Identification of Genetic Factors that Modify Clinical Onset of Huntington’s Disease
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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 significantly enriched in Huntington's disease GWAS analysis.
“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]
SNPs in DNA maintenance genes influence the age of onset of HD.
“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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DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases
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“Indeed, a recent genome-wide association study identified a number of loci with putative disease-modifying variants that appear to influence the age of neurological onset in HD (GeM- Stem Cell This is an open access article under the C HD Consortium, 2015).”
BackgroundLong somatic DNA-repeat expansion drives neurodegeneration in Huntington’s disease
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Disease-associated repeat instability and mismatch repair
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Clinical Features of Huntington’s Disease
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GWAS of epigenetic aging rates in blood reveals a critical role for TERT
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New Avenues for the Treatment of Huntington’s Disease
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“occurs at a median of 18 years after symptom onset, with infections, specifically aspiration pneumonia, being the most common cause of death [5,6].”
BackgroundData Analytics from Enroll‐ HD , a Global Clinical Research Platform for Huntington's Disease
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Self-citationMSH3 modifies somatic instability and disease severity in Huntington’s and myotonic dystrophy type 1
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Self-citationMechanism and therapeutic potential of targeting cGAS-STING signaling in neurological disorders
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Self-citationFrom Pathogenesis to Therapeutics: A Review of 150 Years of Huntington’s Disease Research
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FAN1 modifies Huntington’s disease progression by stabilizing the expanded HTT CAG repeat
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Self-citationBiological and clinical manifestations of juvenile Huntington’s disease: A retrospective analysis
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Self-citationA slipped-CAG DNA-binding small molecule induces trinucleotide-repeat contractions in vivo
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Huntington’s Disease—Update on Treatments
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“Therefore, psychiatric diseases are often termed “complex,” in contrast to “simple” Mendelian diseases [although the latest results suggest that even Mendelian diseases are complex (33)].”
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Mechanisms of protein toxicity in neurodegenerative diseases
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Detecting Expansions of Tandem Repeats in Cohorts Sequenced with Short-Read Sequencing Data
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Redox dysregulation as a driver for DNA damage and its relationship to neurodegenerative diseases
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“Also, defects in DNA repair pathways, including inactivation of DNA mismatch repair genes such as MutS Homolog 3 (MSH3), were associated with modification of age of onset in multiple CAG repeat expansion diseases, suggesting that the CAG repeat itself is the cause of modification [393].”
BackgroundMechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease
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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).”
Genetic architecture of epigenetic and neuronal ageing rates in human brain regions
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Preventing amyotrophic lateral sclerosis: insights from pre-symptomatic neurodegenerative diseases
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Huntingtin is a scaffolding protein in the ATM oxidative DNA damage response complex
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Mutant huntingtin impairs PNKP and ATXN3, disrupting DNA repair and transcription
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“Given that HTT interacts with huntingtin-associated protein 1 (HAP-1; Li et al., 1995), while ATXN3 interacts with HAP-1 (Takeshita et al., 2011) and PNKP (Chatterjee et al., 2015; Gao et al., 2015), we asked whether ATXN3 and PNKP might interact with HTT to form a TCR complex and if this is…”
BackgroundA modifier of Huntington's disease onset at the MLH1 locus
Lee, J., Chao, M. J., Harold, D. H., Elneel, K. A., Gillis, T., Holmans, P., Jones, L., Orth, M., Myers, R. H., Kwak, S., et al. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx286 · Cited by 117 · see citing works
Self-citationGenetic modifiers of Huntington disease differentially influence motor and cognitive domains
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Self-citationTiming and Impact of Psychiatric, Cognitive, and Motor Abnormalities in Huntington Disease
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“In HD gene carriers, these motor symptoms are likely to be specific manifestations of HD.”
BackgroundInfluentialSelf-citationGenetics of neurodegenerative diseases: an overview
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“As APP is located on chromosome21, a similar overload phenomenon is responsible for susceptibility to early-onset dementia in patients with Down syndrome, caused by trisomy 21 (Glenner and Wong, 1984).”
DNA Mismatch Repair and its Role in Huntington’s Disease
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Proteostasis in Huntington's disease: disease mechanisms and therapeutic opportunities
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Huntington’s Disease Pathogenesis: Two Sequential Components
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Self-citationAssembly and function of branched ubiquitin chains
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Huntington disease reduced penetrance alleles occur at high frequency in the general population
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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…”
BackgroundChanges in mental state and behaviour in Huntington's disease
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Movement Disorder Society Task Force Viewpoint: Huntington's Disease Diagnostic Categories
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Self-citationThe central role of DNA damage and repair in CAG repeat diseases
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Self-citationInsights into GABA A ergic system alteration in Huntington's disease
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DNA repair in the trinucleotide repeat disorders
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Self-citationCirculating microRNAs in Huntington’s disease: Emerging mediators in metabolic impairment
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DNA Damage Repair in Huntington's Disease and Other Neurodegenerative Diseases
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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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Modifiers of CAG/CTG Repeat Instability: Insights from Mammalian Models
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Self-citationFrom R.A. Fisher’s 1918 Paper to GWAS a Century Later
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Huntington disease: A quarter century of progress since the gene discovery
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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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Huntington Disease as a Neurodevelopmental Disorder and Early Signs of the Disease in Stem Cells
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Towards precision medicine in heart failure
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Burden of Rare Variants in the OTOG Gene in Familial Meniere’s Disease
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Self-citationFAN1 protects against repeat expansions in a Fragile X mouse model
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DNA repair in the trinucleotide repeat disorders
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Self-citationHuntington's disease in the United States: Variation by demographic and socioeconomic factors
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Self-citationRegulatory mechanisms of incomplete huntingtin mRNA splicing
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Standardizing the CAP Score in Huntington’s Disease by Predicting Age-at-Onset
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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).”
BackgroundNolin, S. L., Glicksman, A., Tortora, N. D., Allen, E. G., Macpherson, J., Milà, M., Vianna‐Morgante, A. M., Sherman, S. L., Dobkin, C., Latham, G. J., et al. (2019) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.61165 · Cited by 73 · see citing works
Cooperation of cancer drivers with regulatory germline variants shapes clinical outcomes
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Self-citationMonckton, D. G. (2021) · Journal of Huntington s Disease · doi:10.3233/jhd-200429 · Cited by 72 · see citing works
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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