Abstract
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.
Highlights
Huntington’s disease (HD; MIM 143100), a familial neurodegenerative disorder characterized by progressive movement disorder, cognitive decline, and psychiatric disturbances, is caused by an expanded CAG glutamine codon repeat in HTT, which encodes huntingtin [1,2,3]
Genome-wide analysis of European HD subjects revealed that age at onset corrected for individual CAG repeat size is modified by other genetic factors, revealing potential disease-delaying pathways that form targets for therapeutic strategies
We set out to identify genetic modifiers in a Venezuelan HD cluster whose families were crucial for discovering the cause of HD
Summary
Huntington’s disease (HD; MIM 143100), a familial neurodegenerative disorder characterized by progressive movement disorder, cognitive decline, and psychiatric disturbances, is caused by an expanded CAG glutamine codon repeat in HTT, which encodes huntingtin [1,2,3]. This genetic defect was originally mapped to chromosome 4p16.3 using linkage analysis in part in Venezuelan families from an HD population cluster whose generous participation in this fundamental HD genetic research contributed, along with many North American and European families carrying a CAG expansion mutation, to the discovery of HTT [3,4,5,6]. The relationship between CAG repeat size and HD clinical onset has played an important role in guiding 1) the generation of animal models [22,23,24,25,26], 2) design/interpretation of molecular studies [27], and 3) identification of genetic modifiers [28]
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