Zhi Dongmei, Sanzo Brandon T, Jung Daniel H, Cabana-Domínguez Judit, Fernàndez-Castillo Noelia, Cormand Bru, Sui Jing, Jiang Rongtao, Evins Eden A, Hadland Scott E, Roffman Joshua L, Liu Richard T, Gilman Jodi, Lee Phil H
Center for Addiction Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
Department of Psychiatry, Mass General Brigham and Harvard Medical School, Boston, MA 02115, USA.
medRxiv. 2025 Mar 24:2025.03.21.25324407. doi: 10.1101/2025.03.21.25324407.
Polysubstance use (PSU), defined as the use of multiple psychoactive substances, is associated with a heightened risk of subsequent health issues, including substance use disorders. However, the interplay between genetic susceptibility and environmental exposures in PSU initiation during adolescence remains understudied.
We examined associations of polygenic scores (PGSs) for general addiction risk, environmental factors, and their joint interactions with PSU initiation among 11,868 adolescents (aged 11-15 years) from the Adolescent Brain and Cognitive Development study. PSU status was assessed through interviews and toxicology screenings.
Our sample included 7,898 adolescents (mean age 12.9 [0.6] years; 4,150 [53%] male). Of these, 541 (6.8%) had initiated single substance use (SSU), and 162 (2.1%) reported PSU). PGSs for general addiction risk were significantly associated with PSU (Odds Ratios [OR]=1.62, 95% CI=1.30-2.01) but not with SSU. Key environmental risk factors for PSU included prenatal substance use and peer victimization, whereas protective factors included planned pregnancy and positive family dynamics. Notably, gene-environment interaction analyses revealed that peer victimization (OR=2.4, 95% CI=1.4-4.2), prenatal substance use (OR=2.1, 95% CI=1.2-3.6), and substance availability (OR=2.3, 95% CI=1.3-3.9) substantially increased PSU risk among adolescents with high genetic susceptibility, while having minimal influence at low genetic risk levels (all < 0.05 after multiple testing correction).
This study provides novel evidence linking polygenic risk to PSU in early adolescence and highlights PSU as a more severe manifestation of substance use liability driven by heightened genetic vulnerability and adverse environmental exposures.
多物质使用（PSU）被定义为使用多种精神活性物质，与随后出现包括物质使用障碍在内的健康问题的风险增加有关。然而，青少年期PSU起始过程中遗传易感性与环境暴露之间的相互作用仍未得到充分研究。
我们在青少年大脑与认知发展研究中，对11868名11至15岁青少年的一般成瘾风险多基因评分（PGS）、环境因素及其与PSU起始的联合相互作用进行了研究。通过访谈和毒理学筛查评估PSU状态。
我们的样本包括7898名青少年（平均年龄12.9[0.6]岁；4150名[53%]为男性）。其中，541名（6.8%）开始单一物质使用（SSU），162名（2.1%）报告有PSU。一般成瘾风险的PGS与PSU显著相关（优势比[OR]=1.62，95%置信区间[CI]=1.30 - 2.01），但与SSU无关。PSU的关键环境风险因素包括产前物质使用和同伴受害，而保护因素包括计划怀孕和积极的家庭动态。值得注意的是，基因 - 环境相互作用分析显示，同伴受害（OR = 2.4，95% CI = 1.4 - 4.2）、产前物质使用（OR = 2.1，95% CI = 1.2 - 3.6）和物质可得性（OR = 2.3，95% CI = 1.3 - 3.9）在高遗传易感性青少年中大幅增加了PSU风险，而在低遗传风险水平影响极小（多重检验校正后均<0.05）。
本研究提供了新的证据，将多基因风险与青春期早期的PSU联系起来，并强调PSU是由遗传易感性增加和不良环境暴露驱动的物质使用易感性更严重的表现形式。
