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Pedigree tests of transmission disequilibrium Goncalo R Abecasis, William OC Cookson and Lon R Cardon

Summary: ARTICLE
Pedigree tests of transmission disequilibrium
Gon¸calo R Abecasis, William OC Cookson and Lon R Cardon
Wellcome Trust Center for Human Genetics, University of Oxford, UK
High-resolution mapping is essential for the positional cloning of complex disease genes. In outbred
populations, linkage disequilibrium is expected to extend for short distances and could provide a powerful
fine-mapping tool. Current family-based association tests use nuclear family members to define 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
information. Family data allows for the construction of an expected genotype for every non-founder, and
orthogonal deviates from this expectation are a measure of allelic transmission. These allelic transmission
scores can be used to extend previously described tests of linkage disequilibrium for dichotomous or
quantitative traits. Some of these tests are illustrated, together with a permutation framework for
estimating exact significance levels. Simulation studies are used to investigate power and error rates of the
approach. As a practical application, the method is used to investigate the relationship between circulating
angiotensin-1 converting enzyme (ACE) levels and polymorphisms in the ACE gene using previously
published data. European Journal of Human Genetics (2000) 8, 545­551.
Keywords: Linkage disequilibrium; gene mapping; SNP; quantitative trait; ACE; large pedigrees
Disease genes can be identified on the basis of their location,


Source: Abecasis, Goncalo - Department of Biostatistics, University of Michigan


Collections: Biology and Medicine; Mathematics