The effects of reduced fertility, method of ascertainment, and a second unlinked locus on affected sib-pair marker allele sharing.

The method of affected sib-pair marker allele sharing has been used not only for the detection of linkage, but also for discerning inheritance. The application of this method has included the tacit assumption of no selective disadvantage for affected individuals. For some of the disorders analyzed by this method, this assumption is not tenable. Also, the method of ascertainment of affected sib pairs is not taken into account. It is shown here that the ascertainment procedure and reduced reproductivity of affected individuals can alter the expected distribution of affected sib-pair marker allele sharing. The effect is greatest for a recessive disease susceptibility locus. While the effect of reduced reproductivity is to inflate the gene frequency necessary to account for the observed distribution, a second unlinked disease susceptibility locus can diminish this effect. Application to type 1 diabetes shows that according to a simple recessive model with 50% penetrance, the observed distribution of affected sib-pair HLA haplotype sharing requires a gene frequency in the range of 0.55-0.60, much greater than estimates previously proposed. According to such a model, the frequency of disease would be around 15%, clearly out of range of the observed frequency of 0.4%.