Background

The relationship between psychotic disorders and cannabis use is heavily debated. Shared underlying genetic risk is one potential explanation. We investigated the genetic association between psychotic disorders (schizophrenia and bipolar disorder) and cannabis phenotypes (lifetime cannabis use and cannabis use disorder).

Methods

We used genome-wide association summary statistics from individuals with European ancestry from the Psychiatric Genomics Consortium, UK Biobank, and International Cannabis Consortium. We estimated heritability, polygenicity, and discoverability of each phenotype. We performed genome-wide and local genetic correlations. Shared loci were identified and mapped to genes, which were tested for functional enrichment. Shared genetic liabilities to psychotic disorders and cannabis phenotypes were explored using causal analyses and polygenic scores, using the Norwegian Thematically Organized Psychosis cohort.

Findings

Psychotic disorders were more heritable than cannabis phenotypes and more polygenic than cannabis use disorder. We observed positive genome-wide genetic correlations between psychotic disorders and cannabis phenotypes (range 0·22–0·35) with a mixture of positive and negative local genetic correlations. Three to 27 shared loci were identified for the psychotic disorder and cannabis phenotype pairs. Enrichment of mapped genes implicated neuronal and olfactory cells as well as drug–gene targets for nicotine, alcohol, and duloxetine. Psychotic disorders showed a causal effect on cannabis phenotypes, and lifetime cannabis use had a causal effect on bipolar disorder. Of 2181 European participants from the Norwegian Thematically Organized Psychosis cohort applied in polygenic risk score analyses, 1060 (48·6%) were females and 1121 (51·4%) were males (mean age 33·1 years [SD 11·8]). 400 participants had bipolar disorder, 697 had schizophrenia, and 1044 were healthy controls. Within this sample, polygenic scores for cannabis phenotypes predicted psychotic disorders independently and improved prediction beyond the polygenic score for the psychotic disorders.

Interpretation

A subgroup of individuals might have a high genetic risk of developing a psychotic disorder and using cannabis. This finding supports public health efforts to reduce cannabis use, particularly in individuals at high risk or patients with psychotic disorders. Identified shared loci and their functional implications could facilitate development of novel treatments.

Funding

US National Institutes of Health, the Research Council Norway, the South-East Regional Health Authority, Stiftelsen Kristian Gerhard Jebsen, EEA-RO-NO-2018–0535, European Union's Horizon 2020 Research and Innovation Programme, the Marie Skłodowska-Curie Actions, and University of Oslo Life Science.

中文翻译：

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大麻使用、精神分裂症和双相情感障碍之间的关系：一项遗传信息研究

背景

精神障碍与大麻使用之间的关系存在激烈争论。共同的潜在遗传风险是一种可能的解释。我们研究了精神障碍（精神分裂症和双相情感障碍）与大麻表型（终身使用大麻和大麻使用障碍）之间的遗传关联。

方法

我们使用了来自精神病基因组学联盟、英国生物银行和国际大麻联盟的欧洲血统个体的全基因组关联汇总统计数据。我们估计了每种表型的遗传力、多基因性和可发现性。我们进行了全基因组和局部遗传相关性。共享基因座被识别并映射到基因，并进行功能富集测试。使用挪威主题组织精神病队列，通过因果分析和多基因评分探讨了精神病和大麻表型的共同遗传倾向。

发现

精神障碍比大麻表型更具遗传性，比大麻使用障碍更具多基因性。我们观察到精神障碍和大麻表型（范围 0·22–0·35）之间存在正的全基因组遗传相关性，以及正向和负向局部遗传相关性的混合。精神障碍和大麻表型对鉴定出 3 至 27 个共享基因座。定位基因的富集涉及神经元和嗅觉细胞以及尼古丁、酒精和度洛西汀的药物基因靶标。精神障碍对大麻表型有因果影响，终身吸食大麻对双相情感障碍有因果影响。在来自挪威主题组织精神病队列的 2181 名欧洲参与者中，应用了多基因风险评分分析，1060 名 (48·6%) 为女性，1121 名 (51·4%) 为男性（平均年龄 33·1 岁 [SD 11·8]）。400 名参与者患有双相情感障碍，697 名参与者患有精神分裂症，1044 名是健康对照。在该样本中，大麻表型的多基因评分独立预测精神障碍，并改进了精神障碍多基因评分的预测。

解释

一部分人可能具有患精神病和吸食大麻的高遗传风险。这一发现支持公共卫生部门减少大麻使用的努力，特别是在高危人群或精神障碍患者中。确定的共享位点及其功能意义可以促进新疗法的开发。

资金

美国国立卫生研究院、挪威研究委员会、东南地区卫生局、Stiftelsen Kristian Gerhard Jebsen、EEA-RO-NO-2018–0535、欧盟地平线 2020 研究与创新计划、Marie Skłodowska-Curie Actions、和奥斯陆生命科学大学。