Polygenic Inherited Predisposition to Breast Cancer

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Abstract
The known breast cancer predisposing genes account for only about 20% of inherited susceptibility. Epidemiological analyses suggest that much of the remaining 80% is explained by the combined effect of many individually weak genetic variants,rather than by further rare, highly penetrant mutations. In the near term, identification of variants may indicate new pathwaysor mechanisms in breast cancer development. The polygenic model implies a wide distribution of risk in the population. Inthe longer term, it may be possible to construct individual risk profiles to guide public health interventions. The search forgenetic variants has so far proved difficult. A key unanswered question is the "genetic architecture" of predisposition—thatis, strong or weak alleles, common or rare. We describe a genome-wide scan designed to provide a first-pass answer to thisquestion.