Risk Locus Identification Ties Alcohol Withdrawal Symptoms to SORCS2

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 (GWAS) 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 datasets, 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.

Recent Efforts to Dissect the Genetic Basis of Alcohol Use and Abuse

“…Animal models provide an opportunity to evaluate the role of newly identified genes (Table 1) at the molecular, cellular and circuit level. We may also be able to perform human genetic studies of specific components of AUD such as DSM-IV AD criterion count (67) and alcohol withdrawal (68). To date these traits have only been studied in smaller samples but this approach will be invaluable as sample sizes increase.…”

Acute alcohol withdrawal and recovery in men lead to profound changes in DNA methylation profiles: a longitudinal clinical study

“…Genetic factors play a role in the development of alcohol use disorder as well as in the severity and time of onset of AWS . Heritable components of AWS have been systematically explored by genome‐wide association studies (GWAS) which have implicated several genes contributing to AWS, among which the sortilin family neurotrophin receptor gene ( SORCS2 ) was observed repeatedly . In addition to genetic factors, environmental factors play a role in the development of AUD and withdrawal responses.…”

Reduced Alcohol Seeking and Withdrawal Symptoms in Mice Lacking the BDNF Receptor SorCS2

“…Thus, three systems, BDNF, NMDA receptor, and dopaminergic activity, that are considered main culprits in AUD (Ron and Barak, 2016), are all perturbed in Sorcs2 −/− mice. Moreover, SORCS2 has been genetically associated with the severity of alcohol withdrawal in alcohol dependent individuals (Smith et al, 2018). We therefore speculated whether Sorcs2 −/− mice would have altered response to alcohol compared to WT mice – and tested this using three paradigms modeling alcohol consumption and withdrawal: (I) alcohol-induced conditioned place preference, (II) the two-bottle choice test, and (III) Handling-induced withdrawal convulsions (HIC) after inducing alcohol dependency.…”