期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：1998
卷号：95
期号：4
页码：1741-1745
DOI：10.1073/pnas.95.4.1741
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Allelic association provides a means to map disease genes that, in a dense map of polymorphic markers, has considerably higher resolution than linkage methods. We describe here a composite likelihood estimate of location for a disease gene against a high-resolution marker map by using allele frequencies at linked loci. Data may be family-based, as in the transmission disequilibrium test, or from a case-control study. {chi}2 tests, logarithm of odds, standard errors, and information weights are provided. The method is illustrated by analysis of published cystic fibrosis haplotypes, in which {Delta}F508 is more accurately localized than by other association studies. This differs from current approaches by adopting a more general Malecot model for isolation by distance, where distance here is between marker and disease locus, allowance for errors in the map and model, and freedom from assumptions about demography, systematic pressures, and the ratio of physical to genetic distance. When these assumptions are introduced the number of generations since the original mutation may be estimated, but this is not required to determine location and its standard error, so that evidence from allelic association may be efficiently combined with linkage evidence to identify a region for positional cloning of a disease gene.
关键词：disease gene mapping ; Malecot model ; cystic fibrosis
