Background

Consumption of nicotine, alcohol, and cannabis commonly co-occurs, which is thought to partly stem from a common heritable liability to substance involvement.

Methods

To elucidate its genetic architecture, we modeled a common liability inferred from genetic correlations among 6 measures of dependence and frequency of use of nicotine, alcohol, and cannabis.

Results

Forty-two genetic variants were identified in the multivariate genome-wide association study on the common liability to substance involvement, of which 67% were novel and not associated with the 6 phenotypes. Mapped genes highlighted the role of dopamine (e.g., dopamine receptor D₂ gene) and showed enrichment for several components of the central nervous system (e.g., mesocorticolimbic brain regions) and molecular pathways (dopaminergic, glutamatergic, GABAergic [gamma-aminobutyric acidergic]) that are thought to modulate drug reinforcement. Genetic correlations with other traits were most prominent for reward-related behaviors (e.g., risk taking, cocaine use, and opioid use) and mood (e.g., depression, insomnia).

Conclusions

These genome-wide results triangulate and expand previous preclinical and human studies focusing on the neurobiological substrates of substance involvement and help to elucidate the genetic architecture underlying the use of common psychoactive substances.

中文翻译：

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对物质参与的共同遗传责任的新生物学见解：一项多变量全基因组关联研究

背景

尼古丁、酒精和大麻的消费通常同时发生，这被认为部分源于对物质参与的共同遗传责任。

方法

为了阐明其遗传结构，我们模拟了一个共同的责任，该责任是从尼古丁、酒精和大麻的 6 种依赖性和使用频率的遗传相关性推断出来的。

结果

在关于物质参与的共同责任的多变量全基因组关联研究中确定了 42 个遗传变异，其中 67% 是新的并且与 6 种表型无关。_{图谱基因突出了多巴胺（例如，多巴胺受体 D 2}基因）的作用，并显示了中枢神经系统（例如，中皮质边缘脑区）和分子通路（多巴胺能、谷氨酸能、氨基丁酸能 [γ-氨基丁酸能]）的几个组成部分的富集被认为可以调节药物强化。与其他特征的遗传相关性在奖赏相关行为（例如，冒险、使用可卡因和使用阿片类药物）和情绪（例如，抑郁、失眠）方面最为突出。

结论

这些全基因组结果对以前的临床前和人类研究进行了三角测量和扩展，这些研究侧重于物质参与的神经生物学底物，并有助于阐明使用常见精神活性物质的遗传结构。