Format

Send to

Choose Destination
Alcohol Clin Exp Res. 2018 Dec;42(12):2337-2348. doi: 10.1111/acer.13890. Epub 2018 Oct 25.

Risk Locus Identification Ties Alcohol Withdrawal Symptoms to SORCS2.

Author information

1
Interdepartmental Neuroscience Program and Medical Scientist Training Program , Yale School of Medicine, New Haven, Connecticut.
2
Department of Psychiatry , Division of Human Genetics, VA CT Healthcare Center, Yale School of Medicine, New Haven, Connecticut.
3
Department of Psychiatry , Icahn School of Medicine at Mount Sinai, New York, New York.
4
Department of Biomedicine , The Lundbeck Foundation Research Center MIND, Danish Research Institute of Translational Neuroscience DANDRITE - Nordic EMBL Partnership for Molecular Medicine, Aarhus University, Aarhus C, Denmark.
5
Laboratory of Neurogenetics , National Institute on Alcohol Abuse and Alcoholism, Rockville, Maryland.
6
Office of the Clinical Director , National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
7
Department of Biostatistics , Yale School of Public Health, New Haven, Connecticut.
8
Departments of Medicine (Biomedical Genetics), Neurology, and Ophthalmology , School of Medicine, Boston University, Boston, Massachusetts.
9
Departments of Biostatistics and Epidemiology , School of Public Health, Boston University, Boston, Massachusetts.
10
Department of Psychiatry , Perelman School of Medicine, University of Pennsylvania and Corporal Michael J. Crescenz VAMC, Philadelphia, Pennsylvania.
11
Department of Neuroscience , Mayo Clinic, Jacksonville, Florida.
12
Departments of Genetics and Neuroscience , Yale School of Medicine, Yale University, New Haven, Connecticut.

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:

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.

KEYWORDS:

Alcohol Withdrawal; Genome-Wide Association Study; Human Genetics; Stress Hormones

PMID:
30252935
PMCID:
PMC6317871
[Available on 2019-12-01]
DOI:
10.1111/acer.13890

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center