Background: Alzheimer’s disease (AD) presents a significant public health problem and major cause of dementia. Not only genetic but epigenetic factors contribute to complex and heterogeneous molecular mechanisms underlying AD risk; in particular, single nucleotide polymorphisms (SNPs) and DNA methylation can lead to dysregulation of gene expression in the AD brain. Each of these regulators has been independently studied well in AD progression, however, their interactive roles, particularly when they are located differently, still remains unclear. Here, we aimed to explore the interplay between SNPs and DNA methylation in regulating transcript expression levels in the AD brain through an integrative analysis of whole-genome sequencing, RNA-seq, and methylation data measured from the dorsolateral prefrontal cortex.

Results: We identified 179 SNP-methylation combination pairs that showed statistically significant interactions associated with the expression of 67 transcripts (63 unique genes), enriched in functional pathways, including immune-related and post-synaptic assembly pathways. Particularly, a number of HLA family genes (HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DRB5, HLA-DPA1, HLA-K, HLA-DQB1, and HLA-DMA) were observed as having expression changes associated with the interplay.

Conclusions: Our findings especially implicate immune-related pathways as targets of these regulatory interactions. SNP-methylation interactions may thus contribute to the molecular complexity underlying immune-related pathogenies in AD patients. Our study provides a new molecular knowledge in the context of the interplay between genetic and epigenetic regulations, in that it concerns transcript expression status in AD.