Shenzhen Key Laboratory of Affective and Social Cognitive Science, College of Psychology and Sociology, Shenzhen University, Shenzhen, 518060, China.
Key Laboratory for NeuroInformation of Ministry of Education, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, 610054, P. R. China.
Sci Rep. 2018 Mar 29;8(1):5372. doi: 10.1038/s41598-018-23191-y.
Dopamine is critical in pathophysiology and therapy of schizophrenia. Many studies have reported altered dopaminergic activity in the dorsal but not ventral striatum in schizophrenia. Based on the largest genome-wide association study of schizophrenia to date, we calculated the polygenic risk score (PGRS) of each subject in a healthy general group, including all variations in the set of functionally related genes involved in dopamine neurotransmitter system. We aimed to test whether the genetic variations in the dopaminergic pathway that have been identified as associated with schizophrenia are related to the function of the striatum and to working memory. We found that a higher PGRS was significantly associated with impairment in working memory. Moreover, resting-state functional connectivity analysis revealed that as the polygenic risk score increased, the connections between left putamen and caudate and the default mode network grew stronger, while the connections with the fronto-parietal network grew weaker. Our findings may shed light on the biological mechanism underlying the "dopamine hypothesis" of schizophrenia and provide some implications regarding the polygenic effects on the dopaminergic activity in the risk for schizophrenia.
多巴胺在精神分裂症的病理生理学和治疗中至关重要。许多研究报告称，精神分裂症患者背侧纹状体而非腹侧纹状体的多巴胺能活性发生改变。基于迄今为止最大的精神分裂症全基因组关联研究，我们计算了健康普通人群中每个个体的多基因风险评分（PGRS），其中包括涉及多巴胺神经递质系统的功能相关基因的所有变异。我们旨在测试与精神分裂症相关的多巴胺途径中的遗传变异是否与纹状体的功能和工作记忆有关。我们发现，较高的 PGRS 与工作记忆障碍显著相关。此外，静息态功能连接分析显示，随着多基因风险评分的增加，左侧壳核和尾状核与默认模式网络之间的连接变得更强，而与额顶叶网络的连接变弱。我们的研究结果可能为精神分裂症的“多巴胺假说”的生物学机制提供一些启示，并为多基因对精神分裂症风险中多巴胺活性的影响提供一些启示。
