Simulation of BRCA1&2 case-control mutation screening as an approach to characterize intermediate-risk susceptibility genes

Abstract

While high-risk susceptibility genes are traditionally found and/or analyzed by linkage analysis-related methods, the case-control association study-based methods are used to assess candidate-modest risk genes. At least a subset of these intermediate-risk genes can be assessed in a case-control mutation screening format using pooled evidence from a set of genetic variants that are intrinsically likely to alter gene function, comprised of a mix of truncating, splice junction, missense and regulatory variants selected via explicit analysis-based criteria. In the present study a systematic approach to assembling such a TSMR pool and use BRCA1 and BRCA2 mutation screening data in simulated tests of association to demonstrate the utility of the TSMR pool/case-control mutation screening strategy.