Interdepartmental Neuroscience Program and Medical Scientist Training Program , Yale School of Medicine, New Haven, Connecticut.
Department of Psychiatry , Division of Human Genetics, VA CT Healthcare Center, Yale School of Medicine, New Haven, Connecticut.
Alcohol Clin Exp Res. 2018 Dec;42(12):2337-2348. doi: 10.1111/acer.13890. Epub 2018 Oct 25.
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.
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.
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 ). 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.
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.
促进有害酒精使用的停止受到酒精戒断（AW）的情感和生理成分的阻碍，包括危及生命的癫痫发作。尽管之前关于 AW 和复发的研究强调了压力的有害作用，但对遗传风险因素知之甚少。
我们对有严重 AW 病史的受试者进行了 AW 症状计数的全基因组关联研究，随后在独立的 AW 受试者中进行了额外的基因分型。
AW 严重程度的最高关联信号是在 4 号染色体上的分选蛋白家族神经生长因子受体基因 SORCS2 上（欧洲裔美国人荟萃分析 n = 1,478，p = 4.3×10）。在非裔美国人中没有全基因组显著发现（n = 1,231）。使用公开的高通量转录组和表观基因组数据集进行了生物信息学分析，表明在人类中，SORCS2 在神经系统中表达最高。鉴定出的 SORCS2 风险单倍型被预测会破坏一个应激激素调节的调节元件，该元件在人类海马体中具有组织特异性活性。我们使用人类神经谱系细胞在体外证明了应激激素水平与 SORCS2 表达之间的因果关系，并表明在培养物中乙醇暴露和戒断后 SORCS2 水平增加。
综上所述，这些发现表明，戒断的病理生理学可能涉及应激激素对神经营养因子信号的影响。进一步研究这些途径可能会产生新的方法来管理突然戒酒的厌恶后果。
