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. 2013;8(2):e54232.
doi: 10.1371/journal.pone.0054232. Epub 2013 Feb 5.

Genome-wide Association Study of Retinopathy in Individuals Without Diabetes

Collaborators, Affiliations
Free PMC article

Genome-wide Association Study of Retinopathy in Individuals Without Diabetes

Richard A Jensen et al. PLoS One. .
Free PMC article

Abstract

Background: Mild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes.

Methods: A working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from six cohorts of 19,411 Caucasians. The primary analysis included individuals without diabetes and secondary analyses were stratified by hypertension status. We also singled out the results from single nucleotide polymorphisms (SNPs) previously shown to be associated with diabetes and hypertension, the two most common causes of retinopathy.

Results: No SNPs reached genome-wide significance in the primary analysis or the secondary analysis of participants with hypertension. SNP, rs12155400, in the histone deacetylase 9 gene (HDAC9) on chromosome 7, was associated with retinopathy in analysis of participants without hypertension, -1.3±0.23 (beta ± standard error), p = 6.6×10(-9). Evidence suggests this was a false positive finding. The minor allele frequency was low (∼2%), the quality of the imputation was moderate (r(2) ∼0.7), and no other common variants in the HDAC9 gene were associated with the outcome. SNPs found to be associated with diabetes and hypertension in other GWAS were not associated with retinopathy in persons without diabetes or in subgroups with or without hypertension.

Conclusions: This GWAS of retinopathy in individuals without diabetes showed little evidence of genetic associations. Further studies are needed to identify genes associated with these signs in order to help unravel novel pathways and determinants of microvascular diseases.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Regional association plot of SNP rs12155400 on chromosome 7 for Caucasians.
This figure is the regional association plot of SNP rs12155400 on chromosome 7 that reached genome-wide significance in the meta-analysis of GWAS results in participants of European ancestry without diabetes or hypertension. The lead and surrounding SNPs are color coded according to the pair-wise linkage disequilibrium (LD) with the lead SNP (presented as a diamond) on a scale of r2 from 0 to 1. Estimated recombination rates reflect the local LD structure in the 500 kb buffer around the index SNP and plotted based on values from HapMap II Centre d’Etude du Polymorphisme Humain collection samples from a Utah (CEU) population.
Figure 2
Figure 2. Forest plot.
This figure display the direction, effect, 95% confidence interval, sample size and % weight from each individual discovery cohort and overall for the association between SNP rs12155400 on chromosome 7 and retinopathy defined as the presence of microaneurysms or dot-blot hemorrhages. The I2 heterogeneity statistic is a measure of the percentage of variation attributable to differences in effect sizes between cohorts. Results from this SNP were not available in CHS.
Figure 3
Figure 3. Regional association plot of SNP rs10486302 on chromosome 7 for Singapore Asian Indians.
This figure is the regional association plot of SNP rs10486302 on chromosome 7 that reached gene-wide significance (p<4.9×10−4) in the testing of transferability of the discovery SNP, rs12155400, to other SNPs in the histone deacetylase 9 gene in a cohort of Singapore Asian Indians without diabetes or hypertension. The lead and surrounding SNPs are color coded according to the pair-wise linkage disequilibrium (LD) with the lead SNP (presented as a diamond) on a scale of r2 from 0 to 1. Estimated recombination rates reflect the local LD structure in the 500kb buffer around the index SNP and plotted based on values from HapMap II Han Chinese of Beijing China (HCT)/Japanese in Tokyo, Japan (JPT) populations.
Figure 4
Figure 4. Regional association plot of SNP rs213276 on chromosome 7 for African Americans.
This figure is the regional association plot of SNP rs213276 on chromosome 7 that reached gene-wide significance (p<5.2×10−5) in the testing of transferability of the discovery SNP, rs12155400, to other SNPs in the histone deacetylase 9 gene in a cohort of African Americans without diabetes or hypertension. The lead and surrounding SNPs are color coded according to the pair-wise linkage disequilibrium (LD) with the lead SNP (presented as a diamond) on a scale of r2 from 0 to 1. Estimated recombination rates reflect the local LD structure in the 500 kb buffer around the index SNP and plotted based on values from HapMap II Yoruba in Ibadan, Nigeria (YRI) population.

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