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

PLoS Genetics
Michael J ChaoJong-Min Lee

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 s...Continue Reading

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Citations

Feb 16, 2020·The Journal of Biological Chemistry·Alexandra N Khristich, Sergei M Mirkin
May 15, 2020·Movement Disorders : Official Journal of the Movement Disorder Society·Haloom RafehiMelanie Bahlo
Jun 17, 2019·Mammalian Genome : Official Journal of the International Mammalian Genome Society·Remya R NairElizabeth M C Fisher
Dec 8, 2020·Movement Disorders : Official Journal of the Movement Disorder Society·Masayuki Nakamori, Hideki Mochizuki
Jan 29, 2021·The Journal of Biological Chemistry·Alexandra N Khristich, Sergei M Mirkin
Mar 8, 2021·Toxicological Sciences : an Official Journal of the Society of Toxicology·Anke M TukkerKimberly A McAllister
Jun 26, 2021·Human Molecular Genetics·James F GusellaMarcy E MacDonald

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Methods Mentioned

BETA
genetic modification
dissection
genotyping
MDS

Software Mentioned

BEAGLE
SHAPEIT
PLINK
Genome Analysis Toolkit
METAL
GenABEL
Complete Genomics
GEMMA
Agilent SureDesign

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