Abstract
BackgroundThe length of the huntingtin (HTT) CAG repeat is strongly correlated with both age at onset of Huntington’s disease (HD) symptoms and age at death of HD patients. Dichotomous analysis comparing HD to controls is widely used to study the effects of HTT CAG repeat expansion. However, a potentially more powerful approach is a continuous analysis strategy that takes advantage of all of the different CAG lengths, to capture effects that are expected to be critical to HD pathogenesis.Methodology/Principal FindingsWe used continuous and dichotomous approaches to analyze microarray gene expression data from 107 human control and HD lymphoblastoid cell lines. Of all probes found to be significant in a continuous analysis by CAG length, only 21.4% were so identified by a dichotomous comparison of HD versus controls. Moreover, of probes significant by dichotomous analysis, only 33.2% were also significant in the continuous analysis. Simulations revealed that the dichotomous approach would require substantially more than 107 samples to either detect 80% of the CAG-length correlated changes revealed by continuous analysis or to reduce the rate of significant differences that are not CAG length-correlated to 20% (n = 133 or n = 206, respectively). Given the superior power of the continuous approach, we calculated the correlation structure between HTT CAG repeat lengths and gene expression levels and created a freely available searchable website, “HD CAGnome,” that allows users to examine continuous relationships between HTT CAG and expression levels of ∼20,000 human genes.Conclusions/SignificanceOur results reveal limitations of dichotomous approaches compared to the power of continuous analysis to study a disease where human genotype-phenotype relationships strongly support a role for a continuum of CAG length-dependent changes. The compendium of HTT CAG length-gene expression level relationships found at the HD CAGnome now provides convenient routes for discovery of candidates influenced by the HD mutation.
Highlights
Huntington’s disease (HD, OMIM # 143100) is an autosomal dominant neurodegenerative disorder caused by an expansion of a polymorphic CAG trinucleotide repeat in the first exon of huntingtin (HTT), the gene encoding huntingtin protein [1]
Continuous analysis was able to detect modest but significant correlations between HTT CAG repeat lengths and genes that were not significant in a dichotomous analytical comparison, supporting the sensitivity of continuous analysis approaches. These results demonstrated the power of continuous analysis strategies to capture HTT CAG length-correlated gene-expression signatures that conform to the criteria expected for effects of the mechanism that contribute to the HD disease process
We performed continuous analysis and dichotomous analysis, respectively, to identify genes whose expression levels were correlated with HTT CAG repeat length (Pearson’s correlation test) or whose expression levels were significantly different between HD (CAG.35) and controls (CAG,36) (Student’s t-test)
Summary
Huntington’s disease (HD, OMIM # 143100) is an autosomal dominant neurodegenerative disorder caused by an expansion of a polymorphic CAG trinucleotide repeat in the first exon of huntingtin (HTT), the gene encoding huntingtin protein [1]. There is a strong inverse correlation of both age at onset of motor symptoms and age at death with the HTT CAG repeat length in HD subjects [1,2,3,4,5,6]. The continuous relationships between HTT CAG repeat lengths and molecular energy phenotypes extend across the range of expanded disease alleles and into the normal HTT CAG repeat range (CAG,36), in a panel of blood-derived lymphoblastoid cell lines [7] These suggested that the HTT CAG repeat is a functional polymorphism directly associated with an alteration of huntingtin function that leads eventually to disease phenotypes. A potentially more powerful approach is a continuous analysis strategy that takes advantage of all of the different CAG lengths, to capture effects that are expected to be critical to HD pathogenesis
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