ArticleAmerican journal of human genetics2022
Genetic modifiers of Huntington disease differentially influence motor and cognitive domains.
Article in American journal of human genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
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Who cites it
62 citing papers in PubMed, 107 citations in OpenAlex.
- Redundant mispair excision mechanisms in eukaryotic DNA mismatch repair.Nucleus (Austin, Tex.) · 2026Review
- Extracellular Vesicles and Exosomes as Biomarkers in Huntington's Disease: Uncovering Pathogenic Insights and Pioneering Therapies.Molecular neurobiology · 2026Review
- Article
- Stage-dependent tau-PET signatures in Huntington's disease revealed by [¹⁸F]PI-2620.European journal of nuclear medicine and molecular imaging · 2026Article
- Genetic variants in pulmonary hypertension associated with chronic obstructive pulmonary disease.Current opinion in pulmonary medicine · 2026Review
- Clinical implications of loss of interruption variants for diagnosis, genetic counselling, and clinical trials in Huntington's disease.Journal of Huntington's disease · 2026Review
- Targeted quantification assays for DNA repair and handling proteins and interactions in Huntington's disease models.bioRxiv : the preprint server for biology · 2026Article
- DNA methylation profiling in Huntington's disease reveals disease associated changes in the striatum.Clinical epigenetics · 2026Article
- Double strand breaks drive toxicity in a Huntington's disease mouse model with or without somatic expansion.Nature communications · 2026Article
- Article
- Genetic or pharmacological disruption of the MSH3 Y245/K246 IDL binding pocket slows CAG repeat expansion.NAR molecular medicine · 2026Article
- ALS and Huntington Disease: Unraveling the Connections between TDP-43 and Huntingtin.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2026Review
- Huntington's disease LIG1 modifier variant increases ligase fidelity and suppresses somatic CAG repeat expansion.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Silencer variants are key drivers of gene up-regulation in Alzheimer's disease.Science advances · 2026Article
- Article
- Sequence Variants in Small CAG Repeat Expansions of theNeurology · 2026Article
- MSH3 is a genetic modifier of somatic repeat instability in X-linked dystonia parkinsonism.American journal of human genetics · 2026Article
- Clinical implications of malnutrition in Huntington's disease progression: evidence from a Chinese cohort and Mendelian randomization.Frontiers in nutrition · 2026Article
- Predicting disease progression in progressive cerebellar ataxias: integrating clinical, imaging, fluid, genetic, and digital biomarkers.Frontiers in neurology · 2026Review
- Huntington disease: somatic expansion, pathobiology and therapeutics.Nature reviews. Neurology · 2026Review
2 more citing papers are in PubMed but not listed here.
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Authors and funding
28 authors at 13 institutions in 4 countries.
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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.
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