Identification of Genetic Factors that Modify Clinical Onset of Huntington’s Disease | Zendy

JongMin Lee | Zendy; Vanessa C. Wheeler | Zendy; Michael J. Chao | Zendy; Jean Paul Vonsattel | Zendy; Ricardo Mouro Pinto | Zendy; Diane Lucente | Zendy; Kawther Abu-Elneel | Zendy; Eliana Marisa Ramos | Zendy; Jayalakshmi Srinidhi Mysore | Zendy; Tammy Gillis | Zendy; Marcy E. MacDonald | Zendy; James F. Gusella | Zendy; Denise Harold | Zendy; Timothy Stone | Zendy; Valentina EscottPrice | Zendy; Jun Han | Zendy; Alexey Vedernikov | Zendy; Peter Holmans | Zendy; Lesley Jones | Zendy; Seung Kwak | Zendy; Mithra Mahmoudi | Zendy; Michael Orth | Zendy; G. Bernhard Landwehrmeyer | Zendy; Jane S. Paulsen | Zendy; E. Ray Dorsey | Zendy; Ira Shoulson | Zendy; Richard H. Myers | Zendy

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Identification of Genetic Factors that Modify Clinical Onset of Huntington’s Disease

Author(s) -

JongMin Lee,

Vanessa C. Wheeler,

Michael J. Chao,

Jean Paul 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 Stone,

Valentina EscottPrice,

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

Publication year - 2015

Publication title -

cell

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 26.304

H-Index - 776

eISSN - 1097-4172

pISSN - 0092-8674

DOI - 10.1016/j.cell.2015.07.003

Subject(s) - biology , huntington's disease , locus (genetics) , genetics , disease , mendelian inheritance , trinucleotide repeat expansion , genome wide association study , age of onset , genetic association , allele , single nucleotide polymorphism , genotype , gene , medicine

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.

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