Vrijenhoek Terry, Buizer-Voskamp Jacobine E, van der Stelt Inge, Strengman Eric, Sabatti Chiara, Geurts van Kessel Ad, Brunner Han G, Ophoff Roel A, Veltman Joris A
Department of Human Genetics, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands.
Am J Hum Genet. 2008 Oct;83(4):504-10. doi: 10.1016/j.ajhg.2008.09.011.
Schizophrenia is a severe psychiatric disease with complex etiology, affecting approximately 1% of the general population. Most genetics studies so far have focused on disease association with common genetic variation, such as single-nucleotide polymorphisms (SNPs), but it has recently become apparent that large-scale genomic copy-number variants (CNVs) are involved in disease development as well. To assess the role of rare CNVs in schizophrenia, we screened 54 patients with deficit schizophrenia using Affymetrix's GeneChip 250K SNP arrays. We identified 90 CNVs in total, 77 of which have been reported previously in unaffected control cohorts. Among the genes disrupted by the remaining rare CNVs are MYT1L, CTNND2, NRXN1, and ASTN2, genes that play an important role in neuronal functioning but--except for NRXN1--have not been associated with schizophrenia before. We studied the occurrence of CNVs at these four loci in an additional cohort of 752 patients and 706 normal controls from The Netherlands. We identified eight additional CNVs, of which the four that affect coding sequences were found only in the patient cohort. Our study supports a role for rare CNVs in schizophrenia susceptibility and identifies at least three candidate genes for this complex disorder.
精神分裂症是一种病因复杂的严重精神疾病，影响着约1%的普通人群。迄今为止，大多数遗传学研究都集中在疾病与常见基因变异（如单核苷酸多态性，SNPs）的关联上，但最近很明显，大规模基因组拷贝数变异（CNVs）也参与了疾病的发展。为了评估罕见CNVs在精神分裂症中的作用，我们使用Affymetrix的GeneChip 250K SNP阵列对54例缺陷型精神分裂症患者进行了筛查。我们总共鉴定出90个CNVs，其中77个先前在未受影响的对照队列中已有报道。其余罕见CNVs破坏的基因包括MYT1L、CTNND2、NRXN1和ASTN2，这些基因在神经元功能中起重要作用，但除NRXN1外，以前尚未与精神分裂症相关联。我们在来自荷兰的另外752例患者和706例正常对照的队列中研究了这四个位点的CNVs发生情况。我们又鉴定出8个CNVs，其中影响编码序列的4个仅在患者队列中发现。我们的研究支持罕见CNVs在精神分裂症易感性中的作用，并为这种复杂疾病鉴定出至少三个候选基因。
