title: The targetable A1 Huntington disease haplotype has distinct Amerindian and European origins in Latin America.
abstract: Huntington disease (HD) is a dominant neurodegenerative disorder caused by a CAG repeat expansion in the Huntingtin (HTT) gene. HD occurs worldwide, but the causative mutation is found on different HTT haplotypes in distinct ethnic groups. In Latin America, HD is thought to have European origins, but indigenous Amerindian ancestry has not been investigated. Here, we report dense HTT haplotypes in 62 mestizo Peruvian HD families, 17 HD families from across Latin America, and 42 controls of defined Peruvian Amerindian ethnicity to determine the origin of HD in populations of admixed Amerindian and European descent. HD in Peru occurs most frequently on the A1 HTT haplotype (73%), as in Europe, but on an unexpected indigenous variant also found in Amerindian controls. This Amerindian A1 HTT haplotype predominates over the European A1 variant among geographically disparate Latin American controls and in HD families from across Latin America, supporting an indigenous origin of the HD mutation in mestizo American populations. We also show that a proportion of HD mutations in Peru occur on a C1 HTT haplotype of putative Amerindian origin (14%). The majority of HD mutations in Latin America may therefore occur on haplotypes of Amerindian ancestry rather than on haplotypes resulting from European admixture. Despite the distinct ethnic ancestry of Amerindian and European A1 HTT, alleles on the parent A1 HTT haplotype allow for development of identical antisense molecules to selectively silence the HD mutation in the greatest proportion of patients in both Latin American and European populations.
authors.affiliation: Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, V5Z 4H4 Canada.
authors.forename: Chris
authors.initials: C
authors.lastname: Kay
authors.affiliation: Neurogenetics Research Center, Instituto Nacional de Ciencias Neurologicas, Lima, Peru.
authors.forename: Indira
authors.initials: I
authors.lastname: Tirado-Hurtado
authors.affiliation: Neurogenetics Research Center, Instituto Nacional de Ciencias Neurologicas, Lima, Peru.
authors.forename: Mario
authors.initials: M
authors.lastname: Cornejo-Olivas
authors.affiliation: Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, V5Z 4H4 Canada.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Collins
authors.affiliation: Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, V5Z 4H4 Canada.
authors.forename: Galen
authors.identifier: 0000-0003-2415-7339
authors.initials: G
authors.lastname: Wright
authors.affiliation: Neurogenetics Research Center, Instituto Nacional de Ciencias Neurologicas, Lima, Peru.
authors.forename: Miguel
authors.initials: M
authors.lastname: Inca-Martinez
authors.affiliation: Neurogenetics Research Center, Instituto Nacional de Ciencias Neurologicas, Lima, Peru.
authors.forename: Diego
authors.initials: D
authors.lastname: Veliz-Otani
authors.affiliation: Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, V5Z 4H4 Canada.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Ketelaar
authors.affiliation: Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, V5Z 4H4 Canada.
authors.forename: Ramy A
authors.initials: RA
authors.lastname: Slama
authors.affiliation: Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, V5Z 4H4 Canada.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Ross
authors.affiliation: Neurogenetics Research Center, Instituto Nacional de Ciencias Neurologicas, Lima, Peru.
authors.forename: Pilar
authors.initials: P
authors.lastname: Mazzetti
authors.affiliation: Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, V5Z 4H4 Canada.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
mesh_terms: D006239:Haplotypes; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics*; D006816:Huntington Disease / Q000208:ethnology / Q000235:genetics*; D007199:Indians, South American / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010568:Peru; D044465:White People / Q000235:genetics*
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein