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Identification of genetic factors that modify clinical onset of Huntington's disease

Lee, J. M., Wheeler, V. C., Chao, M. J., Vonsattel, P., Pinto, R. M., Lucente, D., Abu-Elmeel, K., Ramos, E. M., Mysore, J. S., Gillis, T., MacDonald, M. E., Gusella, J. F., Harold, D., Stone, T. C. ORCID:, Escott-Price, V. ORCID:, Han, J., Vedernikov, A., Holmans, P. A. ORCID:, Jones, L. ORCID:, Kwak, S., Mahmoudi, M., Orth, M., Landwehmeyer, G. B., Paulsen, J. S., Dorsey, R., Shoulson, I. and Myers, R. H. 2015. Identification of genetic factors that modify clinical onset of Huntington's disease. Cell 162 (3) , pp. 516-526. 10.1016/j.cell.2015.07.003

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As a Mendelian neurodegenerative disorder, the genetic risk of Huntington's disease (HD) is conferred entirely by an HTT CAG repeat expansion whose length is the primary determinant of the rate of pathogenesis leading to disease onset. To investigate the pathogenic process that precedes disease, we used genome-wide association (GWA) analysis to identify loci harboring genetic variations that alter the age at neurological onset of HD. A chromosome 15 locus displays two independent effects that accelerate or delay onset by 6.1 years and 1.4 years, respectively, whereas a chromosome 8 locus hastens onset by 1.6 years. Association at MLH1 and pathway analysis of the full GWA results support a role for DNA handling and repair mechanisms in altering the course of HD. Our findings demonstrate that HD disease modification in humans occurs in nature and offer a genetic route to identifying in-human validated therapeutic targets in this and other Mendelian disorders.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Advanced Research Computing @ Cardiff (ARCCA)
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Subjects: R Medicine > R Medicine (General)
Additional Information: Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium
Publisher: Elsevier
ISSN: 0092-8674
Date of Acceptance: 18 June 2015
Last Modified: 04 Mar 2023 03:00

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