Genetic modifiers of somatic expansion and clinical phenotypes in Huntington’s disease highlight shared and tissue-specific effects

• Published in: Nature genetics Vol. 57; no. 6; pp. 1426 - 1436
• Main Authors: Lee, Jong-Min, McLean, Zachariah L., Correia, Kevin, Shin, Jun Wan, Lee, Sujin, Jang, Jae-Hyun, Lee, Yukyeong, Kim, Kyung-Hee, Choi, Doo Eun, Long, Jeffrey D., Lucente, Diane, Seong, Ihn Sik, Mouro Pinto, Ricardo, Giordano, James V., Mysore, Jayalakshmi S., Siciliano, Jacqueline, Elezi, Emanuela, Ruliera, Jayla, Gillis, Tammy, Wheeler, Vanessa C., MacDonald, Marcy E., Gusella, James F., Gatseva, Anna, Ciosi, Marc, Lomeikaite, Vilija, Loay, Hossameldin, Monckton, Darren G., Wills, Christopher, Massey, Thomas H., Jones, Lesley, Holmans, Peter, Kwak, Seung, Sampaio, Cristina, Orth, Michael, Landwehrmeyer, G. Bernhard, Paulsen, Jane S., Dorsey, E. Ray, Myers, Richard H.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2025; Nature Publishing Group
• Subjects: 5' Untranslated regions; 631/208/205/2138; 692/699/375/365; Adenosine Triphosphatases - genetics; Age; Agriculture; Animal Genetics and Genomics; Biomedical and Life Sciences; Biomedicine; Blood; Cancer Research; Chromosomes; Deoxyribonucleic acid; DNA; DNA Mismatch Repair - genetics; DNA repair; DNA Repair Enzymes - genetics; DNA-Binding Proteins - genetics; Endodeoxyribonucleases - genetics; Exodeoxyribonucleases - genetics; Female; Gene Function; Gene loci; Genes; Genes, Modifier; Genetic modification; Genome-wide association studies; Genome-Wide Association Study; Genomes; Haplotypes; Human Genetics; Humans; Huntingtin Protein - genetics; Huntington Disease - genetics; Huntington Disease - pathology; Huntington's disease; Huntingtons disease; Influence; Male; Mismatch repair; Mismatch Repair Endonuclease PMS2 - genetics; Molecular modelling; Multifunctional Enzymes; MutS Homolog 3 Protein - genetics; Organ Specificity - genetics; Pathogenesis; Phenotype; Phenotypes; Polyglutamine; Trinucleotide Repeat Expansion - genetics; Trinucleotide repeats
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/s41588-025-02191-5

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. Comparison of genome-wide association studies of HTT CAG repeat expansion in blood to expansion-driven clinical traits in Huntington’s disease identifies shared and distinct modifiers implicating DNA mismatch repair with tissue and cell-type specificity.