Using affected sib-pairs to uncover rare disease variants.

OBJECTIVE We propose a new test for rare variant mapping, based on an affected sib-pair sample and a control sample. In each sib-pair, only the index case needs to be sequenced, and the number of alleles shared identical-by-descent between the sibs is used as complementary information. The test makes use of both association and linkage information. We compare this test to the Armitage test on case-control data, with cases either from the general population of cases or from a sample of cases having an affected sib. METHODS A score test based on the likelihood in a multiplicative risk model is proposed. Its power is estimated by simulations and compared to Armitage test's power. RESULTS The affected sib-pairs design allows a tremendous gain of power over the case-control design (from 1 to 99% for a moderate sample size and relative risk values around 3, at an α level of 10(-11)). When cases are ascertained in a sample of cases having an affected sib, the use of linkage information in our test allows a gain of power of more than 20% in certain situations. CONCLUSION We demonstrate the interest in using familial data and both association and linkage information for rare variant mapping.