Biostatistics 1:1-26 (2000)
© 2000 Oxford University Press
A score test for the linkage analysis of qualitative and quantitative traits based on identity by descent data from sib-pairs
1 Department of Statistics, University of California, Berkeley, 367 Evans Hall, #3860, Berkeley, CA 94720-3860, USA sandrine{at}stat.berkeley.edu
We propose a general likelihood-based approach to the linkage
analysis of qualitative and quantitative traits using identity by
descent (IBD) data from sib-pairs. We consider the likelihood of IBD
data conditional on phenotypes and test the null hypothesis of no
linkage between a marker locus and a gene influencing the trait using
a score test in the recombination fraction 
between the two
loci. This method unifies the linkage analysis of qualitative and
quantitative traits into a single inferential framework, yielding a
simple and intuitive test statistic. Conditioning on phenotypes
avoids unrealistic random sampling assumptions and allows sib-pairs
from differing ascertainment mechanisms to be incorporated into a
single likelihood analysis. In particular, it allows the selection of
sib-pairs based on their trait values and the analysis of only those
pairs having the most informative phenotypes. The score test is based
on the full likelihood, i.e. the likelihood based on all phenotype
data rather than just differences of sib-pair phenotypes. Considering
only phenotype differences, as in Haseman and Elston (1972) and
Kruglyak and Lander (1995), may result in important losses in power.
The linkage score test is derived under general genetic models for
the trait, which may include multiple unlinked genes. Population
genetic assumptions, such as random mating or linkage equilibrium at
the trait loci, are not required. This score test is thus
particularly promising for the analysis of complex human traits. The
score statistic readily extends to accommodate incomplete IBD data at
the test locus, by using the hidden Markov model implemented in the
programs MAPMAKER/SIBS and GENEHUNTER (Kruglyak and
Lander, 1995; Kruglyak et al., 1996). Preliminary simulation
studies indicate that the linkage score test generally matches or
outperforms the Haseman–Elston test, the largest gains in power
being for selected samples of sib-pairs with extreme phenotypes.
Keywords: Linkage analysis; Complex traits; Qualitative and quantitative phenotypes; Identity by descent (IBD); Score test; Incomplete IBD data; Hidden Markov models; Haseman–Elston test
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