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Population-specific genetic modification of Huntington's disease in Venezuela

Chao, Michael J., Kim, Kyung-Hee, Shin, Jun Wan, Lucente, Diane, Wheeler, Vanessa C., Li, Hong, Roach, Jared C., Hood, Leroy, Wexler, Nancy S., Jardim, Laura B., Holmans, Peter ORCID:, Jones, Lesley ORCID:, Orth, Michael, Kwak, Seung, MacDonald, Marcy E., Gusella, James F. and Lee, Jong-Min 2018. Population-specific genetic modification of Huntington's disease in Venezuela. PLoS Genetics 14 (5) , e1007274. 10.1371/journal.pgen.1007274

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Additional Information: This is an open access article distributedunder the terms of the Creative CommonsAttribution License, which permits unrestricted use, distribution, and reproductionin any medium,provided the original author and source are credited.
Publisher: Public Library of Science
ISSN: 1553-7390
Date of First Compliant Deposit: 11 May 2018
Date of Acceptance: 23 February 2018
Last Modified: 04 May 2023 17:17

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