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

PLoS Genet 2018 05 11;14(5):e1007274. Epub 2018 May 11.

Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America.

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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http://dx.doi.org/10.1371/journal.pgen.1007274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5965898PMC
May 2018
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References

(Supplied by CrossRef)
Huntington disease
GP Bates et al.
Nature Reviews Disease Primers 2015
On chorea
G Huntington et al.
Med Surg Rep 1872
Phenotypic characterization of individuals with 30–40 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36–39 repeats
DC Rubinsztein et al.
Am J Hum Genet 1996
Huntington's disease
FO Walker et al.
Lancet 2007
Sex-dependent mechanisms for expansions and contractions of the CAG repeat on affected Huntington disease chromosomes
B Kremer et al.
Am J Hum Genet 1995
Anticipation and instability of IT-15 (CAG)n repeats in parent-offspring pairs with Huntington disease
NG Ranen et al.
Am J Hum Genet 1995

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