Schizophrenia polygenic risk score predicts mnemonic hippocampal activity
Schizophrenia polygenic risk score predicts mnemonic hippocampal activity
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DOI：
10.1093/brain/awy004
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发表时间：
2018-04-01
期刊：
影响因子：
14.5
通讯作者：
Weinberger, Daniel R.
中科院分区：
文献类型：
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作者：
Chen, Qiang;Ursini, Gianluca;Weinberger, Daniel R.
使用多基因风险评分已经成为研究精神分裂症复杂遗传结构的一种实用的翻译方法，但是多基因风险评分与这种疾病的病理生理成分之间的联系一直是有限研究的主题。我们在健康志愿者中调查了精神分裂症多基因风险评分是否能预测简单记忆编码期间的海马活动，简单记忆编码被认为是精神分裂症的一种风险相关的中间表型。我们分析了191名来自美国的无血缘关系健康志愿者的多基因风险评分与海马活动之间的关系，以及分别来自欧洲和美国的76名和137名无血缘关系健康参与者的两个独立复制样本。每个个体的多基因风险评分计算为参考等位基因的归责概率的总和，加权自然对数比值比来自最近的精神分裂症全基因组关联研究。我们使用依赖于血氧水平的功能性核磁共振检查了新视觉刺激的简单记忆编码过程中的海马活动。多基因风险评分与发现样本中的海马活动显著相关[P = 0.016，家庭误差（FWE）在解剖自动标记（AAL）双侧海马-海马旁掩膜内纠正]和两个复制样本（P = 0.033，在Bari样本中，FWE在AAL右侧后海马-海马旁掩膜内纠正，而在杜克神经遗传学研究样本中，P = 0.002未纠正）。多基因风险评分与海马体活动之间的关系始终呈负相关，即多基因风险评分较高的个体海马体活动较低，这与先前报道精神分裂症患者及其健康兄弟姐妹在陈述性记忆任务中海马体-海马体旁活动减少的研究一致。多基因风险评分占发现样本记忆编码过程中海马活动变异的8%以上。我们的结论是，来自最近的精神分裂症全基因组关联研究的多基因风险评分预测了健康参与者在记忆编码过程中海马活动的显著变异性。我们的研究结果证实了记忆性海马活动是一种与精神分裂症遗传风险相关的中间表型，表明精神分裂症风险等位基因的神经生物学效应聚集在这种神经活动模式上。
The use of polygenic risk scores has become a practical translational approach to investigating the complex genetic architecture of schizophrenia, but the link between polygenic risk scores and pathophysiological components of this disorder has been the subject of limited research. We investigated in healthy volunteers whether schizophrenia polygenic risk score predicts hippocampal activity during simple memory encoding, which has been proposed as a risk-associated intermediate phenotype of schizophrenia. We analysed the relationship between polygenic risk scores and hippocampal activity in a discovery sample of 191 unrelated healthy volunteers from the USA and in two independent replication samples of 76 and 137 healthy unrelated participants from Europe and the USA, respectively. Polygenic risk scores for each individual were calculated as the sum of the imputation probability of reference alleles weighted by the natural log of odds ratio from the recent schizophrenia genome-wide association study. We examined hippocampal activity during simple memory encoding of novel visual stimuli assessed using blood oxygen level-dependent functional MRI. Polygenic risk scores were significantly associated with hippocampal activity in the discovery sample [P = 0.016, family-wise error (FWE) corrected within Anatomical Automatic Labeling (AAL) bilateral hippocampal-parahippocampal mask] and in both replication samples (P = 0.033, FWE corrected within AAL right posterior hippocampal-parahippocampal mask in Bari sample, and P = 0.002 uncorrected in the Duke Neurogenetics Study sample). The relationship between polygenic risk scores and hippocampal activity was consistently negative, i.e. lower hippocampal activity in individuals with higher polygenic risk scores, consistent with previous studies reporting decreased hippocampal-parahippocampal activity during declarative memory tasks in patients with schizophrenia and in their healthy siblings. Polygenic risk scores accounted for more than 8% of variance in hippocampal activity during memory encoding in discovery sample. We conclude that polygenic risk scores derived from the most recent schizophrenia genome-wide association study predict significant variability in hippocampal activity during memory encoding in healthy participants. Our findings validate mnemonic hippocampal activity as a genetic risk associated intermediate phenotype of schizophrenia, indicating that the aggregate neurobiological effect of schizophrenia risk alleles converges on this pattern of neural activity.