title: Dominant effects of the Huntington's disease HTT CAG repeat length are captured in gene-expression data sets by a continuous analysis mathematical modeling strategy.
abstract: In Huntington's disease (HD), the size of the expanded HTT CAG repeat mutation is the primary driver of the processes that determine age at onset of motor symptoms. However, correlation of cellular biochemical parameters also extends across the normal repeat range, supporting the view that the CAG repeat represents a functional polymorphism with dominant effects determined by the longer allele. A central challenge to defining the functional consequences of this single polymorphism is the difficulty of distinguishing its subtle effects from the multitude of other sources of biological variation. We demonstrate that an analytical approach based upon continuous correlation with CAG size was able to capture the modest (∼21%) contribution of the repeat to the variation in genome-wide gene expression in 107 lymphoblastoid cell lines, with alleles ranging from 15 to 92 CAGs. Furthermore, a mathematical model from an iterative strategy yielded predicted CAG repeat lengths that were significantly positively correlated with true CAG allele size and negatively correlated with age at onset of motor symptoms. Genes negatively correlated with repeat size were also enriched in a set of genes whose expression were CAG-correlated in human HD cerebellum. These findings both reveal the relatively small, but detectable impact of variation in the CAG allele in global data in these peripheral cells and provide a strategy for building multi-dimensional data-driven models of the biological network that drives the HD disease process by continuous analysis across allelic panels of neuronal cells vulnerable to the dominant effects of the HTT CAG repeat.
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA. jlee51@partners.org
authors.forename: Jong-Min
authors.initials: JM
authors.lastname: Lee
authors.forename: Ekaterina I
authors.initials: EI
authors.lastname: Galkina
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Levantovsky
authors.forename: Elisa
authors.initials: E
authors.lastname: Fossale
authors.forename: Mary
authors.initials: M
authors.lastname: Anne Anderson
authors.forename: Tammy
authors.initials: T
authors.lastname: Gillis
authors.forename: Jayalakshmi
authors.initials: J
authors.lastname: Srinidhi Mysore
authors.forename: Kathryn R
authors.initials: KR
authors.lastname: Coser
authors.forename: Toshi
authors.initials: T
authors.lastname: Shioda
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Furia
authors.forename: Jonathan
authors.initials: J
authors.lastname: Derry
authors.forename: Isaac S
authors.initials: IS
authors.lastname: Kohane
authors.forename: Ihn Sik
authors.initials: IS
authors.lastname: Seong
authors.forename: Vanessa C
authors.initials: VC
authors.lastname: Wheeler
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
authors.forename: Marcy E
authors.initials: ME
authors.lastname: MacDonald
mesh_terms: D017668:Age of Onset; D000483:Alleles; D002460:Cell Line; D002531:Cerebellum / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008957:Models, Genetic; D009419:Nerve Tissue Proteins / Q000235:genetics*; D011110:Polymorphism, Genetic; D015203:Reproducibility of Results; D059467:Transcriptome; D018911:Trinucleotide Repeats / Q000235:genetics*
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins