The DOI matches its Crossref record; 52 of the 52 references it cites were found in a registry or an index.
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]
In the citing paper
“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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Statistical significance for genomewide studies
Storey, J. D., & Tibshirani, R. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1530509100 · Cited by 9,692 · cited 1×
“Correction for multiple testing of pathways in the Setscreen analysis was performed using the q-value method (Storey and Tibshirani, 2003).”
MACDONALD, M. (1993) · Cell · doi:10.1016/0092-8674(93)90585-e · Cited by 8,366
Self-citationFinding the missing heritability of complex diseases
Manolio, T. A., Collins, F. S., Cox, N. J., Goldstein, D. B., Hindorff, L. A., Hunter, D. J., McCarthy, M. I., Ramos, E. M., Cardon, L. R., Chakravarti, A., et al. (2009) · Nature · doi:10.1038/nature08494 · Cited by 8,336 · cited 1×
“For the past decade, genome-wide association (GWA) analysis with SNPs has extended the power of human genetic studies to complex diseases by identifying a multitude of contributing risk factors, usually of modest or weak effect (Manolio et al., 2009).”
Self-citationThe Reactome pathway Knowledgebase
Fabregat, A., Sidiropoulos, K., Garapati, P., Gillespie, M., Hausmann, K., Haw, R., Jassal, B., Jupe, S., Korninger, F., McKay, S., et al. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkv1351 · Cited by 5,605
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Huntington's disease: a clinical review
McColgan, P., & Tabrizi, S. J. (2017) · European Journal of Neurology · doi:10.1111/ene.13413 · Cited by 1,156
Huntington disease: new insights into molecular pathogenesis and therapeutic opportunities
Tabrizi, S. J., Flower, M. D., Ross, C. A., & Wild, E. J. (2020) · Nature Reviews Neurology · doi:10.1038/s41582-020-0389-4 · Cited by 568
CAG Repeat Not Polyglutamine Length Determines Timing of Huntington’s Disease Onset
Lee, J., Correia, K., Loupe, J. M., Kim, K., Barker, D., Hong, E. P., Chao, M. J., Long, J. D., Lucente, D. E., Vonsattel, J. P., et al. (2019) · Cell · doi:10.1016/j.cell.2019.06.036 · Cited by 543
Self-citationTandem repeats mediating genetic plasticity in health and disease
Hannan, A. J. (2018) · Nature Reviews Genetics · doi:10.1038/nrg.2017.115 · Cited by 446
Converging pathways in neurodegeneration, from genetics to mechanisms
Gan, L., Cookson, M. R., Petrucelli, L., & Spada, A. R. L. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0237-7 · Cited by 495
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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