Journal article
Genetic modifiers of Huntington disease differentially influence motor and cognitive domains
American journal of human genetics, Vol.109(5), pp.885-899
05/05/2022
DOI: 10.1016/j.ajhg.2022.03.004
PMCID: PMC9118113
PMID: 35325614
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.
Details
- Title: Subtitle
- Genetic modifiers of Huntington disease differentially influence motor and cognitive domains
- Creators
- Jong-Min Lee - Harvard UniversityYuan Huang - Yale UniversityMichael Orth - University of BernTammy Gillis - Massachusetts General HospitalJacqueline Siciliano - Massachusetts General HospitalEunpyo Hong - Massachusetts General HospitalJayalakshmi Srinidhi Mysore - Massachusetts General HospitalDiane Lucente - Massachusetts General HospitalVanessa C Wheeler - Massachusetts General HospitalIhn Sik Seong - Harvard UniversityZachariah L McLean - Harvard UniversityJames A Mills - University of IowaBranduff McAllister - Cardiff UniversitySergey V Lobanov - Cardiff UniversityThomas H Massey - Cardiff UniversityMarc Ciosi - University of GlasgowG. Bernhard Landwehrmeyer - Universität UlmJane S Paulsen - University of Wisconsin–MadisonE. Ray Dorsey - University of Rochester Medical CenterIra Shoulson - University of Rochester Medical CenterCristina Sampaio - CHDI FoundationDarren G Monckton - University of GlasgowSeung Kwak - CHDI FoundationPeter Holmans - Cardiff UniversityLesley Jones - Cardiff UniversityMarcy E MacDonald - Broad InstituteJeffrey D Long - University of IowaJames F Gusella - Harvard University
- Resource Type
- Journal article
- Publication Details
- American journal of human genetics, Vol.109(5), pp.885-899
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.ajhg.2022.03.004
- PMID
- 35325614
- PMCID
- PMC9118113
- ISSN
- 0002-9297
- eISSN
- 1537-6605
- Language
- English
- Date published
- 05/05/2022
- Academic Unit
- Psychiatry; Psychological and Brain Sciences; Biostatistics
- Record Identifier
- 9984280873202771
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