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Anthony Musolf, Annechien E.G. Haarman, Deyana D Lewis, Virginie JM Verhoeven, Caroline C. W. Klaver, Joan E Bailey-Wilson; Novel genes are associated with refractive error in Indo-Europeans and East Asians using rare variant aggregation tests. Invest. Ophthalmol. Vis. Sci. 2021;62(8):2341.
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Refractive error is one of the most common eye diseases in the world. While genome-wide association studies (GWAS) have identified many potential risk loci for refractive error, these variants have been common with moderate to small effect on the disease trait. The aggregated Cauchy association test (ACAT) allows for the combination of single variant p-values into an overall gene p-value, providing increased power on rare variants (RV) compared to single marker tests.
We jointly analyzed exome-based genotype data and quantitative mean spherical equivalent (SER) measurements in diopters (D) on 13 population-based cohorts. These cohorts were combined and then split into two ancestry groups, Indo-Europeans (13,037 subjects) and East Asians (4,867 subjects), for analysis. Three additional European cohorts: the Raine Eye Health Study, the Beaver Dam Eye Study, and the EPIC-Norfolk study were used as replication sets, giving a total of five cohorts analyzed.We performed single variant association analysis (one RV at a time with the SER phenotype) using EMMAX, which accounts for cryptic relatedness and ancestry differences. Variants were filtered to MAF ≤ 0.01; only exonic variants were included. We used ACAT to combine the single variant p-values in a given gene into a single p-value for that gene. This is distinct from burden style tests, such as the variable threshold test, which combines RVs into a single, new marker on which association analysis is performed. Different approaches have different strengths and weaknesses, which is beneficial when searching for candidate genes. Fisher’s method was further used to combine the gene p-values.
The meta-analysis across the five cohorts identified 28 genome-wide significant genes using a significance threshold of 1 x 10-5. The most significant gene was MUC16 (p=9.61 x 10-10). 11 of the 28 genes were found to be significant in one cohort and replicated in another. Good candidate genes for causality include GDF15 (p=1.95 x 10-9), which is known to be overexpressed in myopic eyes, ST6GALNAC5 (p=9.03 x 10-10), which may stimulate new rod development in zebrafish, and PER3 (p=1.08 x 10-6) located near the known myopia locus MYP14 on 1p36.
We have identified 28 novel genes that are associated with refractive error using gene-based RV tests. Further validation studies are planned to confirm these results.
This is a 2021 ARVO Annual Meeting abstract.
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