Cited by 657Genetic Neurodegenerative DiseasesGenetic factors in colorectal cancerHereditary Neurological Disorders

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

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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.·2015·Cell

DOI 10.1016/j.cell.2015.07.003PMC PMC4524551

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Abstract

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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Additional file 12 of Machine learning in Huntington’s disease: exploring the Enroll-HD dataset for prognosis and driving capability prediction
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Authors: Lee, J.-M., Wheeler, V. C., Chao, M. J., Vonsattel, J. P. G., Pinto, R. M., Lucente, D., Abu-Elneel, K., Ramos, E. M., Mysore, J. S., Gillis, T., MacDonald, M. E., Gusella, J. F., Harold, D., Stone, T. C., Escott-Price, V., Han, J., Vedernikov, A., Holmans, P., Jones, L., Kwak, S., Mahmoudi, M., Orth, M., Landwehrmeyer, G. B., Paulsen, J. S., Dorsey, E. R., Shoulson, I., & Myers, R. H.
ORCID: Lee, Jong-Min
Wheeler, Vanessa C.
Pinto, Ricardo Mouro
Lucente, Diane
Ramos, Eliana Marisa
Gillis, Tammy
Gusella, James F.
Harold, Denise
Han, Jun
Vedernikov, Alexey
Holmans, Peter
Jones, Lesley
Kwak, Seung
Orth, Michael
Landwehrmeyer, G. Bernhard
Paulsen, Jane S.
Shoulson, Ira
Myers, Richard H.
Venue: Cell
Publisher: Elsevier BV
Published: 2015-07
Volume: 162
Issue: 3
Pages: 516-526
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2015.07.003
PMC: PMC4524551
OpenAlex: W1895398290
Cited by: 655
References: 51
Citations by year: 2026: 50 · 2025: 58 · 2024: 74 · 2023: 45 · 2022: 72 · 2021: 64 · 2020: 64 · 2019: 58 · 2018: 71 · 2017: 52 · 2016: 38 · 2015: 7
FWCI: 26.00
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 395 d)
Locations: Cell (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
Funders: CHDI Foundation
National Institutes of Health
Medical Research Council (MR/L023784/2, MR/L012936/1, MR/L010305/1)
National Human Genome Research Institute (X01HG006074, R01HG002449)
National Institute of Neurological Disorders and Stroke (R01NS040068, R01NS091161, U01NS082079, R01NS073947, P50NS016367)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
Keywords: Huntington's disease, age of onset, genetic modifiers, MLH1, DNA repair, therapeutic target
MeSH terms: MutL Protein Homolog 1, Huntingtin Protein, Chromosomes, Human, Pair 15, Chromosomes, Human, Pair 8, Humans, Huntington Disease, Nerve Tissue Proteins, Nuclear Proteins, Age of Onset, Trinucleotide Repeats, Adaptor Proteins, Signal Transducing, Genome-Wide Association Study, Genes, Modifier

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

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