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Convergence of placenta biology and genetic risk for schizophrenia.
Nature Medicine ( IF 82.9 ) Pub Date : 2018-Jun-01 , DOI: 10.1038/s41591-018-0021-y
Gianluca Ursini 1, 2, 3 , Giovanna Punzi 1, 2 , Qiang Chen 1 , Stefano Marenco 4, 5 , Joshua F Robinson 6 , Annamaria Porcelli 2 , Emily G Hamilton 6 , Marina Mitjans 7 , Giancarlo Maddalena 2 , Martin Begemann 7 , Jan Seidel 7 , Hidenaga Yanamori 8 , Andrew E Jaffe 1, 9 , Karen F Berman 4 , Michael F Egan 10 , Richard E Straub 1 , Carlo Colantuoni 11, 12, 13 , Giuseppe Blasi 2 , Ryota Hashimoto 8, 14 , Dan Rujescu 15 , Hannelore Ehrenreich 7 , Alessandro Bertolino 2 , Daniel R Weinberger 1, 3, 11, 12, 13, 16
Affiliation  

Defining the environmental context in which genes enhance disease susceptibility can provide insight into the pathogenesis of complex disorders. We report that the intra-uterine environment modulates the association of schizophrenia with genomic risk (in this study, genome-wide association study-derived polygenic risk scores (PRSs)). In independent samples from the United States, Italy, and Germany, the liability of schizophrenia explained by PRS is more than five times greater in the presence of early-life complications (ELCs) compared with their absence. Patients with ELC histories have significantly higher PRS than patients without ELC histories, which is confirmed in additional samples from Germany and Japan. The gene set composed of schizophrenia loci that interact with ELCs is highly expressed in placenta, is differentially expressed in placentae from complicated in comparison with normal pregnancies, and is differentially upregulated in placentae from male compared with female offspring. Pathway analyses reveal that genes driving the PRS-ELC interaction are involved in cellular stress response; genes that do not drive such interaction implicate orthogonal biological processes (for example, synaptic function). We conclude that a subset of the most significant genetic variants associated with schizophrenia converge on a developmental trajectory sensitive to events that affect the placental response to stress, which may offer insights into sex biases and primary prevention.

中文翻译:

胎盘生物学与精神分裂症遗传风险的融合。

定义基因增强疾病易感性的环境背景可以深入了解复杂疾病的发病机制。我们报告子宫内环境调节精神分裂症与基因组风险的关联(在本研究中,全基因组关联研究衍生的多基因风险评分 (PRS))。在来自美国、意大利和德国的独立样本中,由 PRS 解释的精神分裂症的责任在生命早期并发症 (ELC) 的存在下比不存在时高 5 倍以上。有 ELC 病史的患者的 PRS 明显高于没有 ELC 病史的患者,这在来自德国和日本的其他样本中得到证实。由与 ELC 相互作用的精神分裂症基因座组成的基因集在胎盘中高表达,与正常妊娠相比,在复杂胎盘中差异表达,与雌性后代相比,在雄性胎盘中差异上调。通路分析表明,驱动 PRS-ELC 相互作用的基因参与细胞应激反应;不驱动这种相互作用的基因涉及正交生物过程(例如,突触功能)。我们得出结论,与精神分裂症相关的最重要遗传变异的一个子集集中在对影响胎盘对压力反应的事件敏感的发育轨迹上,这可能提供对性别偏见和一级预防的见解。通路分析表明,驱动 PRS-ELC 相互作用的基因参与细胞应激反应;不驱动这种相互作用的基因涉及正交生物过程(例如,突触功能)。我们得出结论,与精神分裂症相关的最重要遗传变异的一个子集集中在对影响胎盘对压力反应的事件敏感的发育轨迹上,这可能提供对性别偏见和一级预防的见解。通路分析表明,驱动 PRS-ELC 相互作用的基因参与细胞应激反应;不驱动这种相互作用的基因涉及正交生物过程(例如,突触功能)。我们得出结论,与精神分裂症相关的最重要遗传变异的一个子集集中在对影响胎盘对压力反应的事件敏感的发育轨迹上,这可能提供对性别偏见和一级预防的见解。
更新日期:2018-05-29
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