Strategies and sample-size considerations for mapping a two-locus autosomal recessive disorder.

The problem of detecting linkage, by using the LOD-score method, of polymorphic marker loci to a disorder that is determined by recessive alleles at two independent autosomal diallelic loci has been considered. The expected LOD score and the distribution of the LOD score have been worked out for various scenarios. It is found that the expected numbers of families to be sampled for detection of linkage are within feasible limits if the recombination fractions between the marker loci and the disorder loci are less than or equal to .1. The strategy of studying affected offspring only is shown to be more efficient than the strategy of studying both affected and normal offspring. The efficiency of the "affecteds-only" strategy (1) increases with increase in sibship size, (2) decreases with increase in population prevalence of the disorder, and (3) increases with increase in recombination distances between the marker and the disorder loci. From various considerations, it is found that sampling families of sibship size three with at least one affected, and adopting the affecteds-only strategy for analysis, may be an optimal strategy.