DNA methylation profiling in Huntington’s disease reveals disease associated changes in the striatum

ABSTRACT: Huntington’s disease is caused by a trinucleotide CAG repeat expansion in the HTT gene. Despite displaying autosomal dominance, phenotypic variation exists amongst mutation carriers, in particular relating to the age that symptoms first occur. This variation is predominantly driven by an inverse relationship between CAG expansion size and age of symptom onset. However, the majority of variation in age of onset is thought to be driven by environmental influences, independently of CAG repeat length. Since DNA methylation can be altered by environmental factors, and as methylomic variation is reported in other neurodegenerative diseases, it may offer a potential mechanism underlying disease manifestation. Here, we present the first epigenome-wide association study of Huntington’s disease conducted in the striatum, the primary region of neuropathology, along with the entorhinal cortex and cerebellum in 42 individuals (22 control; 20 Huntington’s disease) on the Illumina EPIC v1 array. We identified seven Bonferroni-significant differentially methylated CpGs within the striatum along with 27 differentially methylated regions. Weighted gene correlation network analysis identified six modules of co-methylated CpGs that were associated with Huntington’s disease, with ontological analyses showing enrichment in disease relevant processes. Furthermore, integration of single-nuclei RNA sequencing data highlighted that genes annotated to these modules are enriched in striatal spiny projection neurons, the primary cell types affected in the disease. These results suggest that DNA methylation is altered at loci associated with Huntington’s disease in disease relevant regions and cell types.

ORGANISM(S): Homo sapiens

PROVIDER: GSE297210 | GEO | 2026/02/17

REPOSITORIES: GEO