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T A. Sivakumaran, Barbara E. Klein, Kris E. Lee, Ronald Gangnon, Barbara Truitt, Ronald Klein, Sudha K. Iyengar; Assessment of Genetic factors for AMD in the Beaver Dam Eye Study. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5254.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate the association of genetic polymorphisms of known AMD susceptibility loci as well as new loci in Beaver Dam Eye Study (BDES) cohort.
Two thousand two hundred and sixty seven unrelated individuals (651 cases with any AMD and 1616 controls) aged 43+ years from the BDES cohort were included in this study. A total of 1742 SNPs from known as well as novel AMD susceptibility loci were genotyped with a custom Illumina infinium SNP array. After quality control and data cleanup, 1644 SNPs were selected for association analysis. Population stratification was estimated using 268 European-specific SNPs, using principal component analysis. The first two principal components (PC) were generated and tested for association along with age, sex and smoking in a step-wise manner. Age showed strong association with the disease. Effects of these factors were adjusted for SNP association using logistic regression implemented in PLINK with age, smoking and the first two principal components as covariates.
As expected, SNPs at CFH-RCA and ARMS2 loci showed the strongest association with AMD (p<0.001) in the BDES cohort. Of several novel and known AMD loci that emerged in the last year, we were able to replicate the association at C2/CFB/SKIV2L, C3, CETP, LPL, LIPC, MYRIP, UNC13C, ABCA1, TIMP3-SYN3 and APOE. We completely canvassed LIPC (> 100 markers), CETP (> 40 markers), and TIMP3-SYN3 (> 100 markers). The evidence of association at LIPC and CETP was marginally significant (p-value < 0.04), whereas evidence at the TIMP3-SYN3 locus was weak at best (best p-value = 0.065 at rs130560; odds ratio = 1.18). The evidence at these loci was equivalent to that obtained for our own novel loci, MYRIP and UNC13C; MYRIP shows a protective effect on AMD. We also observed a marginal association (p < 0.03) at some of genes causing Mendelian retinal degenerations, suggesting that weak common alleles at these loci may mediate the disease process. No evidence for association with some previously identified genes such as CFI was detected (p>0.3).
Our results showed that the etiology of AMD is complex, with CFH and ARMS2 being the major loci contributing to AMD susceptibility in the BDES cohort. We were also able to replicate several other loci of more modest effect. These loci are being further pursued to determine their role in AMD pathogenesis.
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