MAPPING A DISEASE LOCUS BY ALLELIC ASSOCIATION

Allelic association provides a means to map disease genes that, in a d ense map of polymorphic markers, has considerably higher resolution th an linkage methods, We describe here a composite likelihood estimate o f 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 wei ghts are provided, The method is illustrated by analysis of published cystic fibrosis haplotypes, in which Delta F508 is more accurately loc alized than by other association studies, This differs from current ap proaches by adopting a more general Malecot model for isolation by dis tance, where distance here is between marker and disease locus, allowa nce for errors in the map and model, and freedom from assumptions abou t demography, systematic pressures, and the ratio of physical to genet ic distance, When these assumptions are introduced the number of gener ations since the original mutation may be estimated, but this is not r equired to determine location and its standard error, so that evidence from allelic association may be efficiently combined with linkage evi dence to identify a region for positional cloning of a disease gene.