Journal article
CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion
Neurology, Vol.78(10), pp.690-695
03/06/2012
DOI: 10.1212/WNL.0b013e318249f683
PMCID: PMC3306163
PMID: 22323755
Abstract
Objective: Age at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly correlated with an expanded CAG trinucleotide repeat. The length of the normal CAG repeat allele has been reported also to influence age at onset, in interaction with the expanded allele. Due to profound implications for disease mechanism and modification, we tested whether the normal allele, interaction between the expanded and normal alleles, or presence of a second expanded allele affects age at onset of HD motor signs. Methods: We modeled natural log-transformed age at onset as a function of CAG repeat lengths of expanded and normal alleles and their interaction by linear regression. Results: An apparently significant effect of interaction on age at motor onset among 4,068 subjects was dependent on a single outlier data point. A rigorous statistical analysis with a well-behaved dataset that conformed to the fundamental assumptions of linear regression (e.g., constant variance and normally distributed error) revealed significance only for the expanded CAG repeat, with no effect of the normal CAG repeat. Ten subjects with 2 expanded alleles showed an age at motor onset consistent with the length of the larger expanded allele. Conclusions: Normal allele CAG length, interaction between expanded and normal alleles, and presence of a second expanded allele do not influence age at onset of motor manifestations, indicating that the rate of HD pathogenesis leading to motor diagnosis is determined by a completely dominant action of the longest expanded allele and as yet unidentified genetic or environmental factors.
Details
- Title: Subtitle
- CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion
- Creators
- J.-M Lee - Massachusetts General HospitalE M Ramos - University of SydneyJ H Lee - Massachusetts General HospitalT Gillis - Massachusetts General HospitalPREDICT-HD study of the Huntington Study Group (HSG)REGISTRY study of the European Huntington's Disease NetworkHD-MAPS Study GroupCOHORT study of the HSGEric Axelson (Contributor) - University of Iowa, Imaging Section: Administrative and Surface AnalysisStephen Cross (Contributor) - University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA, Site StaffCarissa Gehl (Contributor) - VA Medical Center, Iowa City, IA, Cognitive and Functional Assessment SectionsJ.S Paulsen (Contributor)Eric A Epping (Contributor) - University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA, Steering Committee, Psychiatric Section Chair and Core Ethics SectionJess Fiedorowicz (Contributor) - University of Iowa, Psychiatric SectionHans Johnson (Contributor) - University of Iowa Hospitals and Clinics, Iowa City, IA, Steering Committee and Core IT/Management Section ChairDouglas Langbehn (Contributor) - University of Iowa, Steering Committee and Core Statistics Section ChairVincent A Magnotta (Contributor) - University of Iowa, Imaging Section: DTI ChairDavid J Moser (Contributor) - University of Iowa, Cognitive SectionPeg Nopoulos (Contributor) - University of Iowa, Imaging Section: Surface Analysis ChairRobert Robinson (Contributor) - University of Iowa, Psychiatric SectionRobert Rodnitzky (Contributor) - University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA, Site InvestigatorTeri Thomsen (Contributor) - University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA, Site InvestigatorErgun Uc (Contributor) - University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA, Site InvestigatorThomas Wassink (Contributor) - University of Iowa, Site Investigator and Genetics Section, Co-ChairJanet Williams (Contributor) - University of Iowa, Steering Committee, Functional Assessment Section, Co-Chair and Core Ethics Section
- Resource Type
- Journal article
- Publication Details
- Neurology, Vol.78(10), pp.690-695
- Publisher
- Lippincott Williams & Wilkins; Hagerstown, MD
- DOI
- 10.1212/WNL.0b013e318249f683
- PMID
- 22323755
- PMCID
- PMC3306163
- ISSN
- 0028-3878
- eISSN
- 1526-632X
- Language
- English
- Date published
- 03/06/2012
- Academic Unit
- Neurology; Electrical and Computer Engineering; Psychiatry; Psychological and Brain Sciences; Nursing; Roy J. Carver Department of Biomedical Engineering; Radiology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Epidemiology; Iowa Neuroscience Institute; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Medicine Administration; Internal Medicine
- Record Identifier
- 9984020994602771
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