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Margaret A Pericak-Vance, Rebecca J Sardell, Muneeswar gupta Nittala, Larry Deon Adams, Renee Laux, Debra Dana, William K Scott, Srinivas R Sadda, Dwight Stambolian, Jonathan L Haines; The heritability of choroidal thickness in the Amish. Invest. Ophthalmol. Vis. Sci. 2016;57(12):2644. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Known genetic variants explain up to 60% of the heritability of Age-related Macular Degeneration (AMD). Unexplained heritability may partly reflect challenges defining the complex phenotype; the current classification system uses broad-scale grades that may not adequately represent the underlying biological basis of AMD. Furthermore, most studies compare advanced cases with controls. We hypothesized that parsing the AMD phenotype into heritable sub-phenotypes, each with a distinct genetic basis (“endophenotypes”), will improve prediction of risk and our understanding of the genetic architecture of AMD.
We quantified fine-scale retinal features using Ocular Coherence Tomography (OCT), compared these traits to the traditional Age-Related Eye Disease Study (AREDS) scale and assessed their potential as endophenotypes. We sampled 690 related individuals from Amish families with early/intermediate AMD cases in Pennsylvania, Ohio and Indiana. The Amish provide an excellent opportunity to analyze the heritability of complex traits given their large nuclear families and relatively homogeneous environmental and genetic backgrounds.
Approximately 70% of individuals were controls (AREDS grade 0/1), 12% had early AMD (grade 2), 12% had intermediate AMD (grade 3) and 6% advanced AMD (grades 4/5). AREDS grade (rs=0.84) and choroidal thickness (r=0.82) were highly correlated between left and right eyes. Choroidal thickness was moderately correlated with AREDS grade (rs=-0.24). A generalized linear mixed model accounting for age, gender, spherical equivalent refraction, repeated measures (left and right eyes) confirmed that choroidal thickness was highly repeatable within individuals (0.78, 95% CI=0.75-0.81) and moderately heritable (additive genetic variance h2=0.40, 95% CI=0.25-0.57). Choroidal thickness also decreased with age (p<0.01, r=-0.45), and was thinner in males (p=0.04).
This is the first reported estimate of the heritability of choroidal thickness, highlighting a heritable, quantitative OCT trait that is measurable in all individuals and correlated with AMD severity. Moderate correlation between choroidal thickness and AREDS grade suggested that this OCT trait captures phenotypic variation not captured by the traditional AREDS system. Choroidal thickness therefore defines an AMD endophenotype useful for genetic studies aiming to further establish the genetic architecture of AMD.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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