1. Identification of Genetic Factors that Modify Clinical Onset of Huntington’s Disease
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Diane Lucente, Michael J. Chao, Richard H. Myers, Denise Harold, Seung Kwak, Kawther Abu-Elneel, E. Ray Dorsey, Michael Orth, Vanessa C. Wheeler, Ira Shoulson, Timothy Stone, Lesley Jones, Mithra Mahmoudi, Ricardo Mouro Pinto, Tammy Gillis, Marcy E. MacDonald, Jong-Min Lee, Jun Han, Alexey Vedernikov, Eliana Marisa Ramos, Jane S. Paulsen, James F. Gusella, Valentina Escott-Price, Jean Paul G. Vonsattel, Peter Holmans, G. Bernhard Landwehrmeyer, and Jayalakshmi S. Mysore
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Locus (genetics) ,Nerve Tissue Proteins ,Disease ,Biology ,MLH1 ,General Biochemistry, Genetics and Molecular Biology ,Article ,Chromosome 15 ,symbols.namesake ,Huntington's disease ,Trinucleotide Repeats ,Genetic variation ,medicine ,Humans ,Age of Onset ,Adaptor Proteins, Signal Transducing ,Genetics ,Chromosomes, Human, Pair 15 ,Huntingtin Protein ,Genes, Modifier ,Biochemistry, Genetics and Molecular Biology(all) ,Nuclear Proteins ,medicine.disease ,Huntington Disease ,Mendelian inheritance ,symbols ,Trinucleotide repeat expansion ,MutL Protein Homolog 1 ,Chromosomes, Human, Pair 8 ,Genome-Wide Association Study - Abstract
SummaryAs 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
- Published
- 2015
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