CAG Expansion in the Huntington Disease Gene Is Associated with a Specific and Targetable Predisposing Haplogroup

Abstract

Huntington disease (HD) is an autosomal-dominant disorder that results from >or=36 CAG repeats in the HD gene (HTT). Approximately 10% of patients inherit a chromosome that underwent CAG expansion from an unaffected parent with <36 CAG repeats. This study is a comprehensive analysis of genetic diversity in HTT and reveals that HD patients of European origin (n = 65) have a significant enrichment (95%) of a specific set of 22 tagging single nucleotide polymorphisms (SNPs) that constitute a single haplogroup. The disease association of many SNPs is much stronger than any previously reported polymorphism and was confirmed in a replication cohort (n = 203). Importantly, the same haplogroup is also significantly enriched (83%) in individuals with 27-35 CAG repeats (intermediate alleles, n = 66), who are unaffected by the disease, but have increased CAG tract sizes relative to the general population (n = 116). These data support a stepwise model for CAG expansion into the affected range (>or=36 CAG) and identifies specific haplogroup variants in the general population associated with this instability. The specific variants at risk for CAG expansion are not present in the general population in China, Japan, and Nigeria where the prevalence of HD is much lower. The current data argue that cis-elements have a major predisposing influence on CAG instability in HTT. The strong association between specific SNP alleles and CAG expansion also provides an opportunity of personalized therapeutics in HD where the clinical development of only a small number of allele-specific targets may be sufficient to treat up to 88% of the HD patient population.

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

“…The presence of high-risk variants A1 and A2 in the general population led the authors to suggest a step-wise model for the occurrence of de novo mutations, with expansions arising from a pool of alleles in the general population that were predisposed to expansion. 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.…”

“…Apart from the unassigned alleles (N ¼ 2) in the mixed subpopulation, all the phased HD alleles in the Caucasian and mixed groups fit previously defined haplogroup variants. 16 In stark contrast, CAG-expanded HD alleles in the black subpopulation (N ¼ 35) were found predominantly on haplogroup B (43%); with an equal proportion on haplogroup C (43%) and only a small proportion on haplogroup A (14%) (Figure 2a). The most common haplogroup A variants (A1 and A2) in the Caucasian and mixed subpopulations were absent from the black subpopulation, and the small proportion of HD alleles on haplogroup A were found instead on variant A4 (11%) and novel variant A7 (3%) (Figure 2a).…”

“…In the general population, the mean CAG in black South Africans (16.91±2.73) is significantly lower than the mean CAG in the Caucasian group Haplogroup variants are diverse and ethnically specific to South African subpopulations Phased SNP genotypes for each individual were assigned to one of the three primary haplogroups based on previously published criteria. 16 A total of 72 unrelated HD alleles and 311 unrelated general population alleles were phased and could be broadly categorised into A, B and C haplogroups. Five phased haplotypes were left unassigned as 'other' (O).…”

“…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 In particular, haplogroup A variants A1 and A2 were strongly associated with HD alleles in individuals of European ancestry, whereas variants A4 and A5 were nearly absent from expanded alleles. The presence of high-risk variants A1 and A2 in the general population led the authors to suggest a step-wise model for the occurrence of de novo mutations, with expansions arising from a pool of alleles in the general population that were predisposed to expansion.…”

“…16 Raw fluorescence output was analysed using Illumina GenomeStudio software (Illumina) to assign SNP genotype calls to each individual. For a small number of SNPs, automated clusters were manually adjusted to improve call accuracy.…”