TY - JOUR
T1 - Linkage Disequilibrium Testing when Linkage Phase is Unknown
AU - Schaid, Daniel J.
PY - 2004/1
Y1 - 2004/1
N2 - Linkage disequilibrium, the nonrandom association of alleles from different loci, can provide valuable information on the structure of haplotypes in the human genome and is often the basis for evaluating the association of genomic variation with human traits among unrelated subjects. But, linkage phase of genetic markers measured on unrelated subjects is typically unknown, and so measurement of linkage disequilibrium, and testing whether it differs significantly from the null value of zero, requires statistical methods that can account for the ambiguity of unobserved haplotypes. A common method to test whether linkage disequilibrium differs significantly from zero is the likelihood-ratio statistic, which assumes Hardy-Weinberg equilibrium of the marker phenotype proportions. We show, by simulations, that this approach can be grossly biased, with either extremely conservative or liberal type I error rates. In contrast, we use simulations to show that a composite statistic, proposed by Weir and Cockerham, maintains the correct type I error rates, and, when comparisons are appropriate, has similar power as the likelihood-ratio statistic. We extend the composite statistic to allow for more than two alleles per locus, providing a global composite statistic, which is a strong competitor to the usual likelihood-ratio statistic.
AB - Linkage disequilibrium, the nonrandom association of alleles from different loci, can provide valuable information on the structure of haplotypes in the human genome and is often the basis for evaluating the association of genomic variation with human traits among unrelated subjects. But, linkage phase of genetic markers measured on unrelated subjects is typically unknown, and so measurement of linkage disequilibrium, and testing whether it differs significantly from the null value of zero, requires statistical methods that can account for the ambiguity of unobserved haplotypes. A common method to test whether linkage disequilibrium differs significantly from zero is the likelihood-ratio statistic, which assumes Hardy-Weinberg equilibrium of the marker phenotype proportions. We show, by simulations, that this approach can be grossly biased, with either extremely conservative or liberal type I error rates. In contrast, we use simulations to show that a composite statistic, proposed by Weir and Cockerham, maintains the correct type I error rates, and, when comparisons are appropriate, has similar power as the likelihood-ratio statistic. We extend the composite statistic to allow for more than two alleles per locus, providing a global composite statistic, which is a strong competitor to the usual likelihood-ratio statistic.
UR - http://www.scopus.com/inward/record.url?scp=1642330931&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=1642330931&partnerID=8YFLogxK
U2 - 10.1534/genetics.166.1.505
DO - 10.1534/genetics.166.1.505
M3 - Article
C2 - 15020439
AN - SCOPUS:1642330931
SN - 0016-6731
VL - 166
SP - 505
EP - 512
JO - Genetics
JF - Genetics
IS - 1
ER -