We are following an inbred kindred segregating a very rare autosomal
recessive disease. Due to the rarity of the condition and the small
geographic area from which the ancestors originate, we believe that the
mutation originates from a single founding ancestor. Thus we will be using
the technique known as homozygosity mapping to find a region consistently
homozygous in all affected individuals. This will involve genotyping simple
-sequence-repeat markers at 10 cM intervals throughout the genome.
Assuming we find a marker or haplotype of linked markers consistently
homozygous in all affecteds, we are unsure as to the best statistical
methodology to demonstrate the significance of the association. Since we have
not been able to trace the ancestry to the presumptive founder, the
calculation of LOD scores by conventional linkage analysis will not be very
useful since the power of consanguineous matings will be lost.
We are contemplating using a modified chi-squared test using the
null hypothesis that the homozygosity in the affecteds is a chance
occurrence.
Would anyone like to offer suggestions or otherwise comment on an
appropriate statistical approach in this type of situation?
Roger C. Green, Faculty of Medicine Phone: (709)737-6884
Memorial University , St. John's, Newfoundland FAX : (709)737-7010
