TY - JOUR
T1 - The affected-/discordant-sib-pair design can guarantee validity of multipoint model-free linkage analysis of incomplete pedigrees when there is marker-marker disequilibrium
AU - Xing, Chao
AU - Sinha, Ritwik
AU - Xing, Guan
AU - Lu, Qing
AU - Elston, Robert C.
N1 - Funding Information:
Some of the results in this article were obtained using the program package S.A.G.E., which is supported by U.S. Public Health Service Resource Grant RR03655 from the National Center for Research Resources. This work was supported in part by research grants GM-28356, from the National Institute of General Medical Sciences, and DK-57292, from the National Institute of Diabetes, Digestive and Kidney Diseases, and by Cancer Center Support Grant P30CAD43703, from the National Cancer Institute. C.X. is supported by a fellowship from the Merck Foundation.
PY - 2006/8
Y1 - 2006/8
N2 - Genomewide linkage studies are tending toward the use of single-nucleotide polymorphisms (SNPs) as the markers of choice. However, linkage disequilibrium (LD) between tightly linked SNPs violates the fundamental assumption of linkage equilibrium (LE) between markers that underlies most multipoint calculation algorithms currently available, and this leads to inflated affected-relative- pair allele-sharing statistics when founders' multilocus genotypes are unknown. In this study, we investigate the impact that the degree of LD, marker allele frequency, and association type have on estimating the probabilities of sharing alleles identical by descent in multipoint calculations and hence on type I error rates of different sib-pair linkage approaches that assume LE. We show that marker-marker LD does not inflate type I error rates of affected sib pair (ASP) statistics in the whole parameter space, and that, in any case, discordant sib pairs (DSPs) can be used to control for marker-marker LD in ASPs. We advocate the ASP/DSP design with appropriate sib-pair statistics that test the difference in allele sharing between ASPs and DSPs.
AB - Genomewide linkage studies are tending toward the use of single-nucleotide polymorphisms (SNPs) as the markers of choice. However, linkage disequilibrium (LD) between tightly linked SNPs violates the fundamental assumption of linkage equilibrium (LE) between markers that underlies most multipoint calculation algorithms currently available, and this leads to inflated affected-relative- pair allele-sharing statistics when founders' multilocus genotypes are unknown. In this study, we investigate the impact that the degree of LD, marker allele frequency, and association type have on estimating the probabilities of sharing alleles identical by descent in multipoint calculations and hence on type I error rates of different sib-pair linkage approaches that assume LE. We show that marker-marker LD does not inflate type I error rates of affected sib pair (ASP) statistics in the whole parameter space, and that, in any case, discordant sib pairs (DSPs) can be used to control for marker-marker LD in ASPs. We advocate the ASP/DSP design with appropriate sib-pair statistics that test the difference in allele sharing between ASPs and DSPs.
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U2 - 10.1086/506331
DO - 10.1086/506331
M3 - Article
C2 - 16826532
AN - SCOPUS:33746528598
SN - 0002-9297
VL - 79
SP - 396
EP - 401
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 2
ER -