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Omar García Rodríguez, Susan Hackleman Slifer, William K Scott, Yeunjoo E. Song, Kristy Miskimen, Muneeswar Gupta Nittala, Srinivas R Sadda, Jonathan L Haines, Margaret A Pericak-Vance, Dwight Stambolian; Genome-wide Association Study of Choroidal Thickness in the Amish. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2831.
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Choroidal thickness(CT) is a promising biomarker for evaluating AMD status because it is significantly heritable and inversely associated with the severity of AMD. Of 52 SNPs associated with AMD risk only two variants(rs1329428 and rs800292) in CFH are also associated with CT. To date only one study has performed a genome-wide association approach using changes in CT. We aimed to perform a second GWAS identifying common variants influencing two-year changes in CT.
A family-based prospective cohort of 481 Amish adults over age 65 was studied(23 with AMD). We performed genotyping with the Illumina MEGAex chip and analyzed common SNPs(MAF>1%, n=799,015) after QC analysis. CT measurements were obtained from Heidelberg Spectralis OCT images analyzed at Doheny Image Reading Center. Covariates included sex, age, and pedigree structure(validated by genotypes). We excluded subjects who missing genotypes or CT on at least one visit. For analysis, one eye with measured CT was randomly selected and the second-visit measurements of CT were squared to distribute normally. A linear mixed model was done using GWAF to assess the association between changes in CT and SNP allelic dosage adjusting for age, sex, CT measurement at baseline, population structure (the first 3 principal components from EIGENSTAT analysis), and pedigree structure. We examined the robustness of the genome-wide significant results (p<5x10-8) for the region by randomly resampling one eye per person 10 times.
The sample consisted mainly of women(60%) with an average age of 66(±10 years). Two SNPs in moderate linkage disequilibrium(r2=0.63) provided suggestive association results(p<1x10-5) on chromosome 17 in the SEPT9(Septin 9) gene. Each carrier of the A allele at rs146259357 decreased squared measurement of CT by 71(±29) and at rs129432409 (B=-65±28). No SNPs in CFH were nominally associated with change in CT.
We identified two loci showing suggestive association with two-year change in CT. SEPT9 is involved in cytokinesis and cell cycle control and may influence development of ovarian cancer. Our findings did not support that SNPs in CFH were related to changes in CT. Identification of novel genes associated with CT and/or AMD progression could provide insight into mechanisms underlying the progression to AMD and inform future therapeutic developments.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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