Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease age of onset
Open accessAbstract
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a triplet (CAG) expansion mutation. The length of the triplet repeat is the most important factor in determining age of onset of HD, although substantial variability remains after controlling for repeat length. The Venezuelan HD kindreds encompass 18,149 individuals spanning 10 generations, 15,409 of whom are living. Of the 4,384 immortalized lymphocyte lines collected, 3,989 DNAs were genotyped for their HD alleles, representing a subset of the population at greatest genetic risk. There are 938 heterozygotes, 80 people with variably penetrant alleles, and 18 homozygotes. Analysis of the 83 kindreds that comprise the Venezuelan HD kindreds demonstrates that residual variability in age of onset has both genetic and environmental components. We created a residual age of onset phenotype from a regression analysis of the log of age of onset on repeat length. Familial correlations (correlation ± SE) were estimated for sibling (0.40 ± 0.09), parent-offspring (0.10 ± 0.11), avuncular (0.07 ± 0.11), and cousin (0.15 ± 0.10) pairs, suggesting a familial origin for the residual variance in onset. By using a variance-components approach with all available familial relationships, the additive genetic heritability of this residual age of onset trait is 38%. A model, including shared sibling environmental effects, estimated the components of additive genetic (0.37), shared environment (0.22), and nonshared environment (0.41) variances, confirming that ≈40% of the variance remaining in onset age is attributable to genes other than the HD gene and 60% is environmental.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
There are few examples of mutations that are causative of autosomal dominant neurodegenerative disease achieving the polymorphic frequency observed in the Purosa valley.
“However, there are few examples of mutations that are causative of autosomal dominant neurodegenerative disease achieving the polymorphic frequency observed in the Purosa valley.29”
From A Novel Protective Prion Protein Variant that Colocalizes with Kuru Exposure (2009) · cites this paper as [29]
The paper identifies Huntington’s disease as an autosomal dominant neurodegenerative disease and describes the Venezuelan kindreds as the world’s largest genetically related HD community (opening section; Discussion, page unavailable). It therefore supplies an example of a large affected community, but it does not establish that such mutations rarely reach polymorphic frequency or compare their frequency with that in the Purosa valley. (LLM, conf=0.79)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
MACDONALD, M. (1993) · Cell · doi:10.1016/0092-8674(93)90585-e · Cited by 8,366 · see citing works
Methodology for Genetic Studies of Twins and Families
Neale, M. C., & Cardon, L. R. (1992) · doi:10.1007/978-94-015-8018-2 · Cited by 4,005 · see citing works
A General Test of Association for Quantitative Traits in Nuclear Families
Abecasis, G. R., Cardon, L. R., & Cookson, W. O. C. (2000) · The American Journal of Human Genetics · doi:10.1086/302698 · Cited by 1,126 · see citing works
Trinucleotide repeat length instability and age of onset in Huntington's disease
Duyao, M., Ambrose, C., Myers, R., Novelletto, A., Persichetti, F., Frontali, M., Folstein, S., Ross, C., Franz, M., Abbott, M., et al. (1993) · Nature Genetics · doi:10.1038/ng0893-387 · Cited by 1,089 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 4
- [17]Statistical Solutions (2002) SAGE, Statistical Analysis for Genetic Epidemiology (Statistical Solutions, Cork, Ireland).
- [22]Falconer, D. (1989) Introduction to Quantitative Genetics (Wiley, New York).
- [21]Harper, P. (1991) Huntington's Disease (Saunders, London).
- [24]Yoon, S. R., Dubeau, L., de Young, M., Wexler, N. S. & Arnheim, N. (2003) Proc. Natl. Acad. Sci. USA 100, 8834-8838.
Cited by
Sorted by citations
Enriched environments, experience-dependent plasticity and disorders of the nervous system
Nithianantharajah, J., & Hannan, A. J. (2006) · Nature Reviews Neuroscience · doi:10.1038/nrn1970 · Cited by 1,771 · see citing works
Bates, G. P., Dorsey, R., Gusella, J. F., Hayden, M. R., Kay, C., Leavitt, B. R., Nance, M., Ross, C. A., Scahill, R. I., Wetzel, R., et al. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.5 · Cited by 1,641 · see citing works
Kalaria, R. N., Maestre, G. E., Arizaga, R., Friedland, R. P., Galasko, D., Hall, K., Luchsinger, J. A., Ogunniyi, A., Perry, E. K., Potocnik, F., et al. (2008) · The Lancet Neurology · doi:10.1016/s1474-4422(08)70169-8 · Cited by 1,233 · see citing works
Identification of Genetic Factors that Modify Clinical Onset of Huntington’s Disease
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., et al. (2015) · Cell · doi:10.1016/j.cell.2015.07.003 · Cited by 655 · see citing works
Progressive disruption of cellular protein folding in models of polyglutamine diseases
Gidalevitz, T., Ben-Zvi, A., Ho, K. H., Brignull, H. R., & Morimoto, R. I. (2006) · Science · doi:10.1126/science.1124514 · Cited by 643 · see citing works
Detection of long repeat expansions from PCR-free whole-genome sequence data
Dolzhenko, E., van Vugt, J. J. F. A., Shaw, R. J., Bekritsky, M. A., van Blitterswijk, M., Narzisi, G., Ajay, S. S., Rajan, V., Lajoie, B. R., Johnson, N. H., et al. (2017) · Genome Research · doi:10.1101/gr.225672.117 · Cited by 388 · see citing works
Self-citationHuntington's disease: from pathology and genetics to potential therapies
Imarisio, S., Carmichael, J., Korolchuk, V., Chen, C.-W., Saiki, S., Rose, C., Krishna, G., Davies, J. E., Ttofi, E., Underwood, B. R., et al. (2008) · Biochemical Journal · doi:10.1042/bj20071619 · Cited by 409 · see citing works
The kynurenine pathway and neurodegenerative disease
Maddison, D. C., & Giorgini, F. (2015) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2015.03.002 · Cited by 309 · see citing works
Pang, T. Y. C., Stam, N. C., Nithianantharajah, J., Howard, M. L., & Hannan, A. J. (2006) · Neuroscience · doi:10.1016/j.neuroscience.2006.04.013 · Cited by 265 · see citing works
Pinto, R. M., Dragileva, E., Kirby, A., Lloret, A., Lopez, E., St. Claire, J., Panigrahi, G. B., Hou, C., Holloway, K., Gillis, T., et al. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003930 · Cited by 250 · see citing works
“evidence supporting the contribution of genetic factors [3,4].”
BackgroundDNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases
Bettencourt, C., Hensman‐Moss, D., Flower, M., Wiethoff, S., Brice, A., Goizet, C., Stevanin, G., Koutsis, G., Karadima, G., Panas, M., et al. (2016) · Annals of Neurology · doi:10.1002/ana.24656 · Cited by 227 · see citing works
The HD iPSC Consortium, Lim, R. G., Salazar, L. L., Wilton, D. K., King, A. R., Stocksdale, J. T., Sharifabad, D., Lau, A. L., Stevens, B., Reidling, J. C., et al. (2017) · Nature Neuroscience · doi:10.1038/nn.4532 · Cited by 221 · see citing works
A Novel Protective Prion Protein Variant that Colocalizes with Kuru Exposure
Mead, S., Whitfield, J., Poulter, M., Shah, P., Uphill, J., Campbell, T., Al-Dujaily, H., Hummerich, H., Beck, J., Mein, C. A., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0809716 · Cited by 206 · see citing works
Inflammation and insulin/IGF-1 resistance as the possible link between obesity and neurodegeneration
Spielman, L. J., Little, J. P., & Klegeris, A. (2014) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2014.06.004 · Cited by 182 · see citing works
REGISTRY Investigators of the European Huntington's Disease Network, Bečanović, K., Nørremølle, A., Neal, S. J., Kay, C., Collins, J. A., Arenillas, D., Lilja, T., Gaudenzi, G., Manoharan, S., et al. (2015) · Nature Neuroscience · doi:10.1038/nn.4014 · Cited by 135 · see citing works
Huntington’s disease: Clinical presentation and treatment
Novak, M. J. U., & Tabrizi, S. J. (2011) · International Review of Neurobiology · doi:10.1016/b978-0-12-381328-2.00013-4 · Cited by 137 · see citing works
(2018) · Handbook of Clinical Neurology · doi:10.1016/b978-0-444-63233-3.00017-8 · Cited by 122 · see citing works
Chiang, M.-C., Chen, H.-M., Lee, Y.-H., Chang, H.-H., Wu, Y.-C., Soong, B.-W., Chen, C.-M., Wu, Y.-R., Liu, C.-S., Niu, D.-M., et al. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddl481 · Cited by 95 · see citing works
del Toro, D., Canals, J. M., Ginés, S., Kojima, M., Egea, G., & Alberch, J. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.3873-06.2006 · Cited by 95 · see citing works
Cho, Z., Oh, S., Kim, J., Park, S., Kwon, D., Jeong, H., Kim, Y., Chi, J., Park, C., Huston, J., et al. (2011) · Movement Disorders · doi:10.1002/mds.23465 · Cited by 87 · see citing works
Huntington’s Disease Pathogenesis Is Modified In Vivo by Alfy/Wdfy3 and Selective Macroautophagy
Fox, L. M., Kim, K., Johnson, C. W., Chen, S., Croce, K. R., Victor, M. B., Eenjes, E., Bosco, J. R., Randolph, L. K., Dragatsis, I., et al. (2020) · Neuron · doi:10.1016/j.neuron.2019.12.003 · Cited by 76 · see citing works
Effects of chronic stress on the onset and progression of Huntington’s disease in transgenic mice
Mo, C., Renoir, T., & Hannan, A. J. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.07.008 · Cited by 46 · see citing works
Telomere length analysis on leukocytes derived from patients with Huntington Disease
PerezGrovas-Saltijeral, A., Ochoa-Morales, A., Miranda-Duarte, A., Martínez-Ruano, L., Jara-Prado, A., Camacho-Molina, A., & Hidalgo-Bravo, A. (2020) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2019.111189 · Cited by 19 · see citing works
- Authors
- The U.S.–Venezuela Collaborative Research Project*, & Wexler, N. S.
- Affiliations
- Columbia University (US)
- Corresponding author
- Wexler, Nancy S.
- ORCID
- Wexler, Nancy S.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2004-03
- Volume
- 101
- Issue
- 10
- Pages
- 3498-3503
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC373491
- OpenAlex
- W2103675937
- Cited by
- 761
- References
- 4
- Citations by year
- 2026: 12 · 2025: 20 · 2024: 25 · 2023: 32 · 2022: 36 · 2021: 36 · 2020: 31 · 2019: 36 · 2018: 50 · 2017: 37 · 2016: 27 · 2015: 36 · 2014: 41 · 2013: 44 · 2012: 45
- FWCI
- 10.57
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- NSUWorks (Nova Southeastern University) (submittedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- 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, CAG repeat expansion, heritability, shared environment, nonshared environment, familial correlation, genetic and environmental factors
- MeSH terms
- Adolescent, Adult, Aged, Child, Child, Preschool, Environment, Female, Humans, Huntington Disease, Male, Middle Aged, Models, Genetic, Phenotype, Venezuela, Age of Onset, Trinucleotide Repeat Expansion
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 ›
Are you an author, or do you see a problem with this page? Request a review
