A SNP in the HTT promoter alters NF-κB binding and is a bidirectional genetic modifier of Huntington disease
Abstract
Cis-regulatory variants that alter gene expression can modify disease expressivity, but none have previously been identified in Huntington disease (HD). Here we provide in vivo evidence in HD patients that cis-regulatory variants in the HTT promoter are bidirectional modifiers of HD age of onset. HTT promoter analysis identified a NF-κB binding site that regulates HTT promoter transcriptional activity. A non-coding SNP, rs13102260:G > A, in this binding site impaired NF-κB binding and reduced HTT transcriptional activity and HTT protein expression. The presence of the rs13102260 minor (A) variant on the HD disease allele was associated with delayed age of onset in familial cases, whereas the presence of the rs13102260 (A) variant on the wild-type HTT allele was associated with earlier age of onset in HD patients in an extreme case-based cohort. Our findings suggest a previously unknown mechanism linking allele-specific effects of rs13102260 on HTT expression to HD age of onset and have implications for HTT silencing treatments that are currently in development.
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Improved recognition of variable penetrance of many monogenic disease alleles has invigorated efforts to identify genetic and environmental modifiers.
“Improved recognition of the variable penetrance of many ‘monogenic’ disease alleles has invigorated efforts to identify the genetic and environmental modifiers responsible26,27.”
From A brief history of human disease genetics (2020) · cites this paper as [26]
These developments have enabled researchers to bridge the gap between monogenic and polygenic realms, identifying common variant modifiers of monogenic phenotypes and low-frequency and rare variants influencing common multifactorial traits.
“These developments have enabled researchers to bridge the gap between the monogenic and polygenic realms, identifying common variant modifiers of monogenic phenotypes contributing to the variable expression of rare, large-effect alleles26,93, and low-frequency and rare variants that influence common multifactorial traits94,95.”
From A brief history of human disease genetics (2020) · cites this paper as [26]
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- Authors
- 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., Doty, C. N., Beck, J., Lahiri, N., Portales-Casamar, E., Warby, S. C., Connolly, C., De Souza, R. A. G., Tabrizi, S. J., Hermanson, O., Langbehn, D. R., Hayden, M. R., Wasserman, W. W., & Leavitt, B. R.
- Affiliations
- University of British Columbia (CA)
- University of Copenhagen (DK)
- Karolinska Institutet (SE)
- University of Iowa (US)
- Corresponding author
- Bečanović, Kristina
- Leavitt, Blair R
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2015-05-04
- Volume
- 18
- Issue
- 6
- Pages
- 807-816
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- OpenAlex
- W1529591158
- Cited by
- 135
- References
- 48
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 18 · 2023: 24 · 2022: 14 · 2021: 8 · 2020: 9 · 2019: 13 · 2018: 13 · 2017: 12 · 2016: 11 · 2015: 5
- FWCI
- 6.35
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Medical Research Council (MR/L012936/1, MR/L02053X/1)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- Huntington's disease, non-coding SNPs, NF-kappaB binding site, cis-regulatory variation, age of onset, allele-specific effects
- MeSH terms
- Huntingtin Protein, Adult, Alleles, DNA, Gene Expression Regulation, Humans, Huntington Disease, Middle Aged, Nerve Tissue Proteins, Protein Binding, Cohort Studies, Mutagenesis, Site-Directed, NF-kappa B, Age of Onset, Genes, Reporter, Polymorphism, Single Nucleotide
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