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dc.contributor.authorChao, Michael J.pt_BR
dc.contributor.authorKim, Kyung Heept_BR
dc.contributor.authorShin, Ju Wanpt_BR
dc.contributor.authorLucente, Diane E.pt_BR
dc.contributor.authorWheeler, Vanessa C.pt_BR
dc.contributor.authorLi, Hongpt_BR
dc.contributor.authorRoach, Jared C.pt_BR
dc.contributor.authorHood, Leroypt_BR
dc.contributor.authorWexler, Nancy S.pt_BR
dc.contributor.authorJardim, Laura Bannachpt_BR
dc.contributor.authorHolmans, Peterpt_BR
dc.contributor.authorJones, Lesley A.pt_BR
dc.contributor.authorOrth, Michaelpt_BR
dc.contributor.authorKwak, Seung P.pt_BR
dc.contributor.authorMacDonald, Marcy E.pt_BR
dc.contributor.authorGusella, James F.pt_BR
dc.contributor.authorLee, Jong Minpt_BR
dc.date.accessioned2019-01-12T04:22:47Zpt_BR
dc.date.issued2018pt_BR
dc.identifier.issn1553-7390pt_BR
dc.identifier.urihttp://hdl.handle.net/10183/187727pt_BR
dc.description.abstractModifiers of Mendelian disorders can provide insights into disease mechanisms and guide therapeutic strategies. A recent genome-wide association (GWA) study discovered genetic modifiers of Huntington's disease (HD) onset in Europeans. Here, we performed whole genome sequencing and GWA analysis of a Venezuelan HD cluster whose families were crucial for the original mapping of the HD gene defect. The Venezuelan HD subjects develop motor symptoms earlier than their European counterparts, implying the potential for population- specific modifiers. The main Venezuelan HD family inherits HTT haplotype hap.03, which differs subtly at the sequence level from European HD hap.03, suggesting a different ancestral origin but not explaining the earlier age at onset in these Venezuelans. GWA analysis of the Venezuelan HD cluster suggests both population-specific and population-shared genetic modifiers. Genome-wide significant signals at 7p21.2±21.1 and suggestive association signals at 4p14 and 17q21.2 are evident only in Venezuelan HD, but genome-wide significant association signals at the established European chromosome 15 modifier locus are improved when Venezuelan HD data are included in the meta-analysis. Venezuelan-specific association signals on chromosome 7 center on SOSTDC1, which encodes a bone morphogenetic protein antagonist. The corresponding SNPs are associated with reduced expression of SOSTDC1 in non-Venezuelan tissue samples, suggesting that interaction of reduced SOSTDC1 expression with a population-specific genetic or environmental factor may be responsible for modification of HD onset in Venezuela. Detection of population-specific modification in Venezuelan HD supports the value of distinct disease populations in revealing novel aspects of a disease and population-relevant therapeutic strategies.en
dc.format.mimetypeapplication/pdfpt_BR
dc.language.isoengpt_BR
dc.relation.ispartofPlos Genetics. Cambridge. Vol. 14, no. 5 (2018), e1007274, 25 p.pt_BR
dc.rightsOpen Accessen
dc.subjectIdade de iníciopt_BR
dc.subjectSaúde da famíliapt_BR
dc.subjectGenes modificadorespt_BR
dc.subjectGenética populacionalpt_BR
dc.subjectEstudo de associação genômica amplapt_BR
dc.subjectHaplotipospt_BR
dc.subjectProteína huntingtinapt_BR
dc.subjectDoença de Huntingtonpt_BR
dc.subjectPolimorfismo de nucleotídeo únicopt_BR
dc.subjectSequenciamento completo do genomapt_BR
dc.subjectVenezuelapt_BR
dc.titlePopulation-specific genetic modification of Huntington's disease in Venezuelapt_BR
dc.typeArtigo de periódicopt_BR
dc.identifier.nrb001084230pt_BR
dc.type.originEstrangeiropt_BR


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