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Anna Neustaeter, Anna Leonte, Ilja Nolte, Nomdo M Jansonius, Harold Snieder; Utility of endophenotypic variants in a glaucoma genetic risk score. Invest. Ophthalmol. Vis. Sci. 2020;61(7):57.
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To obtain the increased risk and additionally explained variance of endophenotypic variants added to a glaucoma genetic risk score, based on a glaucoma meta genome-wide association study (GWAS).
We searched the literature for GWAS for glaucoma and related endophenotypes (intraocular pressure [IOP], central corneal thickness [CCT], and optic disc/cup parameters) in Caucasians. The summary statistics of a large glaucoma meta-GWAS were used to create a weighted glaucoma genetic risk score (GRS); variant effect-sizes were multiplied by genotype dosages and summed within a case-control cohort. Endophenotypic variants were weighted for the glaucoma meta-GWAS effect and subsequently added to the GRS. Cases (n=734) were obtained from the Groningen Longitudinal Glaucoma study, and controls (n=1,418) were obtained from the Groningen Expert Center for Kids with Obesity cohort. Adjusted odds ratios (ORs) per standard deviation increase in genetic risk were calculated, in addition to Nagelkerke’s Pseudo R2 and receiver operating characteristic (ROC) curves.
We obtained 47 genome-wide significant variants from the meta-GWAS, 4 additional glaucoma variants, 200 IOP variants, 13 CCT variants, and 4 disc/cup variants, totaling 268 variants of interest. Per standard deviation increase in genetic risk, the OR for glaucoma increased from 1.66, P=6.5*10-25 with glaucoma variants only, to 2.11 P=2.2*10-44 with endophenotypic variants added. The explained variance increased from 7.2% with only glaucoma variants to 14.1% with endophenotypic variants. Associated area under the curves (AUCs) ranged from 63.6% with glaucoma variants to 69.2% with endophenotypic variants added.
The addition of endophenotypic variants to a glaucoma genetic risk score increases both the OR and variance explained. The inclusion of all informative variants for glaucoma genetic risk may improve future population-based genetic screening programs.
This is a 2020 ARVO Annual Meeting abstract.
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