小柯机器人

在受精神分裂症影响的父母及子代中，外显子组测序揭示了从头合成蛋白质突变带来的风险。这一成果由美国麻省总医院Benjamin M. Neale和Daniel P. Howrigan团队合作取得。相关论文2020年1月13日在线发表在《自然—神经科学》上。

研究人员分析了1,695个受精神分裂症（SCZ）影响的父母及子代三人组和1,077个已发布的受SCZ影响的三人的从头合成蛋白质突变（DNM），以更好地了解DNM对SCZ的影响。在2772名SCZ样本中，全基因组DNM变化不大。基因集分析显示，SCZ DNMs高度集中在大脑中高表达的基因中，这些基因在强大的进化约束下和/或与其他神经发育障碍中鉴定的基因重叠。在整个外显子组水平没有一个基因具有显著性。但是，有16个基因受到蛋白质截断DNM的影响，对应的突变率比突变模型预期的高3.15倍（95％置信区间：1-10个基因； P = 3×10^-5）。总体而言，DNM解释了一小部分的SCZ患病风险，单个风险基因的鉴别需要更多的样本量，因为许多基因之间的编码变异赋予了人群SCZ的患病风险。

据介绍，从头合成蛋白质突变是许多神经发育障碍的主要危险因素，而迄今为止，DNM已显示出与精神分裂症有中等相关性。

附：英文原文

Title: Exome sequencing in schizophrenia-affected parent–offspring trios reveals risk conferred by protein-coding de novo mutations

Author: Daniel P. Howrigan, Samuel A. Rose, Kaitlin E. Samocha, Menachem Fromer, Felecia Cerrato, Wei J. Chen, Claire Churchhouse, Kimberly Chambert, Sharon D. Chandler, Mark J. Daly, Ashley Dumont, Giulio Genovese, Hai-Gwo Hwu, Nan Laird, Jack A. Kosmicki, Jennifer L. Moran, Cheryl Roe, Tarjinder Singh, Shi-Heng Wang, Stephen V. Faraone, Stephen J. Glatt, Steven A. McCarroll, Ming Tsuang, Benjamin M. Neale

Issue&Volume: 2020-01-13

Abstract: Protein-coding de novo mutations (DNMs) are significant risk factors in many neurodevelopmental disorders, whereas schizophrenia (SCZ) risk associated with DNMs has thus far been shown to be modest. We analyzed DNMs from 1,695 SCZ-affected trios and 1,077 published SCZ-affected trios to better understand the contribution to SCZ risk. Among 2,772 SCZ probands, exome-wide DNM burden remained modest. Gene set analyses revealed that SCZ DNMs were significantly concentrated in genes that were highly expressed in the brain, that were under strong evolutionary constraint and/or overlapped with genes identified in other neurodevelopmental disorders. No single gene surpassed exome-wide significance; however, 16 genes were recurrently hit by protein-truncating DNMs, corresponding to a 3.15-fold higher rate than the mutation model expectation (permuted 95% confidence interval: 1–10 genes; permuted P = 3 × 105). Overall, DNMs explain a small fraction of SCZ risk, and larger samples are needed to identify individual risk genes, as coding variation across many genes confers risk for SCZ in the population.

DOI: 10.1038/s41593-019-0564-3

Source: https://www.nature.com/articles/s41593-019-0564-3

Nature Neuroscience：《自然—神经科学》，创刊于1998年。隶属于施普林格·自然出版集团，最新IF：28.771
官方网址：https://www.nature.com/neuro/
投稿链接：https://mts-nn.nature.com/cgi-bin/main.plex