Genetic Modifiers

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.

Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium, ORCID: https://orcid.org/0000-0003-1601-5277, ORCID: https://orcid.org/0000-0002-7663-4080, ORCID: https://orcid.org/0000-0003-2933-4808 and ORCID: https://orcid.org/0000-0002-8298-8264 (2025) Genetic modifiers of somatic expansion and clinical phenotypes in Huntington’s disease reveal shared and tissue-specific effects. Nature Genetics, 57(6), pp. 1426-1436.

Abstract Huntington's disease (HD), due to expansion of a CAG repeat in HTT, is representative of a growing number of disorders involving somatically unstable short tandem repeats. We find that overlapping and distinct genetic modifiers of clinical landmarks and somatic expansion in blood DNA reveal an underlying complexity and cell-type specificity to the mismatch repair-related processes that influence disease timing.