Context-dependant enhancers as a reservoir of functional polymorphisms and epigenetic markers linked to alcohol use disorders and comorbidities

Alcohol use disorder (AUD) is one of the major causes of mortality and morbidity world-wide. It is estimated that 50% of the causes of AUD are heritable. Efforts to determine the genetic determinants governing AUD using genome wide association studies (GWAS) show that the most strongly associated SNPs occur within, or in the vicinity of, genes encoding enzymes that metabolise ethanol. However, these studies were not so conclusive in identifying the genes that influenced the choice to drink ethanol or why a proportion of the population become addicted. Most importantly, these studies also found that over 98% of the 1292 SNPs associated with AUD ( p<1 × 10 -6) were found outside of coding regions and within the poorly understood non-coding genome. Many years of study have shown that functional components of the non-coding genome include enigmatic enhancer elements whose biological role is to modulate levels of gene expression in specific cells, in specific amounts and in response to the correct stimuli. The current short review introduces the functional components of the non-coding genome, such as promoters and enhancers, and critically assesses the latest methods of identifying and characterising their context dependant roles in AUD and mental health disorders. We then go on to examine what is known about the roles of enhancers, such as the GAL5.1 enhancer, in alcohol intake and explore how enhancers are affected by polymorphic variation and epigenetic markers such as DNA-methylation and may influence susceptibility to AUD. The review finishes by discussing the future of AUD genetics and what technologies will need to be brought to bear to understand how genetic and environmentally induced changes in enhancer structure may contribute to the need to drink alcohol to excess.