Dataset Information

Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration.

ABSTRACT: Despite significant progress in the identification of genetic loci for age-related macular degeneration (AMD), not all of the heritability has been explained. To identify variants which contribute to the remaining genetic susceptibility, we performed the largest meta-analysis of genome-wide association studies to date for advanced AMD. We imputed 6 036 699 single-nucleotide polymorphisms with the 1000 Genomes Project reference genotypes on 2594 cases and 4134 controls with follow-up replication of top signals in 5640 cases and 52 174 controls. We identified two new common susceptibility alleles, rs1999930 on 6q21-q22.3 near FRK/COL10A1 [odds ratio (OR) 0.87; P = 1.1 × 10(-8)] and rs4711751 on 6p12 near VEGFA (OR 1.15; P = 8.7 × 10(-9)). In addition to the two novel loci, 10 previously reported loci in ARMS2/HTRA1 (rs10490924), CFH (rs1061170, and rs1410996), CFB (rs641153), C3 (rs2230199), C2 (rs9332739), CFI (rs10033900), LIPC (rs10468017), TIMP3 (rs9621532) and CETP (rs3764261) were confirmed with genome-wide significant signals in this large study. Loci in the recently reported genes ABCA1 and COL8A1 were also detected with suggestive evidence of association with advanced AMD. The novel variants identified in this study suggest that angiogenesis (VEGFA) and extracellular collagen matrix (FRK/COL10A1) pathways contribute to the development of advanced AMD.

SUBMITTER: Yu Y

PROVIDER: S-EPMC3159552 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration.

Yu Yi Y Bhangale Tushar R TR Fagerness Jesen J Ripke Stephan S Thorleifsson Gudmar G Tan Perciliz L PL Souied Eric H EH Richardson Andrea J AJ Merriam Joanna E JE Buitendijk Gabriëlle H S GH Reynolds Robyn R Raychaudhuri Soumya S Chin Kimberly A KA Sobrin Lucia L Evangelou Evangelos E Lee Phil H PH Lee Aaron Y AY Leveziel Nicolas N Zack Donald J DJ Campochiaro Betsy B Campochiaro Peter P Smith R Theodore RT Barile Gaetano R GR Guymer Robyn H RH Hogg Ruth R Chakravarthy Usha U Robman Luba D LD Gustafsson Omar O Sigurdsson Haraldur H Ortmann Ward W Behrens Timothy W TW Stefansson Kari K Uitterlinden André G AG van Duijn Cornelia M CM Vingerling Johannes R JR Klaver Caroline C W CC Allikmets Rando R Brantley Milam A MA Baird Paul N PN Katsanis Nicholas N Thorsteinsdottir Unnur U Ioannidis John P A JP Daly Mark J MJ Graham Robert R RR Seddon Johanna M JM

Human molecular genetics 20110610 18

Despite significant progress in the identification of genetic loci for age-related macular degeneration (AMD), not all of the heritability has been explained. To identify variants which contribute to the remaining genetic susceptibility, we performed the largest meta-analysis of genome-wide association studies to date for advanced AMD. We imputed 6 036 699 single-nucleotide polymorphisms with the 1000 Genomes Project reference genotypes on 2594 cases and 4134 controls with follow-up replication ...[more]

PMID: 21665990

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Project description:Purpose To evaluate associations between rare dysfunctional complement factor I (CFI) genetic variant status and progression to advanced age-related macular degeneration (AAMD), geographic atrophy (GA), and neovascular disease (NV). Design Prospective, longitudinal study Participants Patients aged 55 to 80 years at baseline identifying as White with non-AAMD in 1 or both eyes at baseline were included. Follow-up grades were assigned as early, intermediate, or AAMD (GA or NV). CFI variants were categorized using genotyping and sequencing platforms. Methods Analyses were performed using the Seddon Longitudinal Cohort Study (N = 2116 subjects, 3901 eyes, and mean follow-up of 8.3 years) and the Age-Related Eye Disease Study (N = 2837 subjects, 5200 eyes, and mean follow-up of 9.2 years). CFI rare variants associated with low serum factor I (FI) protein levels and decreased FI function (type 1), other AMD genetic variants, and demographic, behavioral, and ocular factors were evaluated. Generalized estimating equations methods were used to assess the association between CFI rare variants and progression, independent of other genetic variants and covariates. Main Outcome Measures Progression to AAMD, GA, or NV. Results In the prospective cohort of 4953 subjects (9101 eyes with non-AAMD at baseline), 1% were type 1 rare CFI carriers. Over 12 years, progression to AAMD was 44% for carriers and 20% for noncarriers (P < 0.001), 30% of carriers versus 10% of noncarriers progressed to GA (P < 0.001), and 18% of carriers compared with 11% of noncarriers progressed to NV (P = 0.049). CFI carriers were more likely to have a family history of AMD (P for trend = 0.035) and a higher baseline AMD grade (P < 0.001). After adjusting for all covariates, CFI carrier status was associated with progression to GA (odds ratio [OR] = 1.91; 95% confidence interval [CI] = 1.03, 3.52) but not NV (OR = 0.96). Higher body mass index was associated with progression among CFI carriers (body mass index ≥ 25 vs. < 25; OR = 5.8; 95% CI 1.5, 22.3) but not for noncarriers (OR = 1.1; 95% CI = 0.9, 1.3), with P_interaction = 0.011. Conclusions Results suggest that carriers of rare dysfunctional type 1 CFI variants are at higher risk for progression to AAMD with GA. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.

Dataset Information

Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration.

Publications

Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration.

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