Population-specific genetic modification of Huntington's disease in Venezuela
Autor(a) principal: | |
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Data de Publicação: | 2018 |
Outros Autores: | , , , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UFRGS |
Texto Completo: | http://hdl.handle.net/10183/187727 |
Resumo: | Modifiers 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. |
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Chao, Michael J.Kim, Kyung HeeShin, Ju WanLucente, Diane E.Wheeler, Vanessa C.Li, HongRoach, Jared C.Hood, LeroyWexler, Nancy S.Jardim, Laura BannachHolmans, PeterJones, Lesley A.Orth, MichaelKwak, Seung P.MacDonald, Marcy E.Gusella, James F.Lee, Jong Min2019-01-12T04:22:47Z20181553-7390http://hdl.handle.net/10183/187727001084230Modifiers 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.application/pdfengPlos Genetics. Cambridge. Vol. 14, no. 5 (2018), e1007274, 25 p.Idade de inícioSaúde da famíliaGenes modificadoresGenética populacionalEstudo de associação genômica amplaHaplotiposProteína huntingtinaDoença de HuntingtonPolimorfismo de nucleotídeo únicoSequenciamento completo do genomaVenezuelaPopulation-specific genetic modification of Huntington's disease in VenezuelaEstrangeiroinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFRGSinstname:Universidade Federal do Rio Grande do Sul (UFRGS)instacron:UFRGSTEXT001084230.pdf.txt001084230.pdf.txtExtracted Texttext/plain93895http://www.lume.ufrgs.br/bitstream/10183/187727/2/001084230.pdf.txt7b45f8edf7c4b5c42b5d3cf08ca26ac2MD52ORIGINAL001084230.pdfTexto completo (inglês)application/pdf3749501http://www.lume.ufrgs.br/bitstream/10183/187727/1/001084230.pdfd746fa315835043f9ba19a9bf2704d54MD5110183/1877272023-09-24 03:40:10.768575oai:www.lume.ufrgs.br:10183/187727Repositório de PublicaçõesPUBhttps://lume.ufrgs.br/oai/requestopendoar:2023-09-24T06:40:10Repositório Institucional da UFRGS - Universidade Federal do Rio Grande do Sul (UFRGS)false |
dc.title.pt_BR.fl_str_mv |
Population-specific genetic modification of Huntington's disease in Venezuela |
title |
Population-specific genetic modification of Huntington's disease in Venezuela |
spellingShingle |
Population-specific genetic modification of Huntington's disease in Venezuela Chao, Michael J. Idade de início Saúde da família Genes modificadores Genética populacional Estudo de associação genômica ampla Haplotipos Proteína huntingtina Doença de Huntington Polimorfismo de nucleotídeo único Sequenciamento completo do genoma Venezuela |
title_short |
Population-specific genetic modification of Huntington's disease in Venezuela |
title_full |
Population-specific genetic modification of Huntington's disease in Venezuela |
title_fullStr |
Population-specific genetic modification of Huntington's disease in Venezuela |
title_full_unstemmed |
Population-specific genetic modification of Huntington's disease in Venezuela |
title_sort |
Population-specific genetic modification of Huntington's disease in Venezuela |
author |
Chao, Michael J. |
author_facet |
Chao, Michael J. Kim, Kyung Hee Shin, Ju Wan Lucente, Diane E. Wheeler, Vanessa C. Li, Hong Roach, Jared C. Hood, Leroy Wexler, Nancy S. Jardim, Laura Bannach Holmans, Peter Jones, Lesley A. Orth, Michael Kwak, Seung P. MacDonald, Marcy E. Gusella, James F. Lee, Jong Min |
author_role |
author |
author2 |
Kim, Kyung Hee Shin, Ju Wan Lucente, Diane E. Wheeler, Vanessa C. Li, Hong Roach, Jared C. Hood, Leroy Wexler, Nancy S. Jardim, Laura Bannach Holmans, Peter Jones, Lesley A. Orth, Michael Kwak, Seung P. MacDonald, Marcy E. Gusella, James F. Lee, Jong Min |
author2_role |
author author author author author author author author author author author author author author author author |
dc.contributor.author.fl_str_mv |
Chao, Michael J. Kim, Kyung Hee Shin, Ju Wan Lucente, Diane E. Wheeler, Vanessa C. Li, Hong Roach, Jared C. Hood, Leroy Wexler, Nancy S. Jardim, Laura Bannach Holmans, Peter Jones, Lesley A. Orth, Michael Kwak, Seung P. MacDonald, Marcy E. Gusella, James F. Lee, Jong Min |
dc.subject.por.fl_str_mv |
Idade de início Saúde da família Genes modificadores Genética populacional Estudo de associação genômica ampla Haplotipos Proteína huntingtina Doença de Huntington Polimorfismo de nucleotídeo único Sequenciamento completo do genoma Venezuela |
topic |
Idade de início Saúde da família Genes modificadores Genética populacional Estudo de associação genômica ampla Haplotipos Proteína huntingtina Doença de Huntington Polimorfismo de nucleotídeo único Sequenciamento completo do genoma Venezuela |
description |
Modifiers 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. |
publishDate |
2018 |
dc.date.issued.fl_str_mv |
2018 |
dc.date.accessioned.fl_str_mv |
2019-01-12T04:22:47Z |
dc.type.driver.fl_str_mv |
Estrangeiro info:eu-repo/semantics/article |
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http://hdl.handle.net/10183/187727 |
dc.identifier.issn.pt_BR.fl_str_mv |
1553-7390 |
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001084230 |
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http://hdl.handle.net/10183/187727 |
dc.language.iso.fl_str_mv |
eng |
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dc.relation.ispartof.pt_BR.fl_str_mv |
Plos Genetics. Cambridge. Vol. 14, no. 5 (2018), e1007274, 25 p. |
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