van der Zwaag Bert, Franke Lude, Poot Martin, Hochstenbach Ron, Spierenburg Henk A, Vorstman Jacob A S, van Daalen Emma, de Jonge Maretha V, Verbeek Nienke E, Brilstra Eva H, van 't Slot Ruben, Ophoff Roel A, van Es Michael A, Blauw Hylke M, Veldink Jan H, Buizer-Voskamp Jacobine E, Beemer Frits A, van den Berg Leonard H, Wijmenga Cisca, van Amstel Hans Kristian Ploos, van Engeland Herman, Burbach J Peter H, Staal Wouter G
Department of Neuroscience and Pharmacology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
PLoS One. 2009 May 28;4(5):e5324. doi: 10.1371/journal.pone.0005324.
The recent identification of copy-number variation in the human genome has opened up new avenues for the discovery of positional candidate genes underlying complex genetic disorders, especially in the field of psychiatric disease. One major challenge that remains is pinpointing the susceptibility genes in the multitude of disease-associated loci. This challenge may be tackled by reconstruction of functional gene-networks from the genes residing in these loci. We applied this approach to autism spectrum disorder (ASD), and identified the copy-number changes in the DNA of 105 ASD patients and 267 healthy individuals with Illumina Humanhap300 Beadchips. Subsequently, we used a human reconstructed gene-network, Prioritizer, to rank candidate genes in the segmental gains and losses in our autism cohort. This analysis highlighted several candidate genes already known to be mutated in cognitive and neuropsychiatric disorders, including RAI1, BRD1, and LARGE. In addition, the LARGE gene was part of a sub-network of seven genes functioning in glycobiology, present in seven copy-number changes specifically identified in autism patients with limited co-morbidity. Three of these seven copy-number changes were de novo in the patients. In autism patients with a complex phenotype and healthy controls no such sub-network was identified. An independent systematic analysis of 13 published autism susceptibility loci supports the involvement of genes related to glycobiology as we also identified the same or similar genes from those loci. Our findings suggest that the occurrence of genomic gains and losses of genes associated with glycobiology are important contributors to the development of ASD.
人类基因组中拷贝数变异的最新发现为发现复杂遗传疾病潜在的定位候选基因开辟了新途径，尤其是在精神疾病领域。仍然存在的一个主要挑战是在众多与疾病相关的基因座中精确找出易感基因。这个挑战可以通过从这些基因座中的基因重建功能基因网络来解决。我们将这种方法应用于自闭症谱系障碍（ASD），使用Illumina Humanhap300 Beadchips鉴定了105名ASD患者和267名健康个体DNA中的拷贝数变化。随后，我们使用人类重建的基因网络Prioritizer对自闭症队列中节段性增减的候选基因进行排名。该分析突出了几个已知在认知和神经精神疾病中发生突变的候选基因，包括RAI1、BRD1和LARGE。此外，LARGE基因是一个由七个在糖生物学中起作用的基因组成的子网络的一部分，存在于在共病有限的自闭症患者中特异性鉴定出的七个拷贝数变化中。这七个拷贝数变化中有三个是患者新发的。在具有复杂表型的自闭症患者和健康对照中未发现这样的子网络。对13个已发表的自闭症易感基因座进行的独立系统分析支持了与糖生物学相关的基因的参与，因为我们也从这些基因座中鉴定出了相同或相似的基因。我们的研究结果表明，与糖生物学相关的基因的基因组增减的发生是ASD发展的重要因素。
