Gaucher disease, a lysosomal storage disease caused by glucocerebrosidase (GBA) deficiency, is far more common in the Ashkenazi Jewish (AJ) population, for reasons which remain controversial. Previous work with GBA polymorphisms suggested that the commonest mutation, N370S, arose from a founder in the AJ population. To investigate the genetic history of this disorder, a 9.2-cM region containing the GBA locus was finely mapped with 10 short tandem repeat markers which were then used for genotyping AJ (n= 140) and non-AJ Portuguese (n=27), and French (n=19) chromosomes carrying N370S mutations. Marker allele frequencies were generated for N370S and control chromosomes from each population. Greater than 92% of the AJ N370S haplotypes were conserved at three of the four central markers, indicating the existence of a common founder. The AJ N370S haplotype was observed frequently in the French and Portuguese populations, although about 26 and 33%, respectively had divergent haplotypes, indicating recurrent N370S mutation events. The linkage disequilibrium parameter, δ, was calculated for the marker loci. The results for the AJ N370S were consistent with a more ancient coalescence for the GBA mutation than for the common AJ idiopathic torsion dystonia mutation which had previously been dated back ∼17 generations (∼1650). French and Portuguese N370S chromosomes carrying the central AJ N370S haplotype had less overall linkage disequilibrium at loci flanking the conserved core haplotype than did the AJ N370S chromosomes. These findings disprove the hypothesis that the N370S mutation arose in the Ashkenazi population and then was bred into the non-Jewish European populations by admixture. Rather, the AJ N370S was ancient in Europe and rose to high prevalence after its introduction into the AJ population. The finding that AJ and European non-AJ N370S chromosomes share a common origin do not support models positing heterozygote advantage as a mechanism to explain the high frequency of the N370S mutation in the AJ population.

Original languageEnglish
Pages (from-to)169A
JournalJournal of Investigative Medicine
Issue number2
StatePublished - Feb 1999


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