In general, the ‘candidate genes’ for AUD that were examined in smaller cohorts have not been replicated by larger and better powered GWAS (10). One exception is the corticotropin releasing hormone receptor 1 (CRHR1), a candidate gene extensively studied in humans and rodents before the advent of large-scale GWAS studies (10). CRHR1 is central to the cortisol stress response as part of the hypothalamic-pituitary-axis. Extensive preclinical literature has shown that CRHR1 is associated with relapse to drug taking in mice [e.g. (36, 37)] and there is some evidence that variation in CRHR1 modulates the role of psychological stress on alcohol intake (e.g. 38, 39). Encouragingly, the genomic region surrounding CRHR1 has been associated with alcohol consumption and misuse in several recent GWAS studies (21, 22, 40). However, CRHR1 is located in an inversion polymorphism of roughly 900kb that is common in Europeans and induces extensive LD spanning many genes (41), including CRHR1 and MAPT (22). MAPT encodes the protein tau, is involved in Parkinson’s and Alzheimer’s disease. Further work is therefore required to determine which variant(s) are causal, as the inversion in this region complicates the ability of GWAS to fully address this question.
