Age and sex based genetic locus heterogeneity in type 1 diabetes

Background-Two genome scans for susceptibility loci for type 1 diabetes usi ng large collections of families have recently been reported. Apart from st rong linkage in both studies of the HLA region on chromosome 6p, clear cons istent evidence for Linkage was not observed at any other loci. One possibl e explanation for this is a high degree of locus heterogeneity in type 1 di abetes, and we hypothesised that the sex of affected offspring, age of diag nosis, and parental origin of shared alleles may be the bases of heterogene ity at some loci. Methods-Using data from a genome wide linkage study of 356 affected sib pai rs with type 1 diabetes, we performed linkage analyses using parental origi n of shared alleles in subgroups based on (1) sex of affected sibs and (2) age of diagnosis. Results-Among the results obtained, we observed that evidence for linkage t o IDDM4 on chromosome 11q13 occurred predominantly from opposite sex, rathe r than same sex sib pairs. At a locus on chromosome 4q, evidence for Linkag e was observed in sibs where one was diagnosed above the age of 10 years an d the other diagnosed below 10 years of age. Conclusions-We show that heterogeneity tests based on age of diagnosis, sex of affected subject, and parental origin of shared alleles may be helpful in reducing locus heterogeneity in type I diabetes. If repeated in other sa mples, these findings may assist in the mapping of susceptibility loci for type 1 diabetes. Similar analyses can be recommended in other complex disea ses.