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Genome-wide association study of retinopathy in individuals without diabetes

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posted on 2023-05-18, 03:41 authored by Jensen, RA, Sim, X, Li, X, Cotch, MF, Ikram, MK, Holliday, EG, Eiriksdottir, G, Harris, TB, Jonasson, F, Klein, BEK, Launer, LJ, Smith, AV, Boerwinkle, E, Cheung, N, Alexander HewittAlexander Hewitt, Liew, G, Mitchell, P, Wang, JJ, Attia, J, Scott, R, Glazer, NL, Lumley, T, McKnight, B, Psaty, BM, Taylor, K, Hofman, A, de Jong, PTVM, Rivadeneira, F, Uitterlinden, AG, Tay, WT, Teo, YY, Seielstad, M, Liu, J, Cheng, CY, Saw, SM, Aung, T, Ganesh, SK, O'Donnell, CJ, Nalls, MA, Wiggins, KL, Kuo, JZ, van Duijn, CM, Gudnason, V, Klein, R, Siscovick, DS, Rotter, J, Tai, ES, Vingerling, J, Wong, TY
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 (r2 ~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.


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PLoS One



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Tasmanian School of Medicine


Public Library of Science

Place of publication

United States

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Licensed under Creative Commons Attribution 3.0 Unported (CC BY 3.0)

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Clinical health not elsewhere classified

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