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研究揭示常见精神分裂症风险突变的协同效应
2019-09-24 12:55

美国西奈山伊坎医学院Kristen J. Brennand小组近期的研究揭示了常见精神分裂症风险突变的协同效应。 这一研究成果2019年9月23日在线发表在《自然—遗传学》上。

研究人员采用了一种遗传手段,即利用等基因人类诱导型多能干细胞,来评估了与精神分裂症(SZ)相关的常见突变的作用,这些突变预计可作为SZ表达定量性状位点(eQTL)。通过整合CRISPR介导的基因编辑、激活和抑制技术来研究一个推定的SZ eQTL(FURIN rs4702)基因和四个排名最高的SZ eQTL基因(FURIN,SNAP91,TSNARE1和CLCN3),研究人员的平台解决了突触前和突触后神经元的缺陷,概述了基因型依赖的基因表达差异,并确定了SZ eQTL基因扰动下游的汇合点。

研究人员的观察结果强调了常见突变的细胞类型特异性效应,并证明了在突触功能上汇合的SZ eQTL基因之间的协同效应。研究人员认为,涉及精神病风险的罕见和常见突变之间的联系构成了复杂遗传疾病中广泛发生的潜在普遍现象。

据悉,影响较小的常见风险突变相互作用以导致复杂遗传疾病的机制尚不清楚。我

附:英文原文

Title: Synergistic effects of common schizophrenia risk variants

Author: Nadine Schrode, Seok-Man Ho, Kazuhiko Yamamuro, Amanda Dobbyn, Laura Huckins, Marliette R. Matos, Esther Cheng, P. J. Michael Deans, Erin Flaherty, Natalie Barretto, Aaron Topol, Khaled Alganem, Sonya Abadali, James Gregory, Emily Hoelzli, Hemali Phatnani, Vineeta Singh, Deeptha Girish, Bruce Aronow, Robert Mccullumsmith, Gabriel E. Hoffman, Eli A. Stahl, Hirofumi Morishita, Pamela Sklar, Kristen J. Brennand

Issue&Volume: 2019-09-23

Abstract: 

The mechanisms by which common risk variants of small effect interact to contribute to complex genetic disorders are unclear. Here, we apply a genetic approach, using isogenic human induced pluripotent stem cells, to evaluate the effects of schizophrenia (SZ)-associated common variants predicted to function as SZ expression quantitative trait loci (eQTLs). By integrating CRISPR-mediated gene editing, activation and repression technologies to study one putative SZ eQTL (FURIN rs4702) and four top-ranked SZ eQTL genes (FURIN, SNAP91, TSNARE1 and CLCN3), our platform resolves pre- and postsynaptic neuronal deficits, recapitulates genotype-dependent gene expression differences and identifies convergence downstream of SZ eQTL gene perturbations. Our observations highlight the cell-type-specific effects of common variants and demonstrate a synergistic effect between SZ eQTL genes that converges on synaptic function. We propose that the links between rare and common variants implicated in psychiatric disease risk constitute a potentially generalizable phenomenon occurring more widely in complex genetic disorders.

DOI: 10.1038/s41588-019-0497-5

Source:https://www.nature.com/articles/s41588-019-0497-5

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:41.307
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex


本期文章:《自然—遗传学》:Online/在线发表

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