Alternative titles; symbols
Other entities represented in this entry:
DO: 0110745;
Cytogenetic location: 18q21 Genomic coordinates (GRCh38): 18:45,900,001-63,900,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 18q21 | {Diabetes mellitus, insulin-dependent, 6} | 601941 | 2 |
Because of previous evidence of linkage of the region of 18q12-q21 containing the Kidd blood group (111000) and the DNA marker D18S64 to type 1 diabetes (IDDM; see 222100) (Hodge et al., 1981), Merriman et al. (1997) evaluated 12 informative microsatellite markers for linkage with disease by the transmission disequilibrium test (TDT) in a U.K. dataset of type 1 diabetic families (n = 195). They detected increased transmission of allele 4 of marker D18S487 to affected children (P = 0.02). Support for this result was extended to a total of 1,067 families from 4 different countries by isolating, and evaluating by TDT, 2 novel microsatellites within 70 kb of D18S487. Evidence for linkage and association was P = 5 x 10(-5) and 3 x 10(-4), respectively. There was no evidence for increased transmission of associated alleles to unaffected sibs. Analysis of an additional 390 families by TDT did not extend the evidence further, and reduced support in the total 1,457 families to P = 0.001 for linkage and P = 0.003 for association. However, evidence for linkage by affected sib pair allele sharing was strong in the second dataset; P = 3.2 x 10(-5). This IDDM locus was designated IDDM6. Heterogeneity in TDT results between datasets was, in part, accounted for by the presence of more than 1 common disease-associated haplotype (allelic heterogeneity), which confounded the analysis of individual alleles by TDT.
Merriman et al. (1997) discussed the enormous challenge of identifying polygenes in a disorder such as IDDM (see 222100), because of the combination of locus, allelic, and clinical heterogeneity. On the basis of their results with IDDM6, they made some recommendations for strategies. Evidence of linkage in affected sib pair families (the most common pedigree configuration in common polygenic diseases) should be sought in several different populations. The ideal family datasets are those drawn from isolated populations, such as Sardinia and Finland, or from countries such as Denmark, Sweden, Spain, Italy, or Norway, which are more homogeneous in population than the U.S. or U.K. If only 1 dataset shows positive evidence of linkage to a chromosome region, evidence of replication should be sought by collecting more families from the same country. Given consistent evidence of linkage, linkage disequilibrium should be evaluated specifically in the linked region using all available microsatellites with an appropriate level of polymorphism. The hope is that by defining different founder chromosomes in different populations, regions of strongest and most consistent linkage disequilibrium with multiple markers can be defined.
Using a single microsatellite marker at each locus, Vaidya et al. (2000) screened the type 1 diabetes loci IDDM4, IDDM5, IDDM6, IDDM8 (600883), and IDDM10 (601942), as well as the fucosyltransferase-2 locus (FUT2; 182100), for linkage in sib pairs with Graves disease (275000). A 2-point nonparametric linkage (NPL) score of 1.57 (P = 0.06) at the IDDM6 marker D18S41 was found, but NPL scores were less than 1.0 at the other 5 loci. The investigation of the IDDM6 locus was extended by genotyping 11 microsatellite markers spanning 48 cM across 18q12-q22 in 81 sib pairs affected with autoimmune thyroid disease (AITD; see 608173). Multipoint analysis showed a peak NPL score of 3.46 (P = 0.0003) at marker D18S487. This locus is also designated AITD5.
Hodge, S. E., Anderson, C. E., Neiswanger, K., Field, L. L., Spence, M. A., Sparkes, R. S., Sparkes, M. C., Crist, M., Terasaki, P. I., Rimoin, D. L., Rotter, J. I. Close genetic linkage between diabetes mellitus and Kidd blood group. Lancet 318: 893-895, 1981. Note: Originally Volume II. [PubMed: 6117683] [Full Text: https://doi.org/10.1016/s0140-6736(81)91391-x]
Merriman, T., Twells, R., Merriman, M., Eaves, I., Cox, R., Cucca, F., McKinney, P., Shield, J., Baum, D., Bosi, E., Pozzilli, P., Nistico, L., Buzzetti, R., Joner, G., Ronningen, K. S., Thorsby, E., Undlien, D., Pociot, F., Nerup, J., Bain, S., Barnett, A., Todd, J. Evidence by allelic association-dependent methods for a type 1 diabetes polygene (IDDM6) on chromosome 18q21. Hum. Molec. Genet. 6: 1003-1010, 1997. Note: Erratum: Hum. Molec. Genet. 16: 3197 only, 2007. [PubMed: 9215667] [Full Text: https://doi.org/10.1093/hmg/6.7.1003]
Vaidya, B., Imrie, H., Perros, P., Young, E. T., Kelly, W. F., Carr, D., Large, D. M., Toft, A. D., Kendall-Taylor, P., Pearce, S. H. S. Evidence for a new Graves disease susceptibility locus at chromosome 18q21. Am. J. Hum. Genet. 66: 1710-1714, 2000. [PubMed: 10762555] [Full Text: https://doi.org/10.1086/302908]