Phenotypic Landscape of Schizophrenia-Associated Genes Defines Candidates and Their Shared Functions
Phenotypic Landscape of Schizophrenia-Associated Genes Defines Candidates and Their Shared Functions
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DOI：
10.1016/j.cell.2019.01.048
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发表时间：
2019-04-04
期刊：
影响因子：
64.5
通讯作者：
Schier, Alexander F.
中科院分区：
文献类型：
--
作者：
Thyme, Summer B.;Pieper, Lindsey M.;Schier, Alexander F.
基因组研究已经确定了数百个与精神分裂症风险相关的候选基因。为了确定候选人及其功能，我们突变了132个人类精神分裂症相关基因的斑马鱼直系同源基因。我们创建了一个表型图谱，包括全脑活动图、脑结构差异和行为异常的概况。表型多样，但具体的，包括改变前脑发育和减少前脉冲抑制。对这些数据集的探索在10多个基因丰富的区域中确定了有希望的候选者，包括镁转运蛋白cnnm2和翻译阻遏蛋白gigyf2，并揭示了活性差异的共同解剖学位点，包括软腭、丘脑和顶盖。单细胞RNA测序揭示了未充分研究的转录因子znf536在涉及社会行为和压力的前脑神经元发育中的重要作用。精神分裂症相关基因的表型景观优先考虑了30多个候选人进行进一步研究，并提供了弥合遗传关联和生物学机制之间鸿沟的假设。
Genomic studies have identified hundreds of candidate genes near loci associated with risk for schizophrenia. To define candidates and their functions, we mutated zebrafish orthologs of 132 human schizophrenia-associated genes. We created a phenotype atlas consisting of whole-brain activity maps, brain structural differences, and profiles of behavioral abnormalities. Phenotypes were diverse but specific, including altered forebrain development and decreased prepulse inhibition. Exploration of these datasets identified promising candidates in more than 10 gene-rich regions, including the magnesium transporter cnnm2 and the translational repressor gigyf2, and revealed shared anatomical sites of activ- ity differences, including the pallium,hydothalamus, and tectum. Single-cell RNA sequencing uncovered an essential role for the understudied transcription factor znf536 in the development of forebrain neurons implicated in social behavior and stress. This phenotypic landscape of schizophrenia-associated genes prioritizes more than 30 candidates for further study and provides hypotheses to bridge the divide between genetic association and biological mechanism.