title: HD CAGnome: a search tool for huntingtin CAG repeat length-correlated genes.
abstract: BACKGROUND
  The 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.
  
  
  RESULTS
  We 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
  Our 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.
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Ekaterina I
authors.initials: EI
authors.lastname: Galkina
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Aram
authors.initials: A
authors.lastname: Shin
authors.affiliation: Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts, United States of America.
authors.forename: Kathryn R
authors.initials: KR
authors.lastname: Coser
authors.affiliation: Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts, United States of America.
authors.forename: Toshi
authors.initials: T
authors.lastname: Shioda
authors.affiliation: Children's Hospital Informatics program, Children's Hospital, Boston, Massachusetts, United States of America; Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, United States of America; i2b2 National center for Biomedical Computing, Boston, Massachusetts, United States of America.
authors.forename: Isaac S
authors.initials: IS
authors.lastname: Kohane
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Ihn Sik
authors.initials: IS
authors.lastname: Seong
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Vanessa C
authors.initials: VC
authors.lastname: Wheeler
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Marcy E
authors.initials: ME
authors.lastname: Macdonald
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Jong-Min
authors.initials: JM
authors.lastname: Lee
mesh_terms: D030541:Databases, Genetic; D005786:Gene Expression Regulation; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D013223:Statistics as Topic; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins
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