Association study of 167 candidate genes for schizophrenia selected by a multi-domain evidence-based prioritization algorithm and neurodevelopmental hypothesis.
Association study of 167 candidate genes for schizophrenia selected by a multi-domain evidence-based prioritization algorithm and neurodevelopmental hypothesis.
复制标题
DOI：
10.1371/journal.pone.0067776
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Fanous AH
中科院分区：
文献类型：
--
作者：
Zhao Z;Webb BT;Jia P;Bigdeli TB;Maher BS;van den Oord E;Bergen SE;Amdur RL;O'Neill FA;Walsh D;Thiselton DL;Chen X;Pato CN;International Schizophrenia Consortium;Riley BP;Kendler KS;Fanous AH
整合多个领域的证据有助于确定疾病候选基因的优先顺序以进行后续测试。我们使用三个不同的证据领域，将所有已知的人类基因 (n = 3819) 排列在爱尔兰高密度精神分裂症家族研究的连锁峰下：1) 使用 Stanley Brain 集合对微阵列基因表达结果进行荟萃分析，2) 精神分裂症蛋白质-蛋白质相互作用网络，以及 3) 系统文献检索。每个基因都被分配了一个特定领域的 p 值，并在评估每个领域内的证据后进行排名。为了与该排名过程进行比较，还通过包含具有与神经发育相关的基因本体术语的基因来测试大规模候选基因假设。随后，使用来自定制 Illumina iSelect 阵列的 167 个基因中的 3725 个 SNP 的基因型来评估排名靠前的基因与假设选择的基因。 73 个基因均排名较高且参与神经发育（类别 1），而 42 个和 52 个基因分别专属于神经发育（类别 2）或排名较高（类别 3）。在基因 PRKG1、PRKCE 和 CNTN4 中观察到最显着的关联，但在多次测试校正后没有单个 SNP 显着。这些方法的比较表明，使用假设驱动的神经发育类别进行了过多的重要测试。从两项独立的精神分裂症全基因组关联研究（GWAS）中随机选择大小相似的基因表明，过量的基因不太可能是偶然的。在对三个 GWAS 数据集的进一步荟萃分析中，四个候选 SNP 达到了名义显着性。尽管使用综合先验信息源的基因排序并没有丰富当前实验中的显着结果，但使用先验假设（神经发育）的基因选择优于随机选择。因此，有必要使用更仔细选择的信息来源进一步开发基因排序策略。
Integrating evidence from multiple domains is useful in prioritizing disease candidate genes for subsequent testing. We ranked all known human genes (n = 3819) under linkage peaks in the Irish Study of High-Density Schizophrenia Families using three different evidence domains: 1) a meta-analysis of microarray gene expression results using the Stanley Brain collection, 2) a schizophrenia protein-protein interaction network, and 3) a systematic literature search. Each gene was assigned a domain-specific p-value and ranked after evaluating the evidence within each domain. For comparison to this ranking process, a large-scale candidate gene hypothesis was also tested by including genes with Gene Ontology terms related to neurodevelopment. Subsequently, genotypes of 3725 SNPs in 167 genes from a custom Illumina iSelect array were used to evaluate the top ranked vs. hypothesis selected genes. Seventy-three genes were both highly ranked and involved in neurodevelopment (category 1) while 42 and 52 genes were exclusive to neurodevelopment (category 2) or highly ranked (category 3), respectively. The most significant associations were observed in genes PRKG1, PRKCE, and CNTN4 but no individual SNPs were significant after correction for multiple testing. Comparison of the approaches showed an excess of significant tests using the hypothesis-driven neurodevelopment category. Random selection of similar sized genes from two independent genome-wide association studies (GWAS) of schizophrenia showed the excess was unlikely by chance. In a further meta-analysis of three GWAS datasets, four candidate SNPs reached nominal significance. Although gene ranking using integrated sources of prior information did not enrich for significant results in the current experiment, gene selection using an a priori hypothesis (neurodevelopment) was superior to random selection. As such, further development of gene ranking strategies using more carefully selected sources of information is warranted.
登录
查看更多内容
影响因子：
30.8
作者：
Marchini, Jonathan;Howie, Bryan;Donnelly, Peter
通讯作者：
Donnelly, Peter
影响因子：
30.8
作者：
de Bakker, PIW;Yelensky, R;Altshuler, D
通讯作者：
Altshuler, D
影响因子：
9.8
作者：
Martin, ER;Monks, SA;Kaplan, NL
通讯作者：
Kaplan, NL
影响因子：
3.5
作者：
Li, Dawei;Collier, David A.;He, Lin
通讯作者：
He, Lin
影响因子：
3.7
作者：
Jia P;Ewers JM;Zhao Z
通讯作者：
Zhao Z