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This article is part of the supplement: Genetic Analysis Workshop 17: Unraveling Human Exome Data

Open Access Proceedings

Do rare variant genotypes predict common variant genotypes?

Jack W Kent*, Vidya Farook, Harald HH Göring, Thomas D Dyer, Laura Almasy, Ravindranath Duggirala and John Blangero

Author Affiliations

Department of Genetics, Texas Biomedical Research Institute, PO Box 760549, San Antonio, TX 78245-0249, USA

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BMC Proceedings 2011, 5(Suppl 9):S87  doi:10.1186/1753-6561-5-S9-S87

Published: 29 November 2011

Abstract

The synthetic association hypothesis proposes that common genetic variants detectable in genome-wide association studies may reflect the net phenotypic effect of multiple rare polymorphisms distributed broadly within the focal gene rather than, as often assumed, the effect of common functional variants in high linkage disequilibrium with the focal marker. In a recent study, Dickson and colleagues demonstrated synthetic association in simulations and in two well-characterized, highly polymorphic human disease genes. The converse of this hypothesis is that rare variant genotypes must be correlated with common variant genotypes often enough to make the phenomenon of synthetic association possible. Here we used the exome genotype data provided for Genetic Analysis Workshop 17 to ask how often, how well, and under what conditions rare variant genotypes predict the genotypes of common variants within the same gene. We found nominal evidence of correlation between rare and common variants in 21-30% of cases examined for unrelated individuals; this rate increased to 38-44% for related individuals, underscoring the segregation that underlies synthetic association.