BACKGROUND There are high levels of comorbidity between schizophrenia and substance use disorder, but little is known about the genetic etiology of this comorbidity. METHODS We tested the hypothesis that shared genetic liability contributes to the high rates of comorbidity between schizophrenia and substance use disorder. To do this, polygenic risk scores for schizophrenia derived from a large meta-analysis by the Psychiatric Genomics Consortium were computed in three substance use disorder datasets: the Collaborative Genetic Study of Nicotine Dependence (ascertained for tobacco use disorder; n = 918 cases; 988 control subjects), the Collaborative Study on the Genetics of Alcoholism (ascertained for alcohol use disorder; n = 643 cases; 384 control subjects), and the Family Study of Cocaine Dependence (ascertained for cocaine use disorder; n = 210 cases; 317 control subjects). Phenotypes were harmonized across the three datasets and standardized analyses were performed. Genome-wide genotypes were imputed to the 1000 Genomes reference panel. RESULTS In each individual dataset and in the mega-analysis, strong associations were observed between any substance use disorder diagnosis and the polygenic risk score for schizophrenia (mega-analysis pseudo-R2 range 0.8-3.7%; minimum p = 4 × 10-23). CONCLUSIONS These results suggest that comorbidity between schizophrenia and substance use disorder is partially attributable to shared polygenic liability. This shared liability is most consistent with a general risk for substance use disorder rather than specific risks for individual substance use disorders and adds to increasing evidence of a blurred boundary between schizophrenia and substance use disorder.

中文翻译：

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物质使用障碍与精神分裂症多基因责任之间的关联


背景精神分裂症和物质使用障碍之间存在高水平的合并症，但人们对这种合并症的遗传病因知之甚少。方法 我们检验了这样的假设：共同的遗传责任导致精神分裂症和物质使用障碍之间的高合并症发生率。为此，精神分裂症的多基因风险评分源自精神科基因组学联盟的一项大型荟萃分析，在三个物质使用障碍数据集中进行了计算：尼古丁依赖的协作遗传研究（针对烟草使用障碍确定；n = 918 例；988 例）对照受试者）、酒精中毒遗传学合作研究（确定酒精使用障碍；n = 643 例；384 名对照受试者）和可卡因依赖家庭研究（确定可卡因使用障碍；n = 210 例；317 名对照受试者）科目）。三个数据集的表型得到了协调，并进行了标准化分析。全基因组基因型被归入 1000 个基因组参考组。结果 在每个单独的数据集中和大型分析中，观察到任何物质使用障碍诊断与精神分裂症多基因风险评分之间存在很强的关联（大型分析伪 R2 范围 0.8-3.7%；最小 p = 4 × 10-23 ）。结论 这些结果表明，精神分裂症和物质使用障碍之间的共病部分归因于共同的多基因责任。这种共同责任与物质使用障碍的一般风险最一致，而不是与个体物质使用障碍的特定风险最一致，并且增加了越来越多的证据表明精神分裂症和物质使用障碍之间的界限模糊。