DNA ANALYSIS OF DISTINCT POPULATIONS SUGGESTS MULTIPLE ORIGINS FOR THE MUTATION CAUSING HUNTINGTON DISEASE

Results of association studies can be significantly biased if the ance stry of the control population is not similar to that of the affected population. One approach to overcome such a bias is to use distinct po pulations where controls and affected individuals are likely to be of similar descent. We have examined homogeneous populations of French, D anish and Swedish ancestry for nonrandom allelic association between H untington disease (HD) and several markers previously shown to be in a ssociation with HD. No evidence for nonrandom allelic association betw een HD and these markers was shown in these populations. The demonstra tion of association in a United Kingdom (UK) sample of similar size, a nd lack of significant differences in allele frequencies between the F rench, Danish, Swedish and UK populations suggested that the absence o f association was not predominantly a consequence of allele frequencie s or sample size. To investigate further the number of potential HD ch romosomes, DNA haplotypes were constructed for the Danish, French, Swe dish and UK populations. The minimum of two HD haplotypes observed in each of the French, Danish and Swedish populations, compared to the on e haplotype in the UK population of a similar size, is an important fa ctor accounting for the absence of association between HD and the DNA markers in these populations. Furthermore, these data are in favour of multiple independent origins for the mutation causing HD.