first="Ruth E." last="Hogg">Ruth E. Hogg</name>
<affiliation><nlm:aff id="A16">Center for Vision and Vascular Science,The Queen’s University, Belfast, Northern Ireland.</nlm:aff>
<wicri:noCountry code="subfield">Northern Ireland.</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Chakravarthy, Usha" sort="Chakravarthy, Usha" uniqKey="Chakravarthy U" first="Usha" last="Chakravarthy">Usha Chakravarthy</name>
<affiliation><nlm:aff id="A16">Center for Vision and Vascular Science,The Queen’s University, Belfast, Northern Ireland.</nlm:aff>
<wicri:noCountry code="subfield">Northern Ireland.</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Behrens, Timothy W" sort="Behrens, Timothy W" uniqKey="Behrens T" first="Timothy W." last="Behrens">Timothy W. Behrens</name>
<affiliation wicri:level="2"><nlm:aff id="A17">ITGR Human Genetics Group, Genentech Inc, South San Francisco, CA 94080</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Californie</region>
</placeName>
<wicri:cityArea>ITGR Human Genetics Group, Genentech Inc, South San Francisco</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Uitterlinden, Andre G" sort="Uitterlinden, Andre G" uniqKey="Uitterlinden A" first="André G." last="Uitterlinden">André G. Uitterlinden</name>
<affiliation wicri:level="3"><nlm:aff id="A18">Department Epidemiology, Department Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Pays-Bas</country>
<wicri:regionArea>Department Epidemiology, Department Internal Medicine, Erasmus Medical Center, Rotterdam</wicri:regionArea>
<placeName><settlement type="city">Rotterdam</settlement>
<region nuts="2" type="province">Hollande-Méridionale</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Van Duijn, Cornelia M" sort="Van Duijn, Cornelia M" uniqKey="Van Duijn C" first="Cornelia M." last="Van Duijn">Cornelia M. Van Duijn</name>
<affiliation wicri:level="1"><nlm:aff id="A19">Department Epidemiology, Erasmus Medical Center Rotterdam, the Netherlands</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Pays-Bas</country>
<wicri:regionArea>Department Epidemiology, Erasmus Medical Center Rotterdam</wicri:regionArea>
<wicri:noRegion>Erasmus Medical Center Rotterdam</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Vingerling, Johannes R" sort="Vingerling, Johannes R" uniqKey="Vingerling J" first="Johannes R." last="Vingerling">Johannes R. Vingerling</name>
<affiliation wicri:level="3"><nlm:aff id="A8">Department Ophthalmology, Department Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Pays-Bas</country>
<wicri:regionArea>Department Ophthalmology, Department Epidemiology, Erasmus Medical Center, Rotterdam</wicri:regionArea>
<placeName><settlement type="city">Rotterdam</settlement>
<region nuts="2" type="province">Hollande-Méridionale</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Brantley, Milam A" sort="Brantley, Milam A" uniqKey="Brantley M" first="Milam A." last="Brantley">Milam A. Brantley</name>
<affiliation wicri:level="2"><nlm:aff id="A12">Ophthalmology & Visual Sciences, Washington University School of Medicine, St Louis, MO 63110, USA and Barnes Retina Institute, St. Louis, MO 63144</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Missouri (État)</region>
</placeName>
<wicri:cityArea>Ophthalmology & Visual Sciences, Washington University School of Medicine, St Louis, MO 63110, USA and Barnes Retina Institute, St. Louis</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Baird, Paul N" sort="Baird, Paul N" uniqKey="Baird P" first="Paul N." last="Baird">Paul N. Baird</name>
<affiliation wicri:level="4"><nlm:aff id="A10">Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria</wicri:regionArea>
<orgName type="university">Université de Melbourne</orgName>
<placeName><settlement type="city">Melbourne</settlement>
<region type="état">Victoria (État)</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Klaver, Caroline C W" sort="Klaver, Caroline C W" uniqKey="Klaver C" first="Caroline C. W." last="Klaver">Caroline C. W. Klaver</name>
<affiliation wicri:level="3"><nlm:aff id="A8">Department Ophthalmology, Department Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Pays-Bas</country>
<wicri:regionArea>Department Ophthalmology, Department Epidemiology, Erasmus Medical Center, Rotterdam</wicri:regionArea>
<placeName><settlement type="city">Rotterdam</settlement>
<region nuts="2" type="province">Hollande-Méridionale</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Allikmets, Rando" sort="Allikmets, Rando" uniqKey="Allikmets R" first="Rando" last="Allikmets">Rando Allikmets</name>
<affiliation wicri:level="4"><nlm:aff id="A9">Department of Ophthalmology, Columbia University, New York, NY, 10032</nlm:aff>
<orgName type="university">Université Columbia</orgName>
<country>États-Unis</country>
<placeName><settlement type="city">New York</settlement>
<region type="state">État de New York</region>
</placeName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="A20">Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pathology and Cell Biology, Columbia University, New York, NY 10032</wicri:regionArea>
<placeName><region type="state">État de New York</region>
<settlement type="city">New York</settlement>
</placeName>
<orgName type="university">Université Columbia</orgName>
</affiliation>
</author>
<author><name sortKey="Katsanis, Nicholas" sort="Katsanis, Nicholas" uniqKey="Katsanis N" first="Nicholas" last="Katsanis">Nicholas Katsanis</name>
<affiliation wicri:level="2"><nlm:aff id="A5">Center for Human Disease Modeling and Departments of Cell Biology and Pediatrics, Duke University, Durham, NC 27710</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Caroline du Nord</region>
</placeName>
<wicri:cityArea>Center for Human Disease Modeling and Departments of Cell Biology and Pediatrics, Duke University, Durham</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Graham, Robert R" sort="Graham, Robert R" uniqKey="Graham R" first="Robert R." last="Graham">Robert R. Graham</name>
<affiliation wicri:level="2"><nlm:aff id="A17">ITGR Human Genetics Group, Genentech Inc, South San Francisco, CA 94080</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Californie</region>
</placeName>
<wicri:cityArea>ITGR Human Genetics Group, Genentech Inc, South San Francisco</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Ioannidis, John P A" sort="Ioannidis, John P A" uniqKey="Ioannidis J" first="John P. A." last="Ioannidis">John P. A. Ioannidis</name>
<affiliation wicri:level="1"><nlm:aff id="A21">Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110, Greece</nlm:aff>
<country xml:lang="fr">Grèce</country>
<wicri:regionArea>Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110</wicri:regionArea>
<wicri:noRegion>Ioannina 45110</wicri:noRegion>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="A22">Stanford Prevention Research Center, Department of Medicine, and Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA 94305, USA;</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Stanford Prevention Research Center, Department of Medicine, and Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA 94305</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="A23">Center for Genetic Epidemiology and Modeling, ICRHPS, and Tufts Clinical and Translational Science Institute, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA;</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Genetic Epidemiology and Modeling, ICRHPS, and Tufts Clinical and Translational Science Institute, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111</wicri:regionArea>
<placeName><region type="state">Massachusetts</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Daly, Mark J" sort="Daly, Mark J" uniqKey="Daly M" first="Mark J." last="Daly">Mark J. Daly</name>
<affiliation wicri:level="2"><nlm:aff id="A2">Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114 and Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114 and Program in Medical and Population Genetics, Broad Institute, Cambridge</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Seddon, Johanna M" sort="Seddon, Johanna M" uniqKey="Seddon J" first="Johanna M." last="Seddon">Johanna M. Seddon</name>
<affiliation wicri:level="2"><nlm:aff id="A3">Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Tufts University School of Medicine, 800 Washington St. #450, Boston, MA 02111</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Tufts University School of Medicine, 800 Washington St. #450, Boston</wicri:cityArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A24">Department of Ophthalmology, Tufts University School of Medicine, Boston, Massachusetts 02111, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Ophthalmology, Tufts University School of Medicine, Boston, Massachusetts 02111</wicri:regionArea>
<wicri:noRegion>Massachusetts 02111</wicri:noRegion>
</affiliation>
</author>
</titleStmt>
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<idno type="doi">10.1016/j.ophtha.2012.03.014</idno>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Heritability and Genome-wide Association Study To Assess Genetic Differences Between Advanced Age-Related Macular Degeneration Subtypes
</title>
<author><name sortKey="Sobrin, Lucia" sort="Sobrin, Lucia" uniqKey="Sobrin L" first="Lucia" last="Sobrin">Lucia Sobrin</name>
<affiliation wicri:level="2"><nlm:aff id="A1">Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, Harvard Medical School, Boston, Massachusetts 02114</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, Harvard Medical School, Boston</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Ripke, Stephan" sort="Ripke, Stephan" uniqKey="Ripke S" first="Stephan" last="Ripke">Stephan Ripke</name>
<affiliation wicri:level="2"><nlm:aff id="A2">Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114 and Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114 and Program in Medical and Population Genetics, Broad Institute, Cambridge</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Yu, Yi" sort="Yu, Yi" uniqKey="Yu Y" first="Yi" last="Yu">Yi Yu</name>
<affiliation wicri:level="2"><nlm:aff id="A3">Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Tufts University School of Medicine, 800 Washington St. #450, Boston, MA 02111</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Tufts University School of Medicine, 800 Washington St. #450, Boston</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Fagerness, Jesen" sort="Fagerness, Jesen" uniqKey="Fagerness J" first="Jesen" last="Fagerness">Jesen Fagerness</name>
<affiliation wicri:level="2"><nlm:aff id="A2">Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114 and Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114 and Program in Medical and Population Genetics, Broad Institute, Cambridge</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Bhangale, Tushar R" sort="Bhangale, Tushar R" uniqKey="Bhangale T" first="Tushar R." last="Bhangale">Tushar R. Bhangale</name>
<affiliation wicri:level="2"><nlm:aff id="A4">Department of Bioinformatics and Computational Biology, Genentech Inc, South San Francisco, CA 94080</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Californie</region>
</placeName>
<wicri:cityArea>Department of Bioinformatics and Computational Biology, Genentech Inc, South San Francisco</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Tan, Perciliz L" sort="Tan, Perciliz L" uniqKey="Tan P" first="Perciliz L." last="Tan">Perciliz L. Tan</name>
<affiliation wicri:level="2"><nlm:aff id="A5">Center for Human Disease Modeling and Departments of Cell Biology and Pediatrics, Duke University, Durham, NC 27710</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Caroline du Nord</region>
</placeName>
<wicri:cityArea>Center for Human Disease Modeling and Departments of Cell Biology and Pediatrics, Duke University, Durham</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Souied, Eric H" sort="Souied, Eric H" uniqKey="Souied E" first="Eric H." last="Souied">Eric H. Souied</name>
<affiliation wicri:level="3"><nlm:aff id="A6">Department of Ophthalmology, University Paris Est Creteil, Hopital Intercommunal de Creteil, Creteil, 94000, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Department of Ophthalmology, University Paris Est Creteil, Hopital Intercommunal de Creteil, Creteil, 94000</wicri:regionArea>
<placeName><region type="region" nuts="2">Île-de-France</region>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="A7">Faculté de Médecine Henri Mondor, Department of ophthalmology. UPEC, Créteil, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Faculté de Médecine Henri Mondor, Department of ophthalmology. UPEC, Créteil</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Créteil</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Buitendijk, Gabrielle H S" sort="Buitendijk, Gabrielle H S" uniqKey="Buitendijk G" first="Gabriëlle H. S." last="Buitendijk">Gabriëlle H. S. Buitendijk</name>
<affiliation wicri:level="3"><nlm:aff id="A8">Department Ophthalmology, Department Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Pays-Bas</country>
<wicri:regionArea>Department Ophthalmology, Department Epidemiology, Erasmus Medical Center, Rotterdam</wicri:regionArea>
<placeName><settlement type="city">Rotterdam</settlement>
<region nuts="2" type="province">Hollande-Méridionale</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Merriam, Joanna E" sort="Merriam, Joanna E" uniqKey="Merriam J" first="Joanna E." last="Merriam">Joanna E. Merriam</name>
<affiliation wicri:level="4"><nlm:aff id="A9">Department of Ophthalmology, Columbia University, New York, NY, 10032</nlm:aff>
<orgName type="university">Université Columbia</orgName>
<country>États-Unis</country>
<placeName><settlement type="city">New York</settlement>
<region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Richardson, Andrea J" sort="Richardson, Andrea J" uniqKey="Richardson A" first="Andrea J." last="Richardson">Andrea J. Richardson</name>
<affiliation wicri:level="4"><nlm:aff id="A10">Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria</wicri:regionArea>
<orgName type="university">Université de Melbourne</orgName>
<placeName><settlement type="city">Melbourne</settlement>
<region type="état">Victoria (État)</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Raychaudhuri, Soumya" sort="Raychaudhuri, Soumya" uniqKey="Raychaudhuri S" first="Soumya" last="Raychaudhuri">Soumya Raychaudhuri</name>
<affiliation wicri:level="2"><nlm:aff id="A11">Divisions of Genetics and Rheumatology, Brigham and Women’s Hospital, Boston, MA 02115</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Divisions of Genetics and Rheumatology, Brigham and Women’s Hospital, Boston</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Reynolds, Robyn" sort="Reynolds, Robyn" uniqKey="Reynolds R" first="Robyn" last="Reynolds">Robyn Reynolds</name>
<affiliation wicri:level="2"><nlm:aff id="A3">Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Tufts University School of Medicine, 800 Washington St. #450, Boston, MA 02111</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Tufts University School of Medicine, 800 Washington St. #450, Boston</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Chin, Kimberly A" sort="Chin, Kimberly A" uniqKey="Chin K" first="Kimberly A." last="Chin">Kimberly A. Chin</name>
<affiliation wicri:level="2"><nlm:aff id="A3">Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Tufts University School of Medicine, 800 Washington St. #450, Boston, MA 02111</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Tufts University School of Medicine, 800 Washington St. #450, Boston</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Lee, Aaron Y" sort="Lee, Aaron Y" uniqKey="Lee A" first="Aaron Y." last="Lee">Aaron Y. Lee</name>
<affiliation wicri:level="2"><nlm:aff id="A12">Ophthalmology & Visual Sciences, Washington University School of Medicine, St Louis, MO 63110, USA and Barnes Retina Institute, St. Louis, MO 63144</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Missouri (État)</region>
</placeName>
<wicri:cityArea>Ophthalmology & Visual Sciences, Washington University School of Medicine, St Louis, MO 63110, USA and Barnes Retina Institute, St. Louis</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Leveziel, Nicolas" sort="Leveziel, Nicolas" uniqKey="Leveziel N" first="Nicolas" last="Leveziel">Nicolas Leveziel</name>
<affiliation wicri:level="1"><nlm:aff id="A6">Department of Ophthalmology, University Paris Est Creteil, Hopital Intercommunal de Creteil, Creteil, 94000, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Department of Ophthalmology, University Paris Est Creteil, Hopital Intercommunal de Creteil, Creteil, 94000</wicri:regionArea>
<wicri:noRegion>94000</wicri:noRegion>
<wicri:noRegion>94000</wicri:noRegion>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="A7">Faculté de Médecine Henri Mondor, Department of ophthalmology. UPEC, Créteil, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Faculté de Médecine Henri Mondor, Department of ophthalmology. UPEC, Créteil</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Créteil</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Zack, Donald J" sort="Zack, Donald J" uniqKey="Zack D" first="Donald J." last="Zack">Donald J. Zack</name>
<affiliation wicri:level="2"><nlm:aff id="A13">McKusick-Nathans Institute of Genetic Medicine, Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Maryland</region>
</placeName>
<wicri:cityArea>McKusick-Nathans Institute of Genetic Medicine, Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore</wicri:cityArea>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="A14">Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Maryland</region>
</placeName>
<wicri:cityArea>Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore</wicri:cityArea>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="A15">Department of Molecular Biology and Genetics and Institut de la Vision, UPMC, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Department of Molecular Biology and Genetics and Institut de la Vision, UPMC, Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Campochiaro, Peter" sort="Campochiaro, Peter" uniqKey="Campochiaro P" first="Peter" last="Campochiaro">Peter Campochiaro</name>
<affiliation wicri:level="2"><nlm:aff id="A13">McKusick-Nathans Institute of Genetic Medicine, Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Maryland</region>
</placeName>
<wicri:cityArea>McKusick-Nathans Institute of Genetic Medicine, Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore</wicri:cityArea>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="A14">Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Maryland</region>
</placeName>
<wicri:cityArea>Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Smith, R Theodore" sort="Smith, R Theodore" uniqKey="Smith R" first="R. Theodore" last="Smith">R. Theodore Smith</name>
<affiliation wicri:level="4"><nlm:aff id="A9">Department of Ophthalmology, Columbia University, New York, NY, 10032</nlm:aff>
<orgName type="university">Université Columbia</orgName>
<country>États-Unis</country>
<placeName><settlement type="city">New York</settlement>
<region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Barile, Gaetano R" sort="Barile, Gaetano R" uniqKey="Barile G" first="Gaetano R." last="Barile">Gaetano R. Barile</name>
<affiliation wicri:level="4"><nlm:aff id="A9">Department of Ophthalmology, Columbia University, New York, NY, 10032</nlm:aff>
<orgName type="university">Université Columbia</orgName>
<country>États-Unis</country>
<placeName><settlement type="city">New York</settlement>
<region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Hogg, Ruth E" sort="Hogg, Ruth E" uniqKey="Hogg R" first="Ruth E." last="Hogg">Ruth E. Hogg</name>
<affiliation><nlm:aff id="A16">Center for Vision and Vascular Science,The Queen’s University, Belfast, Northern Ireland.</nlm:aff>
<wicri:noCountry code="subfield">Northern Ireland.</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Chakravarthy, Usha" sort="Chakravarthy, Usha" uniqKey="Chakravarthy U" first="Usha" last="Chakravarthy">Usha Chakravarthy</name>
<affiliation><nlm:aff id="A16">Center for Vision and Vascular Science,The Queen’s University, Belfast, Northern Ireland.</nlm:aff>
<wicri:noCountry code="subfield">Northern Ireland.</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Behrens, Timothy W" sort="Behrens, Timothy W" uniqKey="Behrens T" first="Timothy W." last="Behrens">Timothy W. Behrens</name>
<affiliation wicri:level="2"><nlm:aff id="A17">ITGR Human Genetics Group, Genentech Inc, South San Francisco, CA 94080</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Californie</region>
</placeName>
<wicri:cityArea>ITGR Human Genetics Group, Genentech Inc, South San Francisco</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Uitterlinden, Andre G" sort="Uitterlinden, Andre G" uniqKey="Uitterlinden A" first="André G." last="Uitterlinden">André G. Uitterlinden</name>
<affiliation wicri:level="3"><nlm:aff id="A18">Department Epidemiology, Department Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Pays-Bas</country>
<wicri:regionArea>Department Epidemiology, Department Internal Medicine, Erasmus Medical Center, Rotterdam</wicri:regionArea>
<placeName><settlement type="city">Rotterdam</settlement>
<region nuts="2" type="province">Hollande-Méridionale</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Van Duijn, Cornelia M" sort="Van Duijn, Cornelia M" uniqKey="Van Duijn C" first="Cornelia M." last="Van Duijn">Cornelia M. Van Duijn</name>
<affiliation wicri:level="1"><nlm:aff id="A19">Department Epidemiology, Erasmus Medical Center Rotterdam, the Netherlands</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Pays-Bas</country>
<wicri:regionArea>Department Epidemiology, Erasmus Medical Center Rotterdam</wicri:regionArea>
<wicri:noRegion>Erasmus Medical Center Rotterdam</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Vingerling, Johannes R" sort="Vingerling, Johannes R" uniqKey="Vingerling J" first="Johannes R." last="Vingerling">Johannes R. Vingerling</name>
<affiliation wicri:level="3"><nlm:aff id="A8">Department Ophthalmology, Department Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Pays-Bas</country>
<wicri:regionArea>Department Ophthalmology, Department Epidemiology, Erasmus Medical Center, Rotterdam</wicri:regionArea>
<placeName><settlement type="city">Rotterdam</settlement>
<region nuts="2" type="province">Hollande-Méridionale</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Brantley, Milam A" sort="Brantley, Milam A" uniqKey="Brantley M" first="Milam A." last="Brantley">Milam A. Brantley</name>
<affiliation wicri:level="2"><nlm:aff id="A12">Ophthalmology & Visual Sciences, Washington University School of Medicine, St Louis, MO 63110, USA and Barnes Retina Institute, St. Louis, MO 63144</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Missouri (État)</region>
</placeName>
<wicri:cityArea>Ophthalmology & Visual Sciences, Washington University School of Medicine, St Louis, MO 63110, USA and Barnes Retina Institute, St. Louis</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Baird, Paul N" sort="Baird, Paul N" uniqKey="Baird P" first="Paul N." last="Baird">Paul N. Baird</name>
<affiliation wicri:level="4"><nlm:aff id="A10">Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria</wicri:regionArea>
<orgName type="university">Université de Melbourne</orgName>
<placeName><settlement type="city">Melbourne</settlement>
<region type="état">Victoria (État)</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Klaver, Caroline C W" sort="Klaver, Caroline C W" uniqKey="Klaver C" first="Caroline C. W." last="Klaver">Caroline C. W. Klaver</name>
<affiliation wicri:level="3"><nlm:aff id="A8">Department Ophthalmology, Department Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Pays-Bas</country>
<wicri:regionArea>Department Ophthalmology, Department Epidemiology, Erasmus Medical Center, Rotterdam</wicri:regionArea>
<placeName><settlement type="city">Rotterdam</settlement>
<region nuts="2" type="province">Hollande-Méridionale</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Allikmets, Rando" sort="Allikmets, Rando" uniqKey="Allikmets R" first="Rando" last="Allikmets">Rando Allikmets</name>
<affiliation wicri:level="4"><nlm:aff id="A9">Department of Ophthalmology, Columbia University, New York, NY, 10032</nlm:aff>
<orgName type="university">Université Columbia</orgName>
<country>États-Unis</country>
<placeName><settlement type="city">New York</settlement>
<region type="state">État de New York</region>
</placeName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="A20">Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pathology and Cell Biology, Columbia University, New York, NY 10032</wicri:regionArea>
<placeName><region type="state">État de New York</region>
<settlement type="city">New York</settlement>
</placeName>
<orgName type="university">Université Columbia</orgName>
</affiliation>
</author>
<author><name sortKey="Katsanis, Nicholas" sort="Katsanis, Nicholas" uniqKey="Katsanis N" first="Nicholas" last="Katsanis">Nicholas Katsanis</name>
<affiliation wicri:level="2"><nlm:aff id="A5">Center for Human Disease Modeling and Departments of Cell Biology and Pediatrics, Duke University, Durham, NC 27710</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Caroline du Nord</region>
</placeName>
<wicri:cityArea>Center for Human Disease Modeling and Departments of Cell Biology and Pediatrics, Duke University, Durham</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Graham, Robert R" sort="Graham, Robert R" uniqKey="Graham R" first="Robert R." last="Graham">Robert R. Graham</name>
<affiliation wicri:level="2"><nlm:aff id="A17">ITGR Human Genetics Group, Genentech Inc, South San Francisco, CA 94080</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Californie</region>
</placeName>
<wicri:cityArea>ITGR Human Genetics Group, Genentech Inc, South San Francisco</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Ioannidis, John P A" sort="Ioannidis, John P A" uniqKey="Ioannidis J" first="John P. A." last="Ioannidis">John P. A. Ioannidis</name>
<affiliation wicri:level="1"><nlm:aff id="A21">Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110, Greece</nlm:aff>
<country xml:lang="fr">Grèce</country>
<wicri:regionArea>Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110</wicri:regionArea>
<wicri:noRegion>Ioannina 45110</wicri:noRegion>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="A22">Stanford Prevention Research Center, Department of Medicine, and Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA 94305, USA;</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Stanford Prevention Research Center, Department of Medicine, and Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA 94305</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="A23">Center for Genetic Epidemiology and Modeling, ICRHPS, and Tufts Clinical and Translational Science Institute, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA;</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Genetic Epidemiology and Modeling, ICRHPS, and Tufts Clinical and Translational Science Institute, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111</wicri:regionArea>
<placeName><region type="state">Massachusetts</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Daly, Mark J" sort="Daly, Mark J" uniqKey="Daly M" first="Mark J." last="Daly">Mark J. Daly</name>
<affiliation wicri:level="2"><nlm:aff id="A2">Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114 and Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114 and Program in Medical and Population Genetics, Broad Institute, Cambridge</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Seddon, Johanna M" sort="Seddon, Johanna M" uniqKey="Seddon J" first="Johanna M." last="Seddon">Johanna M. Seddon</name>
<affiliation wicri:level="2"><nlm:aff id="A3">Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Tufts University School of Medicine, 800 Washington St. #450, Boston, MA 02111</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Tufts University School of Medicine, 800 Washington St. #450, Boston</wicri:cityArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A24">Department of Ophthalmology, Tufts University School of Medicine, Boston, Massachusetts 02111, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Ophthalmology, Tufts University School of Medicine, Boston, Massachusetts 02111</wicri:regionArea>
<wicri:noRegion>Massachusetts 02111</wicri:noRegion>
</affiliation>
</author>
</analytic>
<series><title level="j">Ophthalmology</title>
<idno type="ISSN">0161-6420</idno>
<idno type="eISSN">1549-4713</idno>
<imprint><date when="2012">2012</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><sec id="S1"><title>Purpose</title>
<p id="P1">To investigate whether the two subtypes of advanced age-related macular degeneration (AMD), choroidal neovascularization (CNV) and geographic atrophy (GA), segregate separately in families and to identify which genetic variants are associated with these two subtypes.</p>
</sec>
<sec id="S2"><title>Design</title>
<p id="P2">Sibling correlation study and genome-wide association study (GWAS)</p>
</sec>
<sec id="S3"><title>Participants</title>
<p id="P3">For the sibling correlation study, we included 209 sibling pairs with advanced AMD. For the GWAS, we included 2594 participants with advanced AMD subtypes and 4134 controls. Replication cohorts included 5383 advanced AMD participants and 15,240 controls.</p>
</sec>
<sec id="S4"><title>Methods</title>
<p id="P4">Participants had AMD grade assigned based on fundus photography and/or examination. To determine heritability of advanced AMD subtypes, we performed a sibling correlation study. For the GWAS, we conducted genome-wide genotyping and imputed 6,036,699 single nucleotide polymorphism (SNPs). We then analyzed SNPs with a generalized linear model controlling for genotyping platform and genetic ancestry. The most significant associations were evaluated in independent cohorts.</p>
</sec>
<sec id="S5"><title>Main Outcome Measures</title>
<p id="P5">Concordance of advanced AMD subtypes in sibling pairs and associations between SNPs with GA and CNV advanced AMD subtypes.</p>
</sec>
<sec id="S6"><title>Results</title>
<p id="P6">The difference between the observed and expected proportion of siblings concordant for the same subtype of advanced AMD was different to a statistically significant degree (P=4.2 x 10<sup>−5</sup>
) meaning that siblings of probands with CNV or GA are more likely to develop CNV or GA, respectively. In the analysis comparing participants with CNV to those with GA, we observed a statistically significant association at the <italic>ARMS2/HTRA1</italic>
 locus [rs10490924, odds ratio (OR)=1.47, P=4.3 ×10<sup>−9</sup>
] which was confirmed in the replication samples (OR=1.38, P=7.4 x 10<sup>−14</sup>
 for combined discovery and replication analysis).</p>
</sec>
<sec id="S7"><title>Conclusions</title>
<p id="P7">Whether a patient with AMD develops CNV vs. GA is determined in part by genetic variation. In this large GWAS meta-analysis and replication analysis, the <italic>ARMS2/HTRA1</italic>
 locus confers increased risk for both advanced AMD subtypes but imparts greater risk for CNV than for GA. This locus explains a small proportion of the excess sibling correlation for advanced AMD subtype. Other loci were detected with suggestive associations which differ for advanced AMD subtypes and deserve follow-up in additional studies.</p>
</sec>
</div>
</front>
</TEI>
<affiliations><list><country><li>Australie</li>
<li>France</li>
<li>Grèce</li>
<li>Pays-Bas</li>
<li>États-Unis</li>
</country>
<region><li>Californie</li>
<li>Caroline du Nord</li>
<li>Hollande-Méridionale</li>
<li>Maryland</li>
<li>Massachusetts</li>
<li>Missouri (État)</li>
<li>Victoria (État)</li>
<li>État de New York</li>
<li>Île-de-France</li>
</region>
<settlement><li>Créteil</li>
<li>Melbourne</li>
<li>New York</li>
<li>Paris</li>
<li>Rotterdam</li>
</settlement>
<orgName><li>Université Columbia</li>
<li>Université de Melbourne</li>
</orgName>
</list>
<tree><noCountry><name sortKey="Chakravarthy, Usha" sort="Chakravarthy, Usha" uniqKey="Chakravarthy U" first="Usha" last="Chakravarthy">Usha Chakravarthy</name>
<name sortKey="Hogg, Ruth E" sort="Hogg, Ruth E" uniqKey="Hogg R" first="Ruth E." last="Hogg">Ruth E. Hogg</name>
</noCountry>
<country name="États-Unis"><region name="Massachusetts"><name sortKey="Sobrin, Lucia" sort="Sobrin, Lucia" uniqKey="Sobrin L" first="Lucia" last="Sobrin">Lucia Sobrin</name>
</region>
<name sortKey="Allikmets, Rando" sort="Allikmets, Rando" uniqKey="Allikmets R" first="Rando" last="Allikmets">Rando Allikmets</name>
<name sortKey="Allikmets, Rando" sort="Allikmets, Rando" uniqKey="Allikmets R" first="Rando" last="Allikmets">Rando Allikmets</name>
<name sortKey="Barile, Gaetano R" sort="Barile, Gaetano R" uniqKey="Barile G" first="Gaetano R." last="Barile">Gaetano R. Barile</name>
<name sortKey="Behrens, Timothy W" sort="Behrens, Timothy W" uniqKey="Behrens T" first="Timothy W." last="Behrens">Timothy W. Behrens</name>
<name sortKey="Bhangale, Tushar R" sort="Bhangale, Tushar R" uniqKey="Bhangale T" first="Tushar R." last="Bhangale">Tushar R. Bhangale</name>
<name sortKey="Brantley, Milam A" sort="Brantley, Milam A" uniqKey="Brantley M" first="Milam A." last="Brantley">Milam A. Brantley</name>
<name sortKey="Campochiaro, Peter" sort="Campochiaro, Peter" uniqKey="Campochiaro P" first="Peter" last="Campochiaro">Peter Campochiaro</name>
<name sortKey="Campochiaro, Peter" sort="Campochiaro, Peter" uniqKey="Campochiaro P" first="Peter" last="Campochiaro">Peter Campochiaro</name>
<name sortKey="Chin, Kimberly A" sort="Chin, Kimberly A" uniqKey="Chin K" first="Kimberly A." last="Chin">Kimberly A. Chin</name>
<name sortKey="Daly, Mark J" sort="Daly, Mark J" uniqKey="Daly M" first="Mark J." last="Daly">Mark J. Daly</name>
<name sortKey="Fagerness, Jesen" sort="Fagerness, Jesen" uniqKey="Fagerness J" first="Jesen" last="Fagerness">Jesen Fagerness</name>
<name sortKey="Graham, Robert R" sort="Graham, Robert R" uniqKey="Graham R" first="Robert R." last="Graham">Robert R. Graham</name>
<name sortKey="Ioannidis, John P A" sort="Ioannidis, John P A" uniqKey="Ioannidis J" first="John P. A." last="Ioannidis">John P. A. Ioannidis</name>
<name sortKey="Ioannidis, John P A" sort="Ioannidis, John P A" uniqKey="Ioannidis J" first="John P. A." last="Ioannidis">John P. A. Ioannidis</name>
<name sortKey="Katsanis, Nicholas" sort="Katsanis, Nicholas" uniqKey="Katsanis N" first="Nicholas" last="Katsanis">Nicholas Katsanis</name>
<name sortKey="Lee, Aaron Y" sort="Lee, Aaron Y" uniqKey="Lee A" first="Aaron Y." last="Lee">Aaron Y. Lee</name>
<name sortKey="Merriam, Joanna E" sort="Merriam, Joanna E" uniqKey="Merriam J" first="Joanna E." last="Merriam">Joanna E. Merriam</name>
<name sortKey="Raychaudhuri, Soumya" sort="Raychaudhuri, Soumya" uniqKey="Raychaudhuri S" first="Soumya" last="Raychaudhuri">Soumya Raychaudhuri</name>
<name sortKey="Reynolds, Robyn" sort="Reynolds, Robyn" uniqKey="Reynolds R" first="Robyn" last="Reynolds">Robyn Reynolds</name>
<name sortKey="Ripke, Stephan" sort="Ripke, Stephan" uniqKey="Ripke S" first="Stephan" last="Ripke">Stephan Ripke</name>
<name sortKey="Seddon, Johanna M" sort="Seddon, Johanna M" uniqKey="Seddon J" first="Johanna M." last="Seddon">Johanna M. Seddon</name>
<name sortKey="Seddon, Johanna M" sort="Seddon, Johanna M" uniqKey="Seddon J" first="Johanna M." last="Seddon">Johanna M. Seddon</name>
<name sortKey="Smith, R Theodore" sort="Smith, R Theodore" uniqKey="Smith R" first="R. Theodore" last="Smith">R. Theodore Smith</name>
<name sortKey="Tan, Perciliz L" sort="Tan, Perciliz L" uniqKey="Tan P" first="Perciliz L." last="Tan">Perciliz L. Tan</name>
<name sortKey="Yu, Yi" sort="Yu, Yi" uniqKey="Yu Y" first="Yi" last="Yu">Yi Yu</name>
<name sortKey="Zack, Donald J" sort="Zack, Donald J" uniqKey="Zack D" first="Donald J." last="Zack">Donald J. Zack</name>
<name sortKey="Zack, Donald J" sort="Zack, Donald J" uniqKey="Zack D" first="Donald J." last="Zack">Donald J. Zack</name>
</country>
<country name="France"><region name="Île-de-France"><name sortKey="Souied, Eric H" sort="Souied, Eric H" uniqKey="Souied E" first="Eric H." last="Souied">Eric H. Souied</name>
</region>
<name sortKey="Leveziel, Nicolas" sort="Leveziel, Nicolas" uniqKey="Leveziel N" first="Nicolas" last="Leveziel">Nicolas Leveziel</name>
<name sortKey="Leveziel, Nicolas" sort="Leveziel, Nicolas" uniqKey="Leveziel N" first="Nicolas" last="Leveziel">Nicolas Leveziel</name>
<name sortKey="Souied, Eric H" sort="Souied, Eric H" uniqKey="Souied E" first="Eric H." last="Souied">Eric H. Souied</name>
<name sortKey="Zack, Donald J" sort="Zack, Donald J" uniqKey="Zack D" first="Donald J." last="Zack">Donald J. Zack</name>
</country>
<country name="Pays-Bas"><region name="Hollande-Méridionale"><name sortKey="Buitendijk, Gabrielle H S" sort="Buitendijk, Gabrielle H S" uniqKey="Buitendijk G" first="Gabriëlle H. S." last="Buitendijk">Gabriëlle H. S. Buitendijk</name>
</region>
<name sortKey="Klaver, Caroline C W" sort="Klaver, Caroline C W" uniqKey="Klaver C" first="Caroline C. W." last="Klaver">Caroline C. W. Klaver</name>
<name sortKey="Uitterlinden, Andre G" sort="Uitterlinden, Andre G" uniqKey="Uitterlinden A" first="André G." last="Uitterlinden">André G. Uitterlinden</name>
<name sortKey="Van Duijn, Cornelia M" sort="Van Duijn, Cornelia M" uniqKey="Van Duijn C" first="Cornelia M." last="Van Duijn">Cornelia M. Van Duijn</name>
<name sortKey="Vingerling, Johannes R" sort="Vingerling, Johannes R" uniqKey="Vingerling J" first="Johannes R." last="Vingerling">Johannes R. Vingerling</name>
</country>
<country name="Australie"><region name="Victoria (État)"><name sortKey="Richardson, Andrea J" sort="Richardson, Andrea J" uniqKey="Richardson A" first="Andrea J." last="Richardson">Andrea J. Richardson</name>
</region>
<name sortKey="Baird, Paul N" sort="Baird, Paul N" uniqKey="Baird P" first="Paul N." last="Baird">Paul N. Baird</name>
</country>
<country name="Grèce"><noRegion><name sortKey="Ioannidis, John P A" sort="Ioannidis, John P A" uniqKey="Ioannidis J" first="John P. A." last="Ioannidis">John P. A. Ioannidis</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>

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Heritability and Genome-wide Association Study To Assess Genetic Differences Between Advanced Age-Related Macular Degeneration Subtypes

Heritability and Genome-wide Association Study To Assess Genetic Differences Between Advanced Age-Related Macular Degeneration Subtypes

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