Grade-of-membership sibpair linkage analysis maps IDDM11 to chromosome 14q24.3–q31

Abstract

We demonstrate the use of Grade-of-membership (GoM) (Manton et al. 1994) for sibpair linkage analysis: GoM was used to map the IDDM11 locus to the region of chromosome 14q24.3 identified by Field et al. (1996). Haplotype groups were constructed from sib pair information on the number of shared alleles. The sample consisted of 578 sibling pairs found in 246 multiplex IDDM families. Both siblings were diabetic in 53% of the pairs (AA). Pair members could share 0, 1 or 2 alleles IBS at each of eight linked marker loci spanning IDDM11. Three model-based groups best represented the data on allele sharing: the groups corresponded to ‘No’, ‘One’ and ‘Two’ shared haplotypes for the region. Group ‘Two’ was larger (37% vs. 25%, p<0.0001) and more homogeneous (p<0.0001) than expected by chance consistent with the IDDM11 locus being a determinant of diabetes in multiplex families. Genetic linkage of IDDM to the region was demonstrated by a 19% increase in the proportion of AA pairs over the haplotype groups: ‘No’, 42%; ‘One’, 49%; ‘Two’, 61%, p = 0.0005, representing a 43% relative increase.