VALIDITY OF THE AFFECTED DISCORDANT-SIB-PAIR DESIGN

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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 afected-relative-pair allele-sharing statistics when founders' multilocus genotypes are unknown. We investigated 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 showed 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 (DSP) can be used to control for marker-marker LD in ASPs. Thus, we advocate the ASP/DSP design with appropriate statistics that test the difference in allele sharing between ASPs and DSPs.