New polymorphic microsatellite markers place the haemochromatosis gene telomeric to D6S105

The haemochromatosis gene (HFE) is linked to both HLA-A and D6S105 on the short arm of chromosome 6 but these markers are separated by approximately 2 Mb of DNA. Most chromosomes carrying HFE have a common haplotype which extends from HLA-A to D6S105 and includes HLA-F. To localise the gene more precisely we have examined 10 microsatellite markers extending over a genetic distance of approximately 5 cM from D6S265 (within 100 kb of HLA-A on the centromeric side) to D6S299 (telomeric). The order of markers is D6S265, HLA-F, D6S258, D6S306, CS3, D6S105, D6S464, CS5, D6S461 and D6S299. We confirm that haemochromatosis appears to originate from a founder mutation which has multiplied in the population through successive generations. This mutation is associated with the haplotype D6S306-5, CS3-3, D6S105-8, D6S464-9 and CS5-4 which is found on approximately 70% of HFE chromosomes. We have applied a new and powerful, likelihood analysis for linkage disequilibrium. The maximum value of lambda (proportion of total possible association between a marker and disease) is 0.74 for marker CS5 (allele 4). A multipoint analysis also gives a maximum likelihood near marker CS5. We conclude that the HFE gene is likely to be located telomeric of D6S105 and close to CS5.