Journal article
Genetic modifiers of somatic expansion and clinical phenotypes in Huntington's disease highlight shared and tissue-specific effects
Nature genetics, Vol.57(6), pp.1426-1436
06/2025
DOI: 10.1038/s41588-025-02191-5
PMCID: PMC13132264
PMID: 40490511
Abstract
An inherited, expanded CAG repeat in HTT undergoes further somatic expansion to cause Huntington's disease (HD). To gain insights into this molecular mechanism, we compared genome-wide association studies of somatic expansion in blood and somatic expansion-driven HD clinical phenotypes. Here, we show that somatic expansion is driven by a mismatch repair-related process whose genetic modification and consequences show unexpected complexity, including cell-type specificity. The HD clinical trajectory is further modified by non-DNA repair genes that differentially influence measures of cognitive and motor dysfunction. In addition to shared (DNA repair genes MSH3, PMS2 and FAN1) and distinct trans-modifiers, a synonymous CAG-adjacent variant in HTT dramatically hastens motor onset without increasing somatic expansion, while a cis-acting 5'-untranslated region variant promotes blood repeat expansion without influencing clinical HD. Our findings are directly relevant to the therapeutic suppression of expansion in DNA repeat disorders and provide additional clues to HD pathogenic mechanisms beyond somatic expansion.An inherited, expanded CAG repeat in HTT undergoes further somatic expansion to cause Huntington's disease (HD). To gain insights into this molecular mechanism, we compared genome-wide association studies of somatic expansion in blood and somatic expansion-driven HD clinical phenotypes. Here, we show that somatic expansion is driven by a mismatch repair-related process whose genetic modification and consequences show unexpected complexity, including cell-type specificity. The HD clinical trajectory is further modified by non-DNA repair genes that differentially influence measures of cognitive and motor dysfunction. In addition to shared (DNA repair genes MSH3, PMS2 and FAN1) and distinct trans-modifiers, a synonymous CAG-adjacent variant in HTT dramatically hastens motor onset without increasing somatic expansion, while a cis-acting 5'-untranslated region variant promotes blood repeat expansion without influencing clinical HD. Our findings are directly relevant to the therapeutic suppression of expansion in DNA repeat disorders and provide additional clues to HD pathogenic mechanisms beyond somatic expansion.
Details
- Title: Subtitle
- Genetic modifiers of somatic expansion and clinical phenotypes in Huntington's disease highlight shared and tissue-specific effects
- Creators
- Richard H. Myers - Boston University School of MedicineE. Ray Dorsey - University of Rochester Medical CenterJane S. Paulsen - University of Wisconsin–MadisonG. Bernhard Landwehrmeyer - Universität UlmMichael Orth - University of BernCristina Sampaio - CHDI Management, Inc., Princeton, NJ, United StatesSeung Kwak - CHDI Management, Inc., Princeton, NJ, United StatesPeter Holmans - Cardiff UniversityLesley Jones - Cardiff UniversityThomas H. Massey - Cardiff UniversityChristopher Wills - Cardiff UniversityDarren G. Monckton - University of GlasgowHossameldin Loay - University of GlasgowVilija Lomeikaite - University of GlasgowMarc Ciosi - University of GlasgowAnna Gatseva - University of GlasgowJames F. Gusella - Massachusetts General HospitalMarcy E. MacDonald - Massachusetts General HospitalVanessa C. Wheeler - Massachusetts General HospitalTammy Gillis - Massachusetts General HospitalJayla Ruliera - Massachusetts General HospitalEmanuela Elezi - Massachusetts General HospitalJacqueline Siciliano - Massachusetts General HospitalJayalakshmi S. Mysore - Massachusetts General HospitalJames V. Giordano - Massachusetts General HospitalRicardo Mouro Pinto - Massachusetts General HospitalIhn Sik Seong - Massachusetts General HospitalDiane Lucente - Massachusetts General HospitalJeffrey D. Long - University of IowaDoo Eun Choi - Massachusetts General HospitalKyung Hee Kim - Massachusetts General HospitalYukyeong Lee - Massachusetts General HospitalJae Hyun Jang - Massachusetts General HospitalSujin Lee - Massachusetts General HospitalJun Wan Shin - Massachusetts General HospitalKevin Correia - Massachusetts General HospitalZachariah L. McLean - Massachusetts General HospitalJong Min Lee - Massachusetts General HospitalGenetic Modifiers of Huntington’s Disease (GeM-HD) Consortium
- Resource Type
- Journal article
- Publication Details
- Nature genetics, Vol.57(6), pp.1426-1436
- DOI
- 10.1038/s41588-025-02191-5
- PMID
- 40490511
- PMCID
- PMC13132264
- NLM abbreviation
- Nat Genet
- ISSN
- 1546-1718
- eISSN
- 1546-1718
- Publisher
- NATURE PORTFOLIO
- Grant note
- CHDI Foundation (CHDI Foundation, Inc.)CHDI Foundation: NS082079, NS091161, NS016367, NS049206, NS105709, NS119471, NS114065, NS127866, NS126420 National Institutes of HealthHereditary Disease Foundation: MR/L010305/1 Medical Research Council Centre for Neuropsychiatric Genetics and Genomics: MR/X018253/1 Clinician Scientist Fellowship from the Medical Research Council, UKNational Neurological Research Bank at the Veterans Administration in Los AngelesSimons Foundation Powering Autism Research study for nuclear familyEuropean Huntington Disease Network
This work was supported by the CHDI Foundation (J.F.G., M.E.M., D.G.M. and P.H.), National Institutes of Health (NS082079 (J.F.G.), NS091161 (J.F.G.), NS016367 (J.F.G.), NS049206 (V.C.W.), NS105709 (J.-M.L.), NS119471 (J.-M.L.), NS114065 (I.S.S.), NS127866 (V.C.W., I.S.S.) and NS126420 (R.M.P.)), the Hereditary Disease Foundation (Z.L.M., R.M.P.) and the Medical Research Council Centre for Neuropsychiatric Genetics and Genomics (MR/L010305/1 (P.H.)). T.H.M. was supported by a Clinician Scientist Fellowship from the Medical Research Council, UK (MR/X018253/1). The funders had no role in data collection and analysis or the decision to publish. Two scientific collaborators who are advisors to the CHDI Foundation were involved in the conceptualization of the study or editing the final manuscript. We thank the Harvard Tissue Bank at McLean's Hospital, the National Neurological Research Bank at the Veterans Administration in Los Angeles, the New York Brain Bank at Columbia University and the Massachusetts Alzheimer's Disease Resource Center Bank at the Massachusetts General Hospital for postmortem brain tissue from HD patients. We also thank the Simons Foundation Powering Autism Research study for nuclear family sequencing data. Biosamples and data used in this work were also generously provided by the participants in the Enroll-HD study and made available by the CHDI Foundation. Enroll-HD is a clinical research platform and longitudinal observational study for families of individuals with HD that is intended to accelerate progress towards therapeutics; it is sponsored by the CHDI Foundation, a nonprofit biomedical research organization exclusively dedicated to collaboratively developing therapeutics for HD. Enroll-HD and the previous contributing HD studies of the Huntington Study Group, the European Huntington Disease Network and the Massachusetts HD Center Without Walls would not be possible without the vital contribution of the research participants and their families. We also thank those individuals who contributed to the collection of the Enroll-HD data, listed at https://enroll-hd.org/enrollhd_documents/ENROLL-HD_AcknowledgementsListPDS6_v1.0_20230119.pdf, and to previous HD studies, listed in their supplementary material sections 53,5 .
- Language
- English
- Date published
- 06/2025
- Academic Unit
- Psychiatry; Biostatistics
- Record Identifier
- 9984832083702771
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