A two-susceptibility-allele model for genetic diseases and associated marker loci: differences and similarities to a one-s-allele model.

A model for genetic diseases and associated markers is defined where two distinct susceptibility alleles are possible, each associated with a different marker allele. Marker genotype distributions in a disease population are then expressed in terms of haplotype frequencies and penetrance parameters. It is shown that, if the heterozygote with two different disease alleles has a higher penetrance than the two disease homogzygotes, the observed to 'Hardy-Weinberg-expected' ratio of associated marker genotypes (the alpha/beta ratio of Falk, Mendell & Rubinstein, 1983) will always be greater than or equal to one. When all disease penetrances are equal, the model becomes indistinguishable from a recessive one-s-allele model with alpha/beta = 1. Application of these observations to several data sets for insulin dependent diabetes mellitus suggests the possibility that different marker genotype distributions in different samples may be due to different penetrances of the disease genotypes in the samples. If a particular environment causes the heterozygote disease genotype (with two different disease alleles) to have the highest penetrance, the marker genotype distribution would be compatible with the 2-s-allele model. In other environments where the three disease genotypes have essentially equal penetrances, the marker distribution would be compatible with the 1-s-allele model.