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

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 primarily driven by an inverse relationship between CAG expansion size and age of symptom onset. However, the majority of variation in age of onset that is independent of CAG repeat length is thought to be driven by environmental influences. 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.

We utilized the Illumina EPIC v1 methylation array to profile DNA methylation in 120 samples, including three distinct brain regions (striatum, entorhinal cortex and cerebellum) in 20 Huntington's disease and 22 control donors. We identified seven Bonferroni-significant differentially methylated CpGs within the striatum along with 27 differentially methylated regions, annotated to genes involved in physiological processes known to be disrupted in HD such as the urea cycle and metabolism. Weighted gene correlation network analysis identified 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.

Here, we present the first epigenome-wide association study of Huntington's disease conducted in the striatum, the primary region of neuropathology, along with matched entorhinal cortex and cerebellum on the Illumina EPIC v1 array. Our results suggest that DNA methylation is altered at loci associated with Huntington's disease in disease relevant regions and cell types and strengthens evidence for areas of potential therapeutic intervention.