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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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“In addition, a genome-wide association study investigating genetic modifiers for age of onset of HD found pathways involving mitochondrial fission to significantly modify age of onset of the disease [15].”
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Reduced Cancer Incidence in Huntington’s Disease: Analysis in the Registry Study
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Self-citationThe effects of huntingtin-lowering: what do we know so far?
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Precision medicine — networks to the rescue
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“Even in cases of very high penetrance, such as Huntington’s Disease, where a 40+ CAG triplet nucleotide repeat (encoding glutamine) in HTT leads to the disease in most probands [4], the age-of-onset and severity of the disease in an individual depend on variants in other modifier genes [5].”
BackgroundHuntington’s disease mouse models: unraveling the pathology caused by CAG repeat expansion
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Mutant huntingtin messenger RNA forms neuronal nuclear clusters in rodent and human brains
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Glycation potentiates neurodegeneration in models of Huntington’s disease
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Proteostasis in neurodegenerative diseases
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“2a), demonstrating or contraction of the repeat, with a general bias toward expansions in longer repeat tracts 11–14 .”
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Crosstalk between Different DNA Repair Pathways Contributes to Neurodegenerative Diseases
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Self-citation
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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