Journal article
Genetic Modification of Huntington Disease Acts Early in the Prediagnosis Phase
American journal of human genetics, Vol.103(3), pp.349-357
09/06/2018
DOI: 10.1016/j.ajhg.2018.07.017
PMCID: PMC6128248
PMID: 30122542
Abstract
Age at onset of Huntington disease, an inherited neurodegenerative disorder, is influenced by the size of the disease-causing CAG trinucleotide repeat expansion in HTT and by genetic modifier loci on chromosomes 8 and 15. Stratifying by modifier genotype, we have examined putamen volume, total motor score (TMS), and symbol digit modalities test (SDMT) scores, both at study entry and longitudinally, in normal controls and CAG-expansion carriers who were enrolled prior to the emergence of manifest HD in the PREDICT-HD study. The modifiers, which included onset-hastening and onset-delaying alleles on chromosome 15 and an onset-hastening allele on chromosome 8, revealed no major effect in controls but distinct patterns of modification in prediagnosis HD subjects. Putamen volume at study entry showed evidence of reciprocal modification by the chromosome 15 alleles, but the rate of loss of putamen volume was modified only by the deleterious chromosome 15 allele. By contrast, both alleles modified the rate of change of the SDMT score, but neither had an effect on the TMS. The influence of the chromosome 8 modifier was evident only in the rate of TMS increase. The data indicate that (1) modification of pathogenesis can occur early in the prediagnosis phase, (2) the modifier loci act in genetic interaction with the HD mutation rather than through independent additive effects, and (3) HD subclinical phenotypes are differentially influenced by each modifier, implying distinct effects in different cells or tissues. Together, these findings indicate the potential benefit of using genetic modifier strategies for dissecting the prediagnosis pathogenic process in HD.
Details
- Title: Subtitle
- Genetic Modification of Huntington Disease Acts Early in the Prediagnosis Phase
- Creators
- Jeffrey D Long - Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, IA 52242, USAJong-Min Lee - Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USAElizabeth H Aylward - Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, WA 98101, USATammy Gillis - Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USAJayalakshmi Srinidhi Mysore - Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USAKawther Abu Elneel - Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USAMichael J Chao - Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USAJane S Paulsen - Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USAMarcy E MacDonald - Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USAJames F Gusella - Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
- Resource Type
- Journal article
- Publication Details
- American journal of human genetics, Vol.103(3), pp.349-357
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.ajhg.2018.07.017
- PMID
- 30122542
- PMCID
- PMC6128248
- ISSN
- 0002-9297
- eISSN
- 1537-6605
- Grant note
- DOI: 10.13039/100000002, name: US National Institutes of Health, award: U01NS082079, R01NS091161, R01NS040068
- Language
- English
- Date published
- 09/06/2018
- Academic Unit
- Psychiatry; Psychological and Brain Sciences; Biostatistics
- Record Identifier
- 9984004076602771
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