Genome-wide analysis of disease progression in age-related macular degeneration

AREDS2 Research Group

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Family- and population-based genetic studies have successfully identified multiple disease-susceptibility loci for Age-related macular degeneration (AMD), one of the first batch and most successful examples of genome-wide association study. However, most genetic studies to date have focused on case-control studies of late AMD (choroidal neovascularization or geographic atrophy). The genetic influences on disease progression are largely unexplored. We assembled unique resources to perform a genome-wide bivariate time-to-event analysis to test for association of time-to-late-AMD with ±9 million variants on 2721 Caucasians from a large multi-center randomized clinical trial, the Age-Related Eye Disease Study. To our knowledge, this is the first genome-wide association study of disease progression (bivariate survival outcome) in AMD genetic studies, thus providing novel insights to AMD genetics. We used a robust Cox proportional hazards model to appropriately account for between-eye correlation when analyzing the progression time in the two eyes of each participant. We identified four previously reported susceptibility loci showing genome-wide significant association with AMD progression: ARMS2-HTRA1 (P=8.1 x 10-43), CFH (P = 3.5 x 10-37), C2-CFB-SKIV2L (P = 8.1 x 10-10) and C3 (P = 1.2 x 10-9). Furthermore, we detected association of rs58978565 near TNR (P = 2.3 x 10-8), rs28368872 near ATF7IP2 (P = 2.9 x 10-8) and rs142450006 near MMP9 (P = 0.0006) with progression to choroidal neovascularization but not geographic atrophy. Secondary analysis limited to 34 reported risk variants revealed that LIPC and CTRB2-CTRB1 were also associated with AMD progression (P < 0.0015). Our genome-wide analysis thus expands the genetics in both development and progression of AMD and should assist in early identification of high risk individuals.

Original languageEnglish (US)
Pages (from-to)929-940
Number of pages12
JournalHuman Molecular Genetics
Volume27
Issue number5
DOIs
StatePublished - Mar 1 2018

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Macular Degeneration
Disease Progression
Genome
Geographic Atrophy
Choroidal Neovascularization
Genome-Wide Association Study
Eye Diseases
Disease Susceptibility
Population Genetics
Proportional Hazards Models
Case-Control Studies
Randomized Controlled Trials

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Genome-wide analysis of disease progression in age-related macular degeneration. / AREDS2 Research Group.

In: Human Molecular Genetics, Vol. 27, No. 5, 01.03.2018, p. 929-940.

Research output: Contribution to journalArticle

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abstract = "Family- and population-based genetic studies have successfully identified multiple disease-susceptibility loci for Age-related macular degeneration (AMD), one of the first batch and most successful examples of genome-wide association study. However, most genetic studies to date have focused on case-control studies of late AMD (choroidal neovascularization or geographic atrophy). The genetic influences on disease progression are largely unexplored. We assembled unique resources to perform a genome-wide bivariate time-to-event analysis to test for association of time-to-late-AMD with ±9 million variants on 2721 Caucasians from a large multi-center randomized clinical trial, the Age-Related Eye Disease Study. To our knowledge, this is the first genome-wide association study of disease progression (bivariate survival outcome) in AMD genetic studies, thus providing novel insights to AMD genetics. We used a robust Cox proportional hazards model to appropriately account for between-eye correlation when analyzing the progression time in the two eyes of each participant. We identified four previously reported susceptibility loci showing genome-wide significant association with AMD progression: ARMS2-HTRA1 (P=8.1 x 10-43), CFH (P = 3.5 x 10-37), C2-CFB-SKIV2L (P = 8.1 x 10-10) and C3 (P = 1.2 x 10-9). Furthermore, we detected association of rs58978565 near TNR (P = 2.3 x 10-8), rs28368872 near ATF7IP2 (P = 2.9 x 10-8) and rs142450006 near MMP9 (P = 0.0006) with progression to choroidal neovascularization but not geographic atrophy. Secondary analysis limited to 34 reported risk variants revealed that LIPC and CTRB2-CTRB1 were also associated with AMD progression (P < 0.0015). Our genome-wide analysis thus expands the genetics in both development and progression of AMD and should assist in early identification of high risk individuals.",
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AU - Fritsche, Lars G.

AU - Clemons, Traci

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AU - Klein, Michael

AU - Cook, Richard J.

AU - Liu, Yu

AU - Fan, Ruzong

AU - Wei, Lai

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