The major depressive disorder GWAS-supported variant rs10514299 in TMEM161B-MEF2C predicts putamen activation during reward processing in alcohol dependence.
The major depressive disorder GWAS-supported variant rs10514299 in TMEM161B-MEF2C predicts putamen activation during reward processing in alcohol dependence.
复制标题
DOI：
10.1038/s41398-018-0184-9
复制
发表时间：
2018-07-13
影响因子：
6.8
通讯作者：
Lohoff FW
中科院分区：
文献类型：
--
作者：
Muench C;Schwandt M;Jung J;Cortes CR;Momenan R;Lohoff FW
酒精依赖（AD）经常与重度抑郁症（MDD）共同发生。虽然这种合并症与疾病负担增加、治疗结果恶化和经济成本增加有关，但对潜在的神经生物学仍知之甚少。最近的一项大规模MDD GWAS已将TMEM 161 B-MEF 2C区域中的一个位点（rs 10514299）确定为新型风险变异;然而，尚未研究该变异的生物学相关性。鉴于先前的报告中断奖励加工AD和MDD，我们假设，rs 10514299将与AD奖励/损失预期期间纹状体BOLD反应的差异。从45个最近脱毒的AD患者和45个健康对照（HC）的DNA样本进行rs 10514299基因分型。参与者在3特斯拉MRI扫描仪中执行货币激励延迟任务。研究了rs 10514299对高/低奖励/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[NIAAA：n = 1858（1123例，735例对照）; SAGE：n = 3838（1848例，1990例对照）]中研究了rs 10514299与终身AD诊断之间的关联，以及其与终身AD诊断个体子样本（n = 953）中抑郁严重程度的关联。与HC相比，携带T等位基因的患者在预期高奖励（p = 0.014）、低奖励（在趋势水平; p = 0.081）、高损失（p = 0.024）和低损失（p = 0.046）时表现出显著更大的壳核激活。NIAAA样本中的关联分析显示，在欧洲裔美国人亚组中，rs 10514299与终身AD诊断之间存在趋势水平关系（比值比= 0.82，p = 0.09）。这一发现在SAGE样本中没有重复。在NIAAA样本中，T等位基因与终身诊断为AD的个体中更严重的抑郁症状显著相关（β = 1.25，p = 0.02）;这种关联是由非裔美国人血统亚组驱动的（β = 2.11，p = 0.008）。我们首次表明，先前在TMEM 161 B-MEF 2C中鉴定的MDD风险变体rs 10514299预测了AD表型中奖赏处理的神经元相关性，这可能解释了这些疾病之间共享的病理生理学和共病性的一部分。
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.
登录
查看更多内容
影响因子：
5.7
作者：
Knutson, B;Fong, GW;Homme, D
通讯作者：
Homme, D
DOI：
10.1002/ajmg.b.31071
发表时间：
2010-07-01
影响因子：
2.8
作者：
Nowakowska, Beata A.;Obersztyn, Ewa;Stankiewicz, Pawet
通讯作者：
Stankiewicz, Pawet
影响因子：
6.7
作者：
Lohoff, Falk W.
通讯作者：
Lohoff, Falk W.
影响因子：
10.6
作者：
Beck, Anne;Schlagenhauf, Florian;Wrase, Jana
通讯作者：
Wrase, Jana
影响因子：
2.8
作者：
Hodgkinson, Colin A.;Yuan, Qiaoping;Goldman, David
通讯作者：
Goldman, David