HTT haplotypes contribute to differences in Huntington disease prevalence between Europe and East Asia

Abstract

Huntington disease (HD) results from CAG expansion in the huntingtin (HTT) gene. Although HD occurs worldwide, there are large geographic differences in its prevalence. The prevalence in populations derived from Europe is 10-100 times greater than in East Asia. The European general population chromosomes can be grouped into three major haplogroups (group of similar haplotypes): A, B and C. The majority of HD chromosomes in Europe are found on haplogroup A. However, in the East-Asian populations of China and Japan, we find the majority of HD chromosomes are associated with haplogroup C. The highest risk HD haplotypes (A1 and A2), are absent from the general and HD populations of China and Japan, and therefore provide an explanation for why HD prevalence is low in East Asia. Interestingly, both East-Asian and European populations share a similar low level of HD on haplogroup C. Our data are consistent with the hypothesis that different HTT haplotypes have different mutation rates, and geographic differences in HTT haplotypes explain the difference in HD prevalence. Further, the bias for expansion on haplogroup C in the East-Asian population cannot be explained by a higher average CAG size, as haplogroup C has a lower average CAG size in the general East-Asian population compared with other haplogroups. This finding suggests that CAG-tract size is not the only factor important for CAG instability. Instead, the expansion bias may be because of genetic cis-elements within the haplotype that influence CAG instability in HTT, possibly through different mutational mechanisms for the different haplogroups.

Huntington disease in the South African population occurs on diverse and ethnically distinct genetic haplotypes

“…A similar principle has been shown in European and East Asian populations. 15 The South African population comprises largely Caucasian, 'mixed' and black groups. The Caucasian subpopulation had its origins in European settlers from several countries (Holland, Germany, England and France) who arrived in South Africa around the 17th century; with on-going contributions from European migration.…”

“…Further, the absence of 'high-risk' variants (A1 and A2) found in European populations may account for proportionally lower HD prevalence in the black subpopulation relative to Caucasian and mixed groups, as has been previously suggested for East Asian populations. 15 The prevalence of HD in any population is thought to be the result of a balance between the incidence of de novo mutations and the loss of HD alleles due to negative selection of very large CAG tracts that result in juvenile-onset HD. 29 The new mutation rate has been estimated at approximately 10%.…”

“…Haplogroups were assigned based on 21 previously described tSNPs derived from a European population. 15 Previously unknown variants were defined in part by the addition of tSNP rs10015979, reflecting a linkage disequilibrium block not captured by the initial 21 tSNP panel ( Figure 3). African variants A6 and A7 were added to haplogroup A, whereas haplogroups B and C were sub-divided into B1 and B2, and C and C-South Africa (C-SA), respectively.…”

“…14 Support for the hypothesis that genetic background may modulate the CAG mutation rate has recently been shown at a population level. 15 In a 2011 study by Warby et al 15 , differences in HD prevalence rates reported in European and Asian populations were associated with different haplotype distributions of disease alleles. The genetic diversity in the HTT gene was delineated using a subset of tagging SNPs (tSNPs) associated with disease-causing expanded alleles in the European population.…”

“…16 These high-risk variants were absent from an East Asian cohort, consistent with the hypothesis that HD prevalence could be explained by geographical differences in HTT haplotypes. 15 No such studies have yet been performed in South Africa where the prevalence of HD has been reported to differ significantly between different population groups. 17 The largest proportion of the South African population consists of black, Caucasian (or white) and mixed (or coloured) peoples (www.statssa.gov.za).…”