Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Mental Illness Research, Education and Clinical Center, Veterans Integrated Service Network 4, Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA.
Addiction. 2023 Sep;118(9):1675-1686. doi: 10.1111/add.16210. Epub 2023 May 11.
Genetic risk can influence disease progression. We measured the impact of genetic risk for substance use disorders (SUDs) on substance use onset and progression of symptoms.
DESIGN, SETTING, PARTICIPANTS: Using findings from genome-wide association studies (GWASs) of alcohol use disorder (AUD), opioid use disorder (OUD) and smoking trajectory (SMK) as discovery samples, we calculated polygenic risk scores (PRSs) in a deeply phenotyped independent target sample. Participants in the target sample were recruited from 2000 to 2020 from US inpatient or outpatient settings or through advertisements and comprised 5692 European-ancestry individuals (EUR) (56.2% male) and 4918 African-ancestry individuals (AFR) (54.9% male).
This study measured age of first substance use, regular use, reported problems and dependence diagnosis and progression from regular use to onset of problems and dependence for alcohol, opioids and smoking. We examined the contribution of PRS to each milestone and progression measure.
EUR and males reported an earlier onset and shorter progression times than AFR and females, respectively. Among EUR, higher AUD PRS predicted earlier onset and more rapid progression to alcohol-related milestones (P < 0.001). Although the AUD PRS was a stronger moderator of problem onset among females (P = 0.017), it was more predictive of the progression to problems among males (P = 0.005). OUD and SMK PRS in EUR also predicted earlier onset of the respective milestones (P < 0.001). Among AFR, where power is lower due to the smaller discovery sample, AUD PRS predicted age of regular alcohol use (P = 0.039) and dependence (P = 0.001) and progression from regular use to diagnosis (P = 0.045), while SMK PRS predicted earlier age of initiation (P = 0.036).
Genetic risk for SUDs appears to predict substance use milestones and symptom progression among European-ancestry individuals and, to a lesser extent, African-ancestry individuals.
遗传风险会影响疾病的进展。我们测量了物质使用障碍（SUD）遗传风险对物质使用起始和症状进展的影响。
设计、设置、参与者：使用酒精使用障碍（AUD）、阿片类药物使用障碍（OUD）和吸烟轨迹（SMK）的全基因组关联研究（GWAS）的发现样本，我们在一个深入表型的独立目标样本中计算了多基因风险评分（PRSs）。目标样本中的参与者于 2000 年至 2020 年从美国住院或门诊环境中招募，或通过广告招募，包括 5692 名欧洲血统个体（EUR）（56.2%为男性）和 4918 名非洲血统个体（AFR）（54.9%为男性）。
本研究测量了首次使用物质、规律使用、报告问题和依赖诊断的年龄以及从规律使用到出现问题和依赖的进展，针对酒精、阿片类药物和吸烟分别进行了评估。我们检查了 PRS 对每个里程碑和进展测量的贡献。
EUR 和男性的起始年龄和进展时间均早于 AFR 和女性，AUD PRS 预测了更高的 AUD 起始年龄和更快的进展到与酒精相关的里程碑（P < 0.001）。尽管 AUD PRS 是女性发病的更强调节因子（P = 0.017），但它对男性的问题进展更具预测性（P = 0.005）。AUD PRS 在 AFR 中也预测了各自里程碑的更早出现，AUD PRS 预测了 EUR 中常规酒精使用（P = 0.039）和依赖（P = 0.001）的年龄以及从常规使用到诊断的进展（P = 0.045），而 SMK PRS 预测了更早的起始年龄（P = 0.036）。
SUD 的遗传风险似乎预测了欧洲血统个体的物质使用里程碑和症状进展，在一定程度上也预测了非洲血统个体的物质使用里程碑和症状进展。
