HD CAGnome: A Search Tool for Huntingtin CAG Repeat Length-Correlated Genes

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.

Defective linear and circular RNAs biogenesis in Huntington’s disease: CAG repeat expansion hijacks neuronal splicing

“…While previous reports correlated mutant huntingtin expression to mis-splicing events, locally affecting the Htt locus (Neueder et al 2017;Sathasivam et al 2013;Schilling et al 2019), and also more generally altering the whole brain's transcriptome (Lin et al 2016;Elorza et al 2021), this is the first evidence of a direct correlation between the number of Htt CAG repeats and the degree of AS, extending the repertoire of molecular phenotypes directly linked to the CAG expansion. The concept of CAG-dependency is currently extensively investigated to gain insights into how Htt CAG repeat length might modify HD pathogenesis (Langfelder et al 2016;Galkina et al 2014;Reis et al 2011;Seong et al 2005). Notably, our findings supporting a primary CAG length-dependent effect in striatumwith less involvement of cortex [and liver]is well in line with previous observations that highlighted CAG lengthdependent modules of co-expressed genes (Langfelder et al 2016).…”

CAG repeat expansion in the Huntington’s disease gene shapes linear and circular RNAs biogenesis

“…Similarly, the results obtained from the AS analyses, on the isogenic in vitro KI system [ 34 , 35 , 63 , 65 , 66 ] in the transition from pluripotency to neural committed progenitors, relevant models to study HD early phenotypes, provided an independent, genome-wide validation of the AS Htt CAG correlation. We confirmed an increase of aberrant AS and SE events with increasing CAG length.…”

“…While previous reports correlated mutant huntingtin expression to mis-splicing events, locally affecting the Htt locus [ 11 , 60 , 61 ], and also more generally altering the whole brain’s transcriptome [ 14 , 62 ], this is the first evidence of a direct correlation between the number of Htt CAG repeats and the degree of AS, extending the repertoire of molecular phenotypes directly linked to the CAG expansion. The concept of CAG-dependency is currently extensively investigated to gain insights into how Htt CAG repeat length might modify HD pathogenesis [ 28 , 63 , 64 ]. Notably, our findings supporting a primary CAG length-dependent effect in striatum–with less involvement of cortex [and liver]–is well in line with previous observations that highlighted CAG length-dependent modules of co-expressed genes [ 28 ].…”