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Copyright © 2000 by The American
Journal of Human Genetics. All rights
reserved. A General Test of Association for Quantitative Traits in Nuclear
Families The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford Address for correspondence and reprints: Dr. Gonçalo Abecasis, The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, United Kingdom. E-mail: goncalo/at/well.ox.ac.uk Received April 1, 1999; Accepted September 22, 1999. This article has been cited by other articles in PMC.Summary High-resolution mapping is an important step in the
identification of complex disease genes. In outbred populations, linkage
disequilibrium is expected to operate over short distances and could
provide a powerful fine-mapping tool. Here we build on recently
developed methods for linkage-disequilibrium mapping of quantitative
traits to construct a general approach that can accommodate nuclear
families of any size, with or without parental information. Variance
components are used to construct a test that utilizes information from all
available offspring but that is not biased in the presence of linkage or
familiality. A permutation test is described for situations in which
maximum-likelihood estimates of the variance components are biased.
Simulation studies are used to investigate power and error rates of this
approach and to highlight situations in which violations of multivariate
normality assumptions warrant the permutation test. The relationship
between power and the level of linkage disequilibrium for this test
suggests that the method is well suited to the analysis of dense maps. The
relationship between power and family structure is investigated, and these
results are applicable to study design in complex disease, especially for
late-onset conditions for which parents are usually not available.
When parental genotypes are available, power does not depend greatly on the
number of offspring in each family. Power decreases when parental genotypes
are not available, but the loss in power is negligible when four or more
offspring per family are genotyped. Finally, it is shown that, when
siblings are available, the total number of genotypes required in order to
achieve comparable power is smaller if parents are not
genotyped. |
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