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

Abstract

Huntington disease (HD) is a neurodegenerative disorder resulting from the expansion of a CAG trinucleotide repeat in the huntingtin (HTT) gene. Worldwide prevalence varies geographically with the highest figures reported in populations of European ancestry. HD in South Africa has been reported in Caucasian, black and mixed subpopulations, with similar estimated prevalence in the Caucasian and mixed groups and a lower estimate in the black subpopulation. Recent studies have associated specific HTT haplotypes with HD in distinct populations. Expanded HD alleles in Europe occur predominantly on haplogroup A (specifically high-risk variants A1/A2), whereas in East Asian populations, HD alleles are associated with haplogroup C. Whether specific HTT haplotypes associate with HD in black Africans and how these compare with haplotypes found in European and East Asian populations remains unknown. The current study genotyped the HTT region in unaffected individuals and HD patients from each of the South African subpopulations, and haplotypes were constructed. CAG repeat sizes were determined and phased to haplotype. Results indicate that HD alleles from Caucasian and mixed patients are predominantly associated with haplogroup A, signifying a similar European origin for HD. However, in black patients, HD occurs predominantly on haplogroup B, suggesting several distinct origins of the mutation in South Africa. The absence of high-risk variants (A1/A2) in the black subpopulation may also explain the reported low prevalence of HD. Identification of haplotypes associated with HD-expanded alleles is particularly relevant to the development of population-specific therapeutic targets for selective suppression of the expanded HTT transcript.

Figure 1

Distribution of CAG-tract sizes in the South African population. (a) CAG-tract sizes of 128 unrelated HD alleles. There are no significant differences in mean HD CAG size between the different subpopulations (P=0.308, one-way ANOVA).(b) CAG-tract sizes of 660 unrelated general population alleles. The mean CAG in black South Africans is significantly lower than that in the Caucasian subpopulation (P=3.673E-06, one-way ANOVA with Tukey post-hoc; 95% CI black: 16.63–17.19 versus 95% CI Caucasian: 17.78–18.67). Confidence intervals for mean CAG in the mixed subpopulation overlap Caucasian and black subpopulations (95% CI mixed: 16.78–18.02). The most frequent CAG-tract size is 17 repeats in the Caucasian and mixed subpopulations, but 15 repeats in the black subpopulation. Note that 15 repeats is the second most common CAG size in the mixed subpopulation.

Figure 2

Haplogroup variants on phased, unrelated alleles from the South African population. (a) HD haplogroups and variants (N=72). HD alleles in the Caucasian subpopulation occur almost exclusively on haplogroup A (94%), predominantly variants A1 and A2 (39% and 50%, respectively). In the mixed subpopulation, the largest proportion of HD alleles also occurs on haplogroup A (79%). Similar to the Caucasian subpopulation, variants A1 and A2 (21% and 53%, respectively) predominate. In the black subpopulation, haplogroup A accounts for only a small proportion of HD alleles (14%), with A1 and A2 absent, whereas the largest proportion occurs on novel variant B2 (40%). (b) General population haplogroups and variants (N=311). In all three subpopulations, the largest proportion of general population alleles occurs on haplogroup C. Haplogroup A in the Caucasian subpopulation accounts for 36% of general population alleles, with variants A1 and A2 present at 6% and 9%, respectively. In the mixed subpopulation 28% of general population alleles occur on haplogroup A, but variant A4 predominates (15%). Haplogroup A also occurs in the black subpopulation (27%) but with a markedly different distribution consisting of A4 and novel variants A6 and A7. A large proportion of all the general population haplotypes in the black subpopulation can be additionally grouped into South African group C-SA (27%), consisting of C haplotypes not previously identified in Caucasian or East Asian populations. Mixed general population haplotypes thus represent an admixture of variants observed in Caucasian and black subpopulations.

Figure 3

Definitions of HTT haplogroup variants using 22 tSNPs spanning the gene region. Red, yellow and blue SNP genotypes near the CAG repeat define A, B and C haplogroups, respectively. Boxed SNP genotypes represent variant-specific defining SNPs within haplogroups. Asterisks (*) represent variable SNP alleles within haplogroups C and C-SA. Haplogroup variants are grouped by 93-SNP sequence similarity in a neighbour-joining tree, with branch distances drawn to a constant rate of evolution in units of base substitutions per site. Tree was constructed using the Maximum Composite Likelihood method in MEGA5. Haplogroup variants in brown italics indicate those unique to the South African population.

Figure 4

CAG-tract distributions of haplogroup variants. Only haplogroups with differences between HD and general population alleles are shown. (a) Caucasian subpopulation. Variants A1 and A2 are associated with HD alleles (CAG>35) (OR 10.39, P=0.0019 and OR 9.3, P=0.0007, respectively, Fisher's exact test). Haplogroup C is largely absent from HD alleles (OR 0.04, P=8.09E-05, Fisher's exact test). (b) Mixed subpopulation. Similar to the white subpopulation, variants A1 and A2 are associated with HD alleles (OR 5.51, P=0.0431 and OR 71.11, P=3.27E-07, respectively). Haplogroup C is uncommon on HD alleles versus those in the mixed general population (OR 0.12, P=0.0029, Fisher's exact test). (c) Black subpopulation. In contrast to Caucasian and mixed groups, HD alleles are associated with the novel variant B2 (OR 12.27, P=2.06E-07, Fisher's exact test). Novel South African C group, C-SA is uncommon on HD alleles versus the general population, although this difference does not reach significance (OR 0.34, P=0.0552, Fisher's exact test). Notably, other haplogroup C variants do not significantly differ between HD and general population alleles in the black subpopulation (OR 0.73, P=0.4543).