High-resolution mapping is essential for the positional cloning of complex
disease genes. In outbred populations, linkage disequilibrium is expected t
o extend for short distances and could provide a powerful fine-mapping tool
. Current family-based association tests use nuclear family members to defi
ne allelic transmission and controls, but ignore other types of relatives.
Here we construct a general approach for scoring allelic transmission that
accommodates families of any size and uses all available genotypic informat
ion. Family data allows for the construction of an expected genotype for ev
ery non-founder, and orthogonal deviates from this expectation are a measur
e of allelic transmission. These allelic transmission scores can be used to
extend previously described tests of linkage disequilibrium for dichotomou
s or quantitative traits. Some of these tests are illustrated, together wit
h a permutation framework for estimating exact significance levels. Simulat
ion studies are used to investigate power and error rates of the approach.
As a practical application, the method is used to investigate the relations
hip between circulating angiotensin-l converting enzyme (ACE) levels and po
lymorphisms in the ACE gene using previously published data.