Journal
OPHTHALMOLOGY
Volume 119, Issue 9, Pages 1874-1885Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ophtha.2012.03.014
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Funding
- National Institutes of Health, Bethesda, Maryland [R01-EY11309, R01-EY13435, R24-EY017404, K12-EY16335]
- Massachusetts Lions Eye Research Fund, Inc., New Bedford, Massachusetts
- Research to Prevent Blindness, Inc., New York, New York
- Foundation Fighting Blindness, Owing Mills, Maryland
- Macula Vision Research Foundation, West Conshohocken, Pennsylvania
- Kaplen Foundation, Tenafly, New Jersey
- Widgeon Point Charitable Foundation, Armonk, New York
- Alcon Research Institute, Fort Worth, Texas
- Fight for Sight Postdoctoral Award, New York, New York
- National Health & Medical Research Council of Australia Centre for Clinical Research Excellence, Canberra, Australia [529923]
- American Macular Degeneration Foundation, Northampton, Massachusetts
- Macular Degeneration Research Fund of the Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts
- National Eye Institute, National Institutes of Health, Bethesda, Maryland [EY012211, EY012261, EY012279]
- National Institute of Mental Health, Bethesda, Maryland [R01 MH67257, R01 MH59588, R01 MH59571, R01 MH59565, R01 MH59587, R01 MH60870, R01 MH59566, R01 MH59586, R01 MH61675, R01 MH60879, R01 MH81800, U01 MH46276, U01 MH46289 U01 MH46318, U01 MH79469, U01 MH79470]
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Purpose: To investigate whether the 2 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 2 subtypes. Design: Sibling correlation study and genome-wide association study (GWAS). Participants: For the sibling correlation study, 209 sibling pairs with advanced AMD were included. For the GWAS, 2594 participants with advanced AMD subtypes and 4134 controls were included. Replication cohorts included 5383 advanced AMD participants and 15 240 controls. Methods: Participants had the AMD grade assigned based on fundus photography, examination, or both. To determine heritability of advanced AMD subtypes, a sibling correlation study was performed. For the GWAS, genome-wide genotyping was conducted and 6 036 699 single nucleotide polymorphisms (SNPs) were imputed. Then, the SNPs were analyzed 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 in siblings of probands with CNV or GA, the same advanced subtype is more likely to develop. In the analysis comparing participants with CNV to those with GA, a statistically significant association was observed at the ARMS2/HTRA1 locus (rs10490924; odds ratio [OR], 1.47; P = 4.3 x 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 CNV versus GA develops in a patient with AMD 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 that differ for advanced AMD subtypes and deserve follow-up in additional studies. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. Ophthalmology 2012; 119: 1874-1885 (C) 2012 by the American Academy of Ophthalmology.
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