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

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...

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Bibliographic Details
Published in:PLoS genetics 2018-05, Vol.14 (5), p.e1007274
Main Authors: 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, Jones, Lesley, Orth, Michael, Kwak, Seung, MacDonald, Marcy E, Gusella, James F, Lee, Jong-Min
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing
Age of Onset
Arthritis
Biology
Biology and Life Sciences
Cancer
Chromosome 15
Chromosome 7
Development and progression
Environmental factors
Family Health
Female
Gene mapping
Gene-Environment Interaction
Genes, Modifier - genetics
Genetic aspects
Genetic polymorphisms
Genetics, Population
Genome-Wide Association Study - methods
Genomes
Genomics
Haplotypes
Health aspects
Hispanic Americans
Hospitals
Humans
Huntingtin
Huntingtin Protein - genetics
Huntington Disease - genetics
Huntington's disease
Huntingtons disease
Intracellular Signaling Peptides and Proteins
Lipids
Male
Medical research
Medical schools
Medicine
Medicine and Health Sciences
Mutation
Neurology
People and Places
Polymorphism, Single Nucleotide
Population genetics
Proteins - genetics
Single-nucleotide polymorphism
Venezuela
Whole Genome Sequencing - methods
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Summary: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.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1007274