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Identification of Genetic Factors that Modify Clinical Onset of Huntington’s Disease
Open accessAbstract
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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“DNA damage repair pathways were found to be significantly enriched in Huntington’s disease GWAS analysis”
From Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration (2023) · cites this paper as [111]
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“Gene‐wide association studies have further identified SNPs in DNA maintenance genes that influence the age of onset in this disease (Lee et al, 2015; Moss et al, 2017).”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Lee et al, 2015
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“alleles in the general population suggests that additional genetic and environmental factors may modify the likelihood of manifesting HD from these alleles within a normal human lifespan.(32) Given the small proportion of individuals with CAG 36–38 repeat alleles who manifest with clinical HD, genetic background may p…”
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What do we know about Late Onset Huntington’s Disease?
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A Next Generation Multiscale View of Inborn Errors of Metabolism
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Self-citationMcAllister, B., Donaldson, J., Binda, C. S., Powell, S., Chughtai, U., Edwards, G., Stone, J., Lobanov, S. V., Elliston, L., Schuhmacher, L.-N., et al. (2022) · Nature Neuroscience · doi:10.1038/s41593-022-01033-5 · Cited by 84
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Modifiers of CAG/CTG Repeat Instability: Insights from Mammalian Models
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Human MutLγ, the MLH1–MLH3 heterodimer, is an endonuclease that promotes DNA expansion
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Huntington’s Disease Pathogenesis Is Modified In Vivo by Alfy/Wdfy3 and Selective Macroautophagy
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“In humans, germline mutations in key MMR proteins have been shown to modify somatic instability and disease severity of Huntington's Disease and other disorders (Flower et al., 2019; Genetic Modifiers of Huntington's Disease (GeM- HD) Consortium, 2015; Goold et al., 2021).”
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Cooperation of cancer drivers with regulatory germline variants shapes clinical outcomes
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Metadata
- 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
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-07
- Volume
- 162
- Issue
- 3
- Pages
- 516-526
- ISSN
- 0092-8674 (ISSN-L)
- 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
- 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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