Sun Yan, Zhao Li-Yan, Wang Gui-Bin, Yue Wei-Hua, He Yong, Shu Ni, Lin Qi-Xiang, Wang Fan, Li Jia-Li, Chen Na, Wang Hui-Min, Kosten Thomas R, Feng Jia-Jia, Wang Jun, Tang Yu-De, Liu Shu-Xue, Deng Gui-Fa, Diao Gan-Huan, Tan Yun-Long, Han Hong-Bin, Lin Lu, Shi Jie
National Institute on Drug Dependence, Peking University, China.
Beijing Key Laboratory on Drug Dependence Research, China.
Addict Biol. 2016 May;21(3):657-66. doi: 10.1111/adb.12233. Epub 2015 Feb 24.
Drug addiction shares common neurobiological pathways and risk genes with other psychiatric diseases, including psychosis. One of the commonly identified risk genes associated with broad psychosis has been ZNF804A. We sought to test whether psychosis risk variants in ZNF804A increase the risk of heroin addiction by modulating neurocognitive performance and gray matter volume (GMV) in heroin addiction. Using case-control genetic analysis, we compared the distribution of ZNF804A variants (genotype and haplotype) in 1035 heroin abusers and 2887 healthy subjects. We also compared neurocognitive performance (impulsivity, global cognitive ability and decision-making ability) in 224 subjects and GMV in 154 subjects based on the ZNF804A variants. We found significant differences in the distribution of ZNF804A intronic variants (rs1344706 and rs7597593) allele and haplotype frequencies between the heroin and control groups. Decision-making impairment was worse in heroin abusers who carried the ZNF804A risk allele and haplotype. Subjects who carried more risk alleles and haplotypes of ZNF804A had greater GMV in the bilateral insular cortex, right temporal cortex and superior parietal cortex. The interaction between heroin addiction and ZNF804A variants affected GMV in the left sensorimotor cortex. Our findings revealed several ZNF804A variants that were significantly associated with the risk of heroin addiction, and these variants affected decision making and GMV in heroin abusers compared with controls. The precise neural mechanisms that underlie these associations are unknown, which requires future investigations of the effects of ZNF804A on both dopamine neurotransmission and the relative increases in the volume of various brain areas.
药物成瘾与包括精神病在内的其他精神疾病具有共同的神经生物学途径和风险基因。与广泛的精神病相关的常见风险基因之一是ZNF804A。我们试图测试ZNF804A中的精神病风险变异是否通过调节海洛因成瘾中的神经认知表现和灰质体积（GMV）来增加海洛因成瘾的风险。通过病例对照基因分析，我们比较了1035名海洛因滥用者和2887名健康受试者中ZNF804A变异（基因型和单倍型）的分布。我们还根据ZNF804A变异比较了224名受试者的神经认知表现（冲动性、整体认知能力和决策能力）以及154名受试者的GMV。我们发现海洛因组和对照组之间ZNF804A内含子变异（rs1344706和rs7597593）的等位基因和单倍型频率分布存在显著差异。携带ZNF804A风险等位基因和单倍型的海洛因滥用者的决策障碍更严重。携带更多ZNF804A风险等位基因和单倍型的受试者在双侧岛叶皮质、右侧颞叶皮质和顶上叶皮质中具有更大的GMV。海洛因成瘾与ZNF804A变异之间的相互作用影响了左侧感觉运动皮质的GMV。我们的研究结果揭示了几种与海洛因成瘾风险显著相关的ZNF804A变异，与对照组相比，这些变异影响了海洛因滥用者的决策和GMV。这些关联背后的确切神经机制尚不清楚，这需要未来对ZNF804A对多巴胺神经传递和各个脑区体积相对增加的影响进行研究。
