Ovesen, Peter Lund

BackgroundEfforts to promote the cessation of harmful alcohol use are hindered by the affective and physiological components of alcohol withdrawal (AW), which can include life‐threatening seizures. Although previous studies ofAWand relapse have highlighted the detrimental role of stress, little is known about genetic risk factors.MethodsWe conducted a genome‐wide association study ofAWsymptom count in uniformly assessed subjects with histories of seriousAW, followed by additional genotyping in independentAWsubjects.ResultsThe top association signal forAWseverity was in sortilin family neurotrophin receptor geneSORCS2on chromosome 4 (European American meta‐analysisn = 1,478,p = 4.3 × 10−9). There were no genome‐wide significant findings in African Americans (n = 1,231). Bioinformatic analyses were conducted using publicly available high‐throughput transcriptomic and epigenomic data sets, showing that in humansSORCS2is most highly expressed in the nervous system. The identifiedSORCS2risk haplotype is predicted to disrupt a stress hormone‐modulated regulatory element that has tissue‐specific activity in human hippocampus. We used human neural lineage cells to demonstrate in vitro a causal relationship between stress hormone levels andSORCS2expression, and show thatSORCS2levels in culture are increased upon ethanol exposure and withdrawal.ConclusionsTaken together, these findings indicate that the pathophysiology of withdrawal may involve the effects of stress hormones on neurotrophic factor signaling. Further investigation of these pathways could produce new approaches to managing the aversive consequences of abrupt alcohol cessation.