Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
Office of the Clinical Director, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
Transl Psychiatry. 2018 Jul 13;8(1):131. doi: 10.1038/s41398-018-0184-9.
Alcohol dependence (AD) frequently co-occurs with major depressive disorder (MDD). While this comorbidity is associated with an increase in disease burden, worse treatment outcomes, and greater economic costs, the underlying neurobiology remains poorly understood. A recent large-scale GWAS of MDD has identified a locus in the TMEM161B-MEF2C region (rs10514299) as a novel risk variant; however, the biological relevance of this variant has not yet been studied. Given previous reports of disrupted reward processing in both AD and MDD, we hypothesized that rs10514299 would be associated with differences in striatal BOLD responses during reward/loss anticipation in AD. DNA samples from 45 recently detoxified patients with AD and 45 healthy controls (HC) were genotyped for rs10514299. Participants performed the Monetary Incentive Delay task in a 3-Tesla MRI scanner. Effects of rs10514299 on striatal activation during anticipation of high/low reward/loss were investigated. Furthermore, we examined associations between rs10514299 and lifetime AD diagnosis in two independent clinical samples [NIAAA: n = 1858 (1123 cases, 735 controls); SAGE: n = 3838 (1848 cases, 1990 controls)], as well as its association with depression severity in a subsample of individuals with a lifetime AD diagnosis (n = 953). Patients carrying the T allele showed significantly greater putamen activation during anticipation of high reward (p = 0.014), low reward (at trend-level; p = 0.081), high loss (p = 0.024), and low loss (p = 0.046) compared to HCs. Association analyses in the NIAAA sample showed a trend-level relationship between rs10514299 and a lifetime AD diagnosis in the European American subgroup (odds ratio = 0.82, p = 0.09). This finding was not replicated in the SAGE sample. In the NIAAA sample, the T allele was significantly associated with greater depression symptom severity in individuals with a lifetime AD diagnosis (β = 1.25, p = 0.02); this association was driven by the African American ancestry subgroup (β = 2.11, p = 0.008). We show for the first time that the previously identified MDD risk variant rs10514299 in TMEM161B-MEF2C predicts neuronal correlates of reward processing in an AD phenotype, possibly explaining part of the shared pathophysiology and comorbidity between the disorders.
酒精依赖（AD）常与重度抑郁症（MDD）共病。虽然这种共病与疾病负担增加、治疗效果较差和经济成本增加有关，但神经生物学基础仍知之甚少。最近对 MDD 的大规模全基因组关联研究（GWAS）确定了 TMEM161B-MEF2C 区域中的一个位点（rs10514299）为新的风险变异；然而，该变异的生物学相关性尚未得到研究。鉴于先前有报道称 AD 和 MDD 均存在奖赏处理受损，我们假设 rs10514299 与 AD 患者在奖赏/损失预期期间纹状体的 BOLD 反应差异有关。从 45 名最近戒酒的 AD 患者和 45 名健康对照者（HC）中提取 DNA 样本，对 rs10514299 进行基因分型。参与者在 3T MRI 扫描仪中进行货币奖励延迟任务。研究了 rs10514299 对高/低奖赏/损失预期期间纹状体激活的影响。此外，我们在两个独立的临床样本中检查了 rs10514299 与终生 AD 诊断的关联[NIAAA：n=1858（1123 例，735 例对照）；SAGE：n=3838（1848 例，1990 例对照）]，以及其与具有终生 AD 诊断的个体中抑郁严重程度的关联（n=953）。携带 T 等位基因的患者在预期高奖赏时（p=0.014）、低奖赏时（趋势水平；p=0.081）、高损失时（p=0.024）和低损失时（p=0.046）的纹状体激活显著增加。NIAAA 样本的关联分析显示，rs10514299 与欧洲裔美国人亚组的终生 AD 诊断呈趋势水平相关（优势比=0.82，p=0.09）。这一发现在 SAGE 样本中没有得到复制。在 NIAAA 样本中，T 等位基因与具有终生 AD 诊断的个体的抑郁症状严重程度显著相关（β=1.25，p=0.02）；这种关联由非洲裔美国人遗传背景亚组驱动（β=2.11，p=0.008）。我们首次表明，TMEM161B-MEF2C 中先前确定的 MDD 风险变异 rs10514299 预测了 AD 表型中奖赏处理的神经元相关性，这可能解释了两种疾病之间部分共同的病理生理学和共病。
