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Massachusetts General Hospital / Harvard Medical School

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Nat. Genet., Jun 09 2025, | https://doi.org/10.1038/s41588-025-02191-5 Genetic modifiers of somatic expansion and clinical phenotypes in Huntington's disease highlight shared and tissue-specific effects

Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium

Group 1
Jong-Min Lee ^1,2, Zachariah L. McLean ^1,2,3, Kevin Correia ¹, Jun Wan Shin^1,2, Sujin Lee ^1,2, Jae-Hyun Jang ^1,2, Yukyeong Lee ^1,2, Kyung-Hee Kim ^1,2, Doo Eun Choi ^1,2, Jeffrey D. Long ⁴, Diane Lucente ^1,2, Ihn Sik Seong ^1,2, Ricardo Mouro Pinto ^1,2, James V. Giordano ¹, Jayalakshmi S. Mysore ¹, Jacqueline Siciliano ¹, Emanuela Elezi ¹, Jayla Ruliera ¹, Tammy Gillis ¹, Vanessa C. Wheeler ^1,2, Marcy E. MacDonald^1,2,3 & James F. Gusella ^1,3,5,*

¹Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
²Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
³Medical and Population Genetics Program, the Broad Institute of M.I.T. and Harvard, Cambridge, MA, USA.
⁴Department of Psychiatry, Carver College of Medicine, and Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, IA, USA.
⁵Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
⁶School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
⁷Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
⁸UK Dementia Research Institute at Cardiff University, Cardiff, UK.
⁹CHDI Management, Inc., Princeton, NJ, USA.
¹⁰University Hospital of Old Age Psychiatry and Psychotherapy, Bern University, Bern, Switzerland.
¹¹Department of Neurology, University of Ulm, Ulm, Germany.
¹²Department of Neurology, School of Medicine and Public Health, University of Wisconsin–Madison, Madison, WI, USA.
¹³Department of Neurology, University of Rochester Medical Center, Rochester, NY, USA.
¹⁴Boston University School of Medicine, Boston, MA, USA. 15These authors contributed equally: Lesley Jones, Peter Holmans.

^*Corresponding author: correspondence to James F. Gusella

Please refer to the original text for details.

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.

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