학술논문
Identification of Genetic Factors that Modify Clinical Onset of Huntington's Disease
Document Type
Academic Journal
Author
Lee, Jong-Min; Wheeler, Vanessa C.; Chao, Michael J.; Vonsattel, Jean Paul G.; Pinto, Ricardo Mouro; Lucente, Diane; Abu-Elneel, Kawther; Ramos, Eliana Marisa; Mysore, Jayalakshmi Srinidhi; Gillis, Tammy; MacDonald, Marcy E.; Gusella, James F.; Harold, Denise; Stone, Timothy C.; Escott-Price, Valentina; Han, Jun; Vedernikov, Alexey; Holmans, Peter; Jones, Lesley; Kwak, Seung; Mahmoudi, Mithra; Orth, Michael; Landwehrmeyer, G. Bernhard; Paulsen, Jane S.; Dorsey, E. Ray; Shoulson, Ira; Myers, Richard H.
Source
Cell. July 30, 2015, Vol. 162 Issue 3, 516
Subject
Language
English
ISSN
0092-8674
Abstract
To access, purchase, authenticate, or subscribe to the full-text of this article, please visit this link: http://dx.doi.org/10.1016/j.cell.2015.07.003 Byline: Jong-Min Lee, Vanessa C. Wheeler, Michael J. Chao, Jean Paul G. Vonsattel, Ricardo Mouro Pinto, Diane Lucente, Kawther Abu-Elneel, Eliana Marisa Ramos, Jayalakshmi Srinidhi Mysore, Tammy Gillis, Marcy E. MacDonald, James F. Gusella, Denise Harold, Timothy C. Stone, Valentina Escott-Price, Jun Han, Alexey Vedernikov, Peter Holmans, Lesley Jones, Seung Kwak, Mithra Mahmoudi, Michael Orth, G. Bernhard Landwehrmeyer, Jane S. Paulsen, E. Ray Dorsey, Ira Shoulson, Richard H. Myers Highlights * GWA signals reveal loci that modify the age at onset of Huntington's disease * Effects at the chr15 locus hasten or delay onset by 6 or 1.4 years, respectively * A single effect at the chr8 locus hastens onset by 1.6 years * MLH1 association & pathway analysis implicate DNA handling in disease modification Summary 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. PaperClip Display Omitted * Corresponding author Article History: Received 25 January 2015; Revised 16 April 2015; Accepted 18 June 2015 (miscellaneous) Published: July 30, 2015