Lee, Jong-Min, Huang, Yuan, Orth, Michael, Gillis, Tammy, Siciliano, Jacqueline, Hong, Eunpyo, Mysore, Jayalakshmi Srinidhi, Lucente, Diane, Wheeler, Vanessa C., Seong, Ihn Sik, McLean, Zachariah L., Mills, James A., McAllister, Branduff, Lobanov, Sergey V.  ORCID: https://orcid.org/0000-0002-3126-1903, Massey, Thomas H. ORCID: https://orcid.org/0000-0002-9804-2131, Ciosi, Marc, Landwehrmeyer, G. Bernhard, Paulsen, Jane S., Dorsey, E. Ray, Shoulson, Ira, Sampaio, Cristina, Monckton, Darren G., Kwak, Seung, Holmans, Peter ORCID: https://orcid.org/0000-0003-0870-9412, Jones, Lesley ORCID: https://orcid.org/0000-0002-3007-4612, MacDonald, Marcy E., Long, Jeffrey D. and Gusella, James F.
2022.
Genetic modifiers of Huntington disease differentially influence motor and cognitive domains.
American Journal of Human Genetics
109
(5)
, pp. 885-899.
10.1016/j.ajhg.2022.03.004
|
Preview |
PDF
- Accepted Post-Print Version
Available under License Creative Commons Attribution Non-commercial No Derivatives. Download (306kB) | Preview |
Abstract
Genome-wide association studies (GWASs) of Huntington disease (HD) have identified six DNA maintenance gene loci (among others) as modifiers and implicated a two step-mechanism of pathogenesis: somatic instability of the causative HTT CAG repeat with subsequent triggering of neuronal damage. The largest studies have been limited to HD individuals with a rater-estimated age at motor onset. To capitalize on the wealth of phenotypic data in several large HD natural history studies, we have performed algorithmic prediction by using common motor and cognitive measures to predict age at other disease landmarks as additional phenotypes for GWASs. Combined with imputation with the Trans-Omics for Precision Medicine reference panel, predictions using integrated measures provided objective landmark phenotypes with greater power to detect most modifier loci. Importantly, substantial differences in the relative modifier signal across loci, highlighted by comparing common modifiers at MSH3 and FAN1, revealed that individual modifier effects can act preferentially in the motor or cognitive domains. Individual components of the DNA maintenance modifier mechanisms may therefore act differentially on the neuronal circuits underlying the corresponding clinical measures. In addition, we identified additional modifier effects at the PMS1 and PMS2 loci and implicated a potential second locus on chromosome 7. These findings indicate that broadened discovery and characterization of HD genetic modifiers based on additional quantitative or qualitative phenotypes offers not only the promise of in-human validated therapeutic targets but also a route to dissecting the mechanisms and cell types involved in both the somatic instability and toxicity components of HD pathogenesis.
| Item Type: | Article |
|---|---|
| Date Type: | Publication |
| Status: | Published |
| Schools: | Professional Services > Advanced Research Computing @ Cardiff (ARCCA) Research Institutes & Centres > MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) Schools > Medicine |
| Publisher: | Cell Press |
| ISSN: | 0002-9297 |
| Date of First Compliant Deposit: | 3 August 2022 |
| Date of Acceptance: | 1 March 2022 |
| Last Modified: | 08 Sep 2025 13:45 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/151657 |
Citation Data
Cited 2 times in Scopus. View in Scopus. Powered By Scopus® Data
Actions (repository staff only)
 |
Edit Item |
Dimensions
Dimensions