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

• Published in: Cell Vol. 162; no. 3; pp. 516 - 526
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.07.2015
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Age of Onset; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 8; Genes, Modifier; Genome-Wide Association Study; Humans; Huntingtin Protein; Huntington Disease - epidemiology; Huntington Disease - genetics; Huntington Disease - physiopathology; MutL Protein Homolog 1; Nerve Tissue Proteins - genetics; Nuclear Proteins - metabolism; Trinucleotide Repeats
• DOI: 10.1016/j.cell.2015.07.003
• ISSN: 0092-8674

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. [Display omitted] [Display omitted] •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 The identification of gene loci that delay or hasten Huntington’s disease onset demonstrates that the disease is modifiable prior to clinical diagnosis and offers a genetic route to targets for treatment prior to disease onset.