Science：罕见基因突变促成精神分裂症

3月27日的《科学》（Science）杂志报道说，许多小型的基因突变可能会促成精神分裂症的形成，而这些基因突变中的每一种都是罕见的。尽管像精神分裂症这样的复杂疾病常常具有家族性，但似乎没有一种单一的基因突变可以引起该种疾病。目前有关基因对精神分裂症影响的研究工作假设是“常见疾病—常见等位基因”模型。该模型提出，精神分裂症是由普通基因突变的结合所引起的，其中每种基因突变都贡献了其适度的影响。

Tom Walsh及其同事现在提出了一个另类的模型，即某些使人易患精神分裂症的单个基因突变是罕见但效应强大的，其对某些单一病例或家族病例甚至还具有特异性。文章的作者将150名精神分裂症患者的基因组DNA与268名健康个人的基因组DNA进行了对比，他们发现有多种DNA小段序列的重复或缺失形式的突变（但每种突变本身都很罕见）在精神分裂症患者中的发生率比对照组的发生率要高出约3倍以上。在那些18岁或之前就发病的患者中，这种类型的基因突变发生率比对照组要高出4倍以上。（即：这些基因突变在对照组中的发生率为5%，在患者中为15%，而在年轻时发病的患者中为20%。）那些参与控制神经信号通路及脑发育的基因容易出现这类突变。（来源：EurekAlert!中文版）

生物谷推荐原始出处：

（Science），DOI: 10.1126/science.1155174，Tom Walsh，Jonathan Sebat

Rare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia

Tom Walsh ¹, Jon M. McClellan ²^*, Shane E. McCarthy ³, Anjene M. Addington ⁴, Sarah B. Pierce ¹, Greg M. Cooper ⁵, Alex S. Nord ⁵, Mary Kusenda ⁶, Dheeraj Malhotra ³, Abishek Bhandari ³, Sunday M. Stray ¹, Caitlin F. Rippey ⁵, Patricia Roccanova ³, Vlad Makarov ³, B. Lakshmi ³, Robert L. Findling ⁷, Linmarie Sikich ⁸, Thomas Stromberg ⁴, Barry Merriman ⁹, Nitin Gogtay ⁴, Philip Butler ⁴, Kristen Eckstrand ⁴, Laila Noory ⁴, Peter Gochman ⁴, Robert Long ⁴, Zugen Chen ⁹, Sean Davis ¹⁰, Carl Baker ⁵, Evan E. Eichler ⁵, Paul S. Meltzer ¹⁰, Stanley F. Nelson ⁹, Andrew B. Singleton ¹¹, Ming K. Lee ¹, Judith L. Rapoport ⁴, Mary-Claire King ¹², Jonathan Sebat ³

¹ Department of Medicine, University of Washington, Seattle, WA 98195, USA.
² Department of Psychiatry, University of Washington, Seattle, WA 98195, USA.
³ Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
⁴ Child Psychiatry Branch, National Institute of Mental Health, NIH, Bethesda, MD 20892, USA.
⁵ Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
⁶ Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.; Graduate Program in Genetics, State University of New York at Stony Brook, NY 11794, USA.
⁷ Department of Psychiatry, Case Medical Center, Cleveland, OH 44106, USA.
⁸ Department of Psychiatry, University of North Carolina, Chapel Hill, NC 27599, USA.
⁹ Department of Human Genetics, University of California, Los Angeles, CA 90095, USA.
¹⁰ Cancer Genetics Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
¹¹ Neurogenetics Laboratory, National Institute on Aging, NIH, Bethesda, MD 20892, USA.
¹² Department of Medicine, University of Washington, Seattle, WA 98195, USA.; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.

^* To whom correspondence should be addressed.
Jon M. McClellan , E-mail: drjack@u.washington.edu

These authors contributed equally to this work.

Schizophrenia is a devastating neurodevelopmental disorder whosegenetic influences remain elusive. We hypothesize that individuallyrare structural variants contribute to the illness. Microdeletionsand microduplications >100 kb were identified by microarraycomparative genomic hybridization (CGH) of genomic DNA from150 individuals with schizophrenia and 268 ancestry-matchedcontrols. All variants were validated by high-resolution platforms.Novel deletions and duplications of genes were present in 5%of controls versus 15% of cases (P = 0.0008) and 20% of youngonset cases (P = 0.0001). The association was independentlyreplicated in patients with childhood-onset schizophrenia comparedto their parents (P = 0.03). Mutations in cases disrupted genesdisproportionately from signaling networks controlling neurodevelopment,including neuregulin and glutamate pathways. These results suggestthat multiple, individually rare mutations impacting genes inneurodevelopmental pathways contribute to schizophrenia.