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Risk Locus Identification Ties Alcohol Withdrawal Symptoms to SORCS2

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  • Andrew H Smith, Department of Psychiatry, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, USA.
  • ,
  • Peter L Ovesen
  • ,
  • Sune Skeldal
  • ,
  • Seungeun Yeo, Laboratory of Neurogenetics , National Institute on Alcohol Abuse and Alcoholism, Rockville, Maryland.
  • ,
  • Kevin P Jensen, Department of Psychiatry , Division of Human Genetics, VA CT Healthcare Center, Yale School of Medicine, New Haven, Connecticut.
  • ,
  • Ditte Olsen
  • Nancy Diazgranados, Office of the Clinical Director , National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
  • ,
  • Hongyu Zhao, Department of Biostatistics , Yale School of Public Health, New Haven, Connecticut.
  • ,
  • Lindsay A Farrer, Departments of Biostatistics and Epidemiology , School of Public Health, Boston University, Boston, Massachusetts.
  • ,
  • David Goldman, Office of the Clinical Director , National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
  • ,
  • Simon Glerup
  • Henry R Kranzler, Department of Psychiatry , Perelman School of Medicine, University of Pennsylvania and Corporal Michael J. Crescenz VAMC, Philadelphia, Pennsylvania.
  • ,
  • Anders Nykjaer
  • Joel Gelernter, Departments of Genetics and Neuroscience , Yale School of Medicine, Yale University, New Haven, Connecticut.

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: The top association signal for AW severity was in sortilin family neurotrophin receptor gene SORCS2 on chromosome 4 (European American meta-analysis n = 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 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.

Original languageEnglish
JournalAlcoholism: Clinical and Experimental Research
Pages (from-to)2337-2348
Number of pages12
Publication statusPublished - Dec 2018

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