Risk Locus Identification Ties Alcohol Withdrawal Symptoms to SORCS 2
Year: 2018
Type: article
Study design: Observational Study
Abstract: BACKGROUND: Efforts 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 of AW and relapse have highlighted the detrimental role of stress, little is known about genetic risk factors. METHODS: We conducted a genome-wide association study of AW symptom count in uniformly assessed subjects with histories of serious AW, followed by additional genotyping in independent AW subjects. RESULTS: ). 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 humans SORCS2 is most highly expressed in the nervous system. The identified SORCS2 risk 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 and SORCS2 expression, and show that SORCS2 levels in culture are increased upon ethanol exposure and withdrawal. CONCLUSIONS: Taken 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.
DOI: 10.1111/acer.13890
Institutions: Yale University, Icahn School of Medicine at Mount Sinai, Aarhus University, Lundbeck Foundation, National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, Boston University, Philadelphia VA Medical Center, University of Pennsylvania, Mayo Clinic, Mayo Clinic in Florida
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Lundbeckfonden, National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, National Institute on Drug Abuse, National Human Genome Research Institute, National Institute of General Medical Sciences, Fogarty International Center, National Center for Research Resources, National Center for Advancing Translational Sciences
Awards: G1054401548, G2229242666, Yale Biomedical Supercomputer, G2273635344, G2312969642, G2349309202, G2388451852, G292646880, GENOTYPING FOR LOCATING HUMAN DISEASE GENES, Genetics of Alcohol Dependence in African-Americans, G5359555627, Genetics of Opioid Dependence, Genetics of Alcohol Dependence in American Populations, Genetics of Cocaine Dependence, Medical Scientist Training Program, G7794390789, Yale University Clinical and Translational Science Award Program, Genetics of Cocaine Dependence, Systems genetics of smoking, G9000036580, G9000094767, G9000146960, G9000240960
OpenAlex ID: W2892663739