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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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Self-citationThe Emerging Landscape of Natural Small-molecule Therapeutics for Huntington’s Disease
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“Recently, genome-wide association studies have identified numerous genes of DNA damage repair mechanism in neurons for HD pathogenesis (like, MLH1, FAN1, MSH3, LIG1, PMS1, and PMS2) as important determinants of disease severity and onset, implying that a faulty or impaired DNA repair pathway is associated with HD path…”
BackgroundCAG repeat mosaicism is gene specific in spinocerebellar ataxias
Kacher, R., Lejeune, F., David, I., Boluda, S., Coarelli, G., Leclère-Turbant, S., Heinzmann, A., Marelli, C., Charles, P., Goizet, C., et al. (2024) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2024.03.015 · Cited by 32
Latest advances on new promising molecular-based therapeutic approaches for Huntington’s disease
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Self-citationHaplotype-based stratification of Huntington's disease
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Self-citationAntibody-based therapies for Huntington’s disease: current status and future directions
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Astrocytes in Huntington’s Disease
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Mouse genetics reveals Barttin as a genetic modifier of Joubert syndrome
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“UBR5 has been identified as a possible mediator of the age of onset of HD in Genome Wide Association Studies (GWAS) (Lee et al., 2015).”
BackgroundRetinoic acid catabolizing enzyme CYP26C1 is a genetic modifier in SHOX deficiency
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“Variants that delay or hasten disease onset [10,53].”
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“…in cerebral white and grey matter may be detectable as far as 15–20 years before onset of unequivocal signs of HD and have been reported using VBM (Tabrizi et al., 2013) and DTI (Matsui et al., 2015) (Aylward, 2007; Georgiou-Karistianis et al., 2013; Rosas et al., 2008; Thieben et al., 2002).”
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Self-citationAdvances in gene and cellular therapeutic approaches for Huntington’s disease
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deutetrabenazine for the treatment of chorea associated with Huntington’s disease
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“However, most of these TNR expansion diseases share a common feature, ataxia with prominent cerebellar degeneration in clinical, whereas DNA damage response and DNA repair aberrance in genetic, especially the Huntington’s disease (HD) and multiple spinocerebellar ataxias (SCAs) (Martins et al., 2014; Lee et al., 2015;…”
BackgroundRepeat Instability in the Fragile X-Related Disorders: Lessons from a Mouse Model
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“Although HD is caused by inheritance of at least one mutant HTT allele, additional genetic factors that modify HD age-ofonset and severity are emerging (Gusella et al., 1983; Lee et al., 2015; Genetic Modifiers of Huntington’s Disease Consortium, 2019) and are being explored as potential therapeutic targets.”
BackgroundKoval, I., Dighiero-Brecht, T., Tobin, A. J., Tabrizi, S. J., Scahill, R. I., du Montcel, S. T., Durrleman, S., & Dürr, A. (2022) · Scientific Reports · doi:10.1038/s41598-022-18848-8 · Cited by 24
Huntington disease – Update on ongoing therapeutic developments and a look toward the future
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Flexible Non-Negative Matrix Factorization to Unravel Disease-Related Genes
Jiang, X., Zhang, H., Zhang, Z., & Quan, X. (2018) · IEEE Transactions on Computational Biology and Bioinformatics · doi:10.1109/tcbb.2018.2823746 · Cited by 21
“HD is one kind of neurodegenerative diseases [42], [43].”
BackgroundYalçın, M., El‐Athman, R., Ouk, K., Priller, J., & Relógio, A. (2020) · Cancers · doi:10.3390/cancers12040963 · Cited by 21
Natural biological variation of white matter microstructure is accentuated in Huntington's disease
Gregory, S., Crawford, H. E., Seunarine, K. K., Leavitt, B. R., Dürr, A., Roos, R. A. C., Scahill, R. I., Tabrizi, S. J., Rees, G. E., Langbehn, D. R., et al. (2018) · Human Brain Mapping · doi:10.1002/hbm.24191 · Cited by 20
Self-citationCRISPR-Based Genome-Editing Tools for Huntington’s Disease Research and Therapy
Qin, Y., Li, S., Li, X., & Yang, S. (2022) · Neuroscience Bulletin · doi:10.1007/s12264-022-00880-3 · Cited by 24
Replication dependent and independent mechanisms of GAA repeat instability
Masnovo, C., Lobo, A. F., & Mirkin, S. M. (2022) · DNA repair · doi:10.1016/j.dnarep.2022.103385 · Cited by 24
Furr-Stimming, E. E., & Bega, D. (2022) · CONTINUUM Lifelong Learning in Neurology · doi:10.1212/con.0000000000001169 · Cited by 20
Ko, J., Furby, H., Ma, X., Long, J. D., Lu, X., Slowiejko, D. M., & Gandhy, R. (2023) · Frontiers in Neurology · doi:10.3389/fneur.2022.1034269 · Cited by 20
Driscoll, R., Hampton, L., Abraham, N. A., Larigan, J. D., Joseph, N. F., Hernández-Vega, J. C., Geisler, S. B., Yang, F.-C., Deninger, M., Tran, D. T., et al. (2024) · Scientific Reports · doi:10.1038/s41598-024-52667-3 · Cited by 20
COMT Val158Met Polymorphism Modulates Huntington's Disease Progression
de Diego‐Balaguer, R., Schramm, C., Cournu‐Rebeix, I., Emmanuel Dupoux, A., Dürr, A., Brice, A., Charles, P., de Langavant, L. C., Youssov, K., Verny, C., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0161106 · Cited by 18
Alexander-Floyd, J., Haroon, S., Ying, M., Entezari, A. A., Jaeger, C., Vermulst, M., & Gidalevitz, T. (2020) · BMC Biology · doi:10.1186/s12915-020-0750-5 · Cited by 19
Mustafa, R., Kreiner, G., Kamińska, K., Wood, A.-E. J., Kirsch, J., Tucker, K. L., & Parlato, R. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00565 · Cited by 18
Luca, A. D., Morella, A., Consoli, F., Fanelli, S., Thibert, J. R., Statt, S. N., Latham, G. J., & Squitieri, F. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22041689 · Cited by 20
PAM-altering SNP-based allele-specific CRISPR-Cas9 therapeutic strategies for Huntington’s disease
Shin, J. W., Hong, E. P., Park, S. S., Choi, D. E., Zeng, S., Chen, R. Z., & Lee, J. (2022) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2022.08.005 · Cited by 23
Self-citationHuntington’s disease age at motor onset is modified by the tandem hexamer repeat in TCERG1
Lobanov, S. V., McAllister, B., McDade‐Kumar, M., Landwehrmeyer, G. B., Orth, M., Rosser, A., REGISTRY Investigators of the European Huntington’s disease network, Paulsen, J. S., PREDICT-HD Investigators of the Huntington Study Group, Lee, J., et al. (2022) · npj Genomic Medicine · doi:10.1038/s41525-022-00317-w · Cited by 19
Self-citationPoly ADP-ribose signaling is dysregulated in Huntington disease
Maiuri, T., Bazan, C. B., Harding, R., Begeja, N., Kam, T., Byrne, L. M., Rodrigues, F. B., Warner, M. M., Neuman, K., Mansoor, M., et al. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2318098121 · Cited by 21
Using Mendelian randomization to understand and develop treatments for neurodegenerative disease
Storm, C. S., Kia, D. A., Almramhi, M. M., & Wood, N. W. (2020) · Brain Communications · doi:10.1093/braincomms/fcaa031 · Cited by 19
“The trinucleotide repeat length determines some but not all variability in age at motor symptom onset (GeM-HD Consortium, 2015), and an MR study suggests that longer telomeres (repetitive DNA sequences at the end of chromosomes) may delay Huntington’s disease onset (Aziz and Weydt, 2018).”
BackgroundHypertension Is Associated With an Earlier Age of Onset of Huntington's Disease
Schultz, J. L., Harshman, L. A., Langbehn, D. R., & Nopoulos, P. (2020) · Movement Disorders · doi:10.1002/mds.28062 · Cited by 19
Repeat length increases disease penetrance and severity in C9orf72 ALS/FTD BAC transgenic mice
Pattamatta, A., Nguyen, L., Olafson, H. R., Scotti, M. M., Laboissonniere, L. A., Richardson, J. I., Berglund, J. A., Zu, T., Wang, E. T., & Ranum, L. P. W. (2020) · Human Molecular Genetics · doi:10.1093/hmg/ddaa279 · Cited by 22
Lee, J., McLean, Z. L., Correia, K., Shin, J. W., Lee, S., Jang, J.-H., Lee, Y., Kim, K., Choi, D. E., Long, J. D., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.06.10.597797 · Cited by 19
Self-citationA genetic modifier suggests that endurance exercise exacerbates Huntington's disease
Corrochano, S., Blanco, G., Williams, D. J., Wettstein, J., Simon, M., Kumar, S., Moir, L., Agnew, T., Stewart, M. E., Landman, A. S., et al. (2018) · Human Molecular Genetics · doi:10.1093/hmg/ddy077 · Cited by 17
Huntington disease update: new insights into the role of repeat instability in disease pathogenesis
Arning, L., & Nguyen, H. P. (2021) · Medizinische Genetik · doi:10.1515/medgen-2021-2101 · Cited by 20
“The first GWAS of 4,082 HD patients using the difference between AO predicted by CAG length and actual AO of motor symptoms identified FAN1 (FANCD2 and FANCI associated nuclease 1) on chromosome 15 and RRM2B (ribonucleotide reductase regulatory TP53 inducible subunit M2B) on chromosome 8 [21].”
MethodTaylor, A. S., Barros, D., Gobet, N., Schuepbach, T., McAllister, B., Aeschbach, L., Randall, E. L., Trofimenko, E., Heuchan, E. R., Barszcz, P., et al. (2022) · NAR Genomics and Bioinformatics · doi:10.1093/nargab/lqac089 · Cited by 18
Self-citationMore than just a number: the gut microbiota and brain function across the extremes of life
Nuzum, N. D., Deady, C., Kittel‐Schneider, S., Cryan, J. F., O’Mahony, S. M., & Clarke, G. A. (2024) · Gut Microbes · doi:10.1080/19490976.2024.2418988 · Cited by 22
When repetita no-longer iuvant: somatic instability of the CAG triplet in Huntington’s disease
Cattaneo, E. F., Scalzo, D., Zobel, M., Iennaco, R., Maffezzini, C., Besusso, D., & Maestri, S. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkae1204 · Cited by 20
Velasco, S. L., García‐Redondo, A., Martín, A. H.-S., Puertas‐Martín, V., González‐Sánchez, M., Pérez-Martínez, D. A., & Villarejo‐Galende, A. (2018) · Neurocase · doi:10.1080/13554794.2018.1428353 · Cited by 18
Hypomorphic mutation of the mouse Huntington’s disease gene orthologue
Murthy, V., Tebaldi, T., Yoshida, T., Erdin, S., Calzonetti, T., Vijayvargia, R., Tripathi, T., Kerschbamer, E., Seong, I. S., Quattrone, A., et al. (2019) · PLoS Genetics · doi:10.1371/journal.pgen.1007765 · Cited by 17
Self-citationMathkar, P. P., Suresh, D., Dunn, J., Tom, C. M., & Mattis, V. B. (2019) · Journal of Huntington s Disease · doi:10.3233/jhd-180333 · Cited by 18
The Startling Role of Mismatch Repair in Trinucleotide Repeat Expansions
Richard, G. (2021) · Cells · doi:10.3390/cells10051019 · Cited by 18
“The two other categories were genes involved in oxydo-reductase activity or in mitochondrial and peroxisomal metabolisms [73].”
Background
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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