Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease age of onset
Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease age of onset
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DOI：
10.1073/pnas.0308479101
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发表时间：
2004-03-09
影响因子：
11.1
通讯作者：
Wexler, NS
中科院分区：
文献类型：
--
作者：
Wexler, NS
亨廷顿病（Huntington 'sdisease，HID）是一种由CAG三联体扩增突变引起的常染色体显性遗传性神经退行性疾病。三重重复序列的长度是确定HID发病年龄的最重要因素，尽管在控制重复序列长度后仍存在很大的变异性。委内瑞拉HID亲属包括18，149人，跨越10代，其中15，409人活着。在收集的4，384个永生化淋巴细胞系中，3，989个DNA被基因分型为HD等位基因，代表了遗传风险最大的人群子集。其中杂合子938例，非外显等位基因80例，纯合子18例。分析的83个kinases，包括委内瑞拉HID kinases表明，发病年龄的残余变异性有遗传和环境的成分。我们从发病年龄对重复长度的对数的回归分析中创建了一个剩余的发病年龄表型。估计兄弟姐妹（0.40 +/- 0.09）、父母-子女（0.10 +/- 0.11）、叔伯（0.07 +/- 0.11）和堂兄弟（0.15 +/- 0.10）对的家族相关性（相关性SE），表明发病的剩余方差有家族起源。通过使用方差分量法与所有可用的家族关系，加性遗传力的剩余发病年龄性状是38%。一个模型，包括共享的兄弟姐妹环境的影响，估计加性遗传（0.37），共享的环境（0.22），和非共享的环境（0.41）的方差的组成部分，证实了约40%的方差剩余的发病年龄是归因于基因以外的HID基因和60%是环境。
Huntington's disease (HID) is an autosomal dominant neurodegenerative disease caused by a triplet (CAG) expansion mutation. The length of the triplet repeat is the most important factor in determining age of onset of HID, although substantial variability remains after controlling for repeat length. The Venezuelan HID kindreds encompass 18,149 individuals spanning 10 generations, 15,409 of whom are living. Of the 4,384 immortalized lymphocyte lines collected, 3,989 DNAs were genotyped for their HD alleles, representing a subset of the population at greatest genetic risk. There are 938 heterozygotes, 80 people with variably penetrant alleles, and 18 homozygotes. Analysis of the 83 kindreds that comprise the Venezuelan HID kindreds demonstrates that residual variability in age of onset has both genetic and environmental components. We created a residual age of onset phenotype from a regression analysis of the log of age of onset on repeat length. Familial correlations (correlation SE) were estimated for sibling (0.40 +/- 0.09), parent-offspring (0.10 +/- 0.11), avuncular (0.07 +/- 0.11), and cousin (0.15 +/- 0.10) pairs, suggesting a familial origin for the residual variance in onset. By using a variance-components approach with all available familial relationships, the additive genetic heritability of this residual age of onset trait is 38%. A model, including shared sibling environmental effects, estimated the components of additive genetic (0.37), shared environment (0.22), and nonshared environment (0.41) variances, confirming that approximate to40% of the variance remaining in onset age is attributable to genes other than the HID gene and 60% is environmental.