Genome screens using linkage disequilibrium tests: optimal marker characteristics and feasibility.
Linkage disequilibrium (LD) testing has become a popular and effective method of fine-scale disease-gene localization. It has been proposed that LD testing could also be used for genome screening, particularly as dense maps of diallelic markers become available and automation allows inexpensive genotyping of diallelic markers. We compare diallelic markers and multiallelic markers in terms of sample sizes required for detection of LD, by use of a single marker locus in a case-control study, for rare monophyletic diseases with Mendelian inheritance. We extrapolate from our results to discuss the feasibility of single-marker LD screening in more-complex situations. We have used a deterministic population genetic model to calculate the expected power to detect LD as a function of marker density, age of mutation, number of marker alleles, mode of inheritance of a rare disease, and sample size. Our calculations show that multiallelic markers always have more power to detect LD than do diallelic markers (under otherwise equivalent conditions) and that the ratio of the number of diallelic to the number of multiallelic markers needed for equivalent power increases with mutation age and complexity of mode of inheritance. Power equivalent to that achieved by a multiallelic screen can theoretically be achieved by use of a more dense diallelic screen, but mapping panels of the necessary resolution are not currently available and may be difficult to achieve. Genome screening that uses single-marker LD testing may therefore be feasible only for young (<20 generations), rare, monophyletic Mendelian diseases, such as may be found in rapidly growing genetic isolates.
Chapman
N H
NH
Department of Biostatistics, Department of Medicine, University of Washington, Seattle, USA. nicky@biostat.washington.edu
Wijsman
E M
EM
D000483:Alleles; D016022:Case-Control Studies; D005787:Gene Frequency; D005799:Genes, Dominant / Q000235:genetics; D005808:Genes, Recessive / Q000235:genetics; D030342:Genetic Diseases, Inborn / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics*; D005820:Genetic Testing; D005828:Genetics, Population; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics*; D008957:Models, Genetic; D018401:Sample Size; D012680:Sensitivity and Specificity; D013997:Time Factors
D005819:Genetic Markers