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Huntington disease (HD) is a fatal neurodegenerative disorder caused by a gain-of-function mutation in HTT. Suppression of mutant HTT has emerged as a leading therapeutic strategy for HD, with allele-selective approaches targeting HTT SNPs now in clinical trials. Haplotypes associated with the HD mutation (A1, A2, A3a) represent panels of allele-specific gene silencing targets for efficient treatment of individuals with HD of Northern European and indigenous South American ancestry. Here we extend comprehensive haplotype analysis of the HD mutation to key populations of Southern European, South Asian, Middle Eastern, and admixed African ancestry. In each of these populations, the HD mutation occurs predominantly on the A2 HTT haplotype. Analysis of HD haplotypes across all affected population groups enables rational selection of candidate target SNPs for development of allele-selective gene silencing therapeutics worldwide. Targeting SNPs on the A1 and A2 haplotypes in parallel is essential to achieve treatment of the most HD-affected subjects in populations where HD is most prevalent. Current allele-specific approaches will leave a majority of individuals with HD untreated in populations where the HD mutation occurs most frequently on the A2 haplotype. We further demonstrate preclinical development of potent and selective ASOs targeting SNPs on the A2 HTT haplotype, representing an allele-specific treatment strategy for these individuals. On the basis of comprehensive haplotype analysis, we show the maximum proportion of HD-affected subjects that may be treated with three or four allele targets in different populations worldwide, informing current allele-specific HTT silencing strategies.

Background Mutations in the glucocerebrosidase (GBA) gene are an important risk factor for Parkinson's disease (PD). However, most GBA genetic studies in PD have been performed in patients of European origin and very few data are available in other populations. Methods We sequenced the entire GBA coding region in 602 PD patients and 319 controls from Colombia and Peru enrolled as part of the Latin American Research Consortium on the Genetics of Parkinson's disease (LARGE-PD). Results We observed a significantly higher proportion of GBA mutation carriers in patients compared to healthy controls (5.5% vs 1.6%; OR = 4.3, p = 0.004). Interestingly, the frequency of mutations in Colombian patients (9.9%) was more than two-fold greater than in Peruvian patients (4.2%) and other European-derived populations reported in the literature (4–5%). This was primarily due to the presence of a population-specific mutation (p.K198E) found only in the Colombian cohort. We also observed that the age at onset was significantly earlier in GBA carriers when compared to non-carriers (47.1 ± 14.2 y vs. 55.9 ± 14.2 y; p = 0.0004). Conclusion These findings suggest that GBA mutations are strongly associated with PD risk and earlier age at onset in Peru and Colombia. The high frequency of GBA carriers among Colombian PD patients (∼10%) makes this population especially well-suited for novel therapeutic approaches that target GBA-related PD.