Data from: 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 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.孟德尔遗传病的修饰因子可为疾病机制研究提供重要洞见，并为治疗策略的制定提供指导。近期一项全基因组关联（Genome-Wide Association, GWA）研究在欧洲人群中发现了亨廷顿病（Huntington's disease, HD）发病年龄的遗传修饰因子。本研究对委内瑞拉亨廷顿病聚集队列开展了全基因组测序与全基因组关联分析，该队列的家系曾为亨廷顿病基因缺陷的初始定位作出关键贡献。委内瑞拉亨廷顿病患者的运动症状发病早于欧洲患者，提示存在人群特异性遗传修饰因子的可能性。该委内瑞拉亨廷顿病核心家系携带HTT单倍型hap.03，该单倍型与欧洲人群的HD hap.03在序列层面仅存在细微差异，提示二者祖先起源不同，但这无法解释委内瑞拉患者更早的发病年龄。针对委内瑞拉亨廷顿病聚集队列的全基因组关联分析显示，既存在人群特异性的遗传修饰因子，也存在人群共有的遗传修饰因子。仅在委内瑞拉亨廷顿病患者中观察到7p21.2-21.1区域的全基因组显著关联信号，以及4p14和17q21.2区域的提示性关联信号；而当将委内瑞拉亨廷顿病数据纳入荟萃分析时，已被证实的欧洲人群15号染色体修饰基因座的全基因组显著关联信号得到了显著增强。委内瑞拉人群特异性的7号染色体关联信号以SOSTDC1为核心，该基因编码骨形态发生蛋白拮抗剂。上述单核苷酸多态性（Single Nucleotide Polymorphism, SNP）位点在非委内瑞拉人群的组织样本中与SOSTDC1的表达降低相关，这提示：SOSTDC1表达降低与人群特异性遗传或环境因素的相互作用，可能是委内瑞拉人群亨廷顿病发病年龄修饰效应的成因。在委内瑞拉亨廷顿病患者中检测到人群特异性的修饰效应，这印证了利用差异化疾病人群揭示疾病新机制与制定人群适配性治疗策略的重要价值。