Genetic modifiers of Huntington disease differentially influence motor and cognitive domains

Lee, J.-M. et al. (2022) Genetic modifiers of Huntington disease differentially influence motor and cognitive domains. American Journal of Human Genetics, 109(5), pp. 885-899. (doi: 10.1016/j.ajhg.2022.03.004) (PMID:35325614)

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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:Articles
Glasgow Author(s) Enlighten ID:Monckton, Professor Darren and Ciosi, Dr Marc
Authors: Lee, J.-M., Huang, Y., Orth, M., Gillis, T., Siciliano, J., Hong, E., Mysore, J. S., Lucente, D., Wheeler, V. C., Seong, I. S., McLean, Z. L., Mills, J. A., McAllister, B., Lobanov, S. V., Massey, T. H., Ciosi, M., Landwehrmeyer, G. B., Paulsen, J. S., Dorsey, E. R., Shoulson, I., Sampaio, C., Monckton, D. G., Kwak, S., Holmans, P., Jones, L., MacDonald, M. E., Long, J. D., and Gusella, J. F.
College/School:College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
Journal Name:American Journal of Human Genetics
Publisher:Elsevier (Cell Press)
ISSN (Online):1537-6605
Published Online:23 March 2022
Copyright Holders:Copyright © 2022 American Society of Human Genetics
First Published:First published in American Journal of Human Genetics 109(5):885-899
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher
Data DOI:10.5061/dryad.dr7sqvb11

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