Non-coding variation in dementias: mechanisms, insights, and challenges

Abstract

Dementia encompasses many neurodegenerative disorders. While some causal coding variants are known, most GWAS variants are in non-coding regions of the genome, making understanding functional impacts challenging. This review explores the role of non-coding variation in dementia, covering methods to identify enhancers and their target genes, prioritize GWAS variants, and validate the functional effects of variation, providing a comprehensive framework for investigating non-coding variation and its implications in dementia research.

Keywords: Dementia; Genetics; Neurodegeneration; Neurodegenerative diseases.

Fig. 1. Regulation of gene expression mediated by enhancers.

Illustration of chromosomal looping, mediated by CTCF and cohesin, that allows a distal enhancer to be in close proximity and interact with the promoter of its target gene. These interactions increase binding of transcription factors, chromatin remodelers, and the Mediator complex to recruit RNA polymerase II (RNAPII) at the promoter of the target gene. Active promoters and enhancers are in regions of open chromatin, depleted of nucleosomes. Active enhancers are flanked by nucleosomes with specific histone modifications (H3K4Me1 and H3K27Ac).