Whole-exome sequencing in obsessive-compulsive disorder identifies rare mutations in immunological and neurodevelopmental pathways.
Whole-exome sequencing in obsessive-compulsive disorder identifies rare mutations in immunological and neurodevelopmental pathways.
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DOI：
10.1038/tp.2016.30
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发表时间：
2016-03-29
影响因子：
6.8
通讯作者：
Fernandez TV
中科院分区：
文献类型：
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作者：
Cappi C;Brentani H;Lima L;Sanders SJ;Zai G;Diniz BJ;Reis VN;Hounie AG;Conceição do Rosário M;Mariani D;Requena GL;Puga R;Souza-Duran FL;Shavitt RG;Pauls DL;Miguel EC;Fernandez TV
罕见的遗传变异的研究已经确定了分子途径赋予发育性神经精神障碍的风险。到目前为止，还没有发表的全外显子组测序研究报告强迫症（OCD）。我们对20例散发性强迫症病例及其未受影响的父母的所有基因组编码区进行测序，以确定罕见的从头（DN）单核苷酸变异（SNV）。这项初步研究的主要目的是确定DN的变化是否有助于强迫症的风险。为了这个目的，我们评估了在强迫症中DN突变率是否升高，这将证明这种方法在更大规模的疾病研究中发现基因是合理的。此外，探索功能分子之间的相关性与非同义DN SNVs的基因在强迫症先证者，蛋白质-蛋白质相互作用（PPI）网络的基础上产生的直接分子相互作用的数据库。我们应用程度感知疾病基因优先化（DADA）来基于PPI网络基因与来自两个OCD全基因组关联研究的一组OCD候选基因的相关性对PPI网络基因进行排序（Stewart et al.，2013; Mattheisen等人，2014年）。此外，我们对PPI网络中的基因进行了通路分析。强迫症患者DN SNV的发生率为每代2.51 × 10−8个碱基，显著高于之前使用相同测序平台和分析管道的未受影响受试者的估计发生率。在强迫症中携带DN SNV的几个基因在PPI网络中高度互连，并且在DADA分析中排名靠前。在这项研究中，几乎所有的DN SNV都在人脑中表达的基因中，并且通路分析显示在免疫和中枢神经系统功能和发育中富集。这项初步研究的结果表明，在较大的强迫症队列中进一步调查DN的变化是必要的，以确定特定的风险基因，并确认我们的初步发现，关于PPI网络富集特定的生物学途径和功能。
Studies of rare genetic variation have identified molecular pathways conferring risk for developmental neuropsychiatric disorders. To date, no published whole-exome sequencing studies have been reported in obsessive-compulsive disorder (OCD). We sequenced all the genome coding regions in 20 sporadic OCD cases and their unaffected parents to identify rare de novo (DN) single-nucleotide variants (SNVs). The primary aim of this pilot study was to determine whether DN variation contributes to OCD risk. To this aim, we evaluated whether there is an elevated rate of DN mutations in OCD, which would justify this approach toward gene discovery in larger studies of the disorder. Furthermore, to explore functional molecular correlations among genes with nonsynonymous DN SNVs in OCD probands, a protein–protein interaction (PPI) network was generated based on databases of direct molecular interactions. We applied Degree-Aware Disease Gene Prioritization (DADA) to rank the PPI network genes based on their relatedness to a set of OCD candidate genes from two OCD genome-wide association studies (Stewart et al., 2013; Mattheisen et al., 2014). In addition, we performed a pathway analysis with genes from the PPI network. The rate of DN SNVs in OCD was 2.51 × 10−8 per base per generation, significantly higher than a previous estimated rate in unaffected subjects using the same sequencing platform and analytic pipeline. Several genes harboring DN SNVs in OCD were highly interconnected in the PPI network and ranked high in the DADA analysis. Nearly all the DN SNVs in this study are in genes expressed in the human brain, and a pathway analysis revealed enrichment in immunological and central nervous system functioning and development. The results of this pilot study indicate that further investigation of DN variation in larger OCD cohorts is warranted to identify specific risk genes and to confirm our preliminary finding with regard to PPI network enrichment for particular biological pathways and functions.