Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Australia; Faculty of Medicine, the University of Queensland, Brisbane, Australia.
Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Australia; Institute for Molecular Bioscience, the University of Queensland, Brisbane, Australia.
Drug Alcohol Depend. 2019 Apr 1;197:271-279. doi: 10.1016/j.drugalcdep.2019.01.015. Epub 2019 Feb 16.
Co-morbid substance use is very common. Despite a historical focus using genetic epidemiology to investigate comorbid substance use and misuse, few studies have examined substance-substance associations using polygenic risk score (PRS) methods.
Using summary statistics from the largest substance use GWAS to date (258,797- 632,802 subjects), GWAS and Sequencing Consortium of Alcohol and Nicotine use (GSCAN), we constructed PRSs for smoking initiation (PRS-SI), age of initiation of regular smoking (PRS-AI), cigarettes per day (PRS-CPD), smoking cessation (PRS-SC), and drinks per week (PRS-DPW). We then estimated the fixed effect of individual PRSs on 22 lifetime substance use and substance use disorder phenotypes collected in an independent sample of 2463 young Australian adults using genetic restricted maximal likelihood (GREML) in Genome-wide Complex Trait Analysis (GCTA), separately in females, males and both sexes together.
After accounting for multiple testing, PRS-SI significantly explained variation in the risk of cocaine (0.67%), amphetamine (1.54%), hallucinogens (0.72%), ecstasy (1.66%) and cannabis initiation (0.97%), as well as DSM-5 alcohol use disorder (0.72%). PRS-DPW explained 0.75%, 0.59% and 0.90% of the variation of cocaine, amphetamine and ecstasy initiation respectively. None of the 22 phenotypes including emergent classes of substance use were significantly predicted by PRS-AI, PRS-CPD, and PRS-SC.
To our knowledge, this is the first study to report significant genetic overlap between the polygenic risks for smoking initiation and alcohol consumption and the risk of initiating major classes of illicit substances. PRSs constructed from large discovery GWASs allows the detection of novel genetic associations.
共病物质使用非常普遍。尽管历史上侧重于使用遗传流行病学来研究共病物质使用和滥用，但很少有研究使用多基因风险评分（PRS）方法来检查物质-物质关联。
利用迄今为止最大的物质使用 GWAS 的汇总统计数据（258797-632802 名受试者）、GWAS 和酒精与尼古丁使用的测序联盟（GSCAN），我们构建了吸烟起始的 PRS（PRS-SI）、常规吸烟起始年龄的 PRS（PRS-AI）、每天吸烟的香烟数（PRS-CPD）、戒烟的 PRS（PRS-SC）和每周饮酒量的 PRS（PRS-DPW）。然后，我们使用全基因组复杂性状分析（GCTA）中的遗传限制最大似然（GREML），在一个包含 2463 名年轻澳大利亚成年人的独立样本中，分别在女性、男性和男女混合样本中，估计个体 PRS 对 22 种终生物质使用和物质使用障碍表型的固定效应。
在考虑到多次检验后，PRS-SI 显著解释了可卡因（0.67%）、安非他命（1.54%）、迷幻剂（0.72%）、摇头丸（1.66%）和大麻起始（0.97%）风险的变异，以及 DSM-5 酒精使用障碍（0.72%）。PRS-DPW 分别解释了可卡因、安非他命和摇头丸起始变异的 0.75%、0.59%和 0.90%。PRS-AI、PRS-CPD 和 PRS-SC 均未显著预测 22 种表型，包括新兴的物质使用类别。
据我们所知，这是第一项报告吸烟起始和酒精消费的多基因风险与启动主要类非法物质的风险之间存在显著遗传重叠的研究。从大型发现 GWAS 构建的 PRS 允许检测到新的遗传关联。
