University of Chicago, Departments of Human Genetics, 920 East 58 th St., Chicago, IL 60637, USA; Radiation Oncology Department, Beaumont Health, 3811 W Thirteen Mile Road, Royal Oak, MI, 48073, USA.
La Universidad del Zulia, Computer Science Department, Laboratories for Computational Models & Languages, and Bioinformatics, Edif. Grano de Oro, Planta Baja, Departamento de Computación, Ave. Universidad con Ave. 22, Maracaibo, 4002, Venezuela.
J Autoimmun. 2019 Feb;97:48-58. doi: 10.1016/j.jaut.2018.10.002. Epub 2018 Nov 1.
Convergent evidence from multiple and independent genetics studies implicate a small number of genes that predispose individuals to multiple autoimmune disorders (AuD). These intersecting loci reinforced the hypothesis that disorders with overlapping etiology group into a cluster of closely related genes within a whole genome molecular interaction network. We tested the hypothesis that "biological network proximity" within a whole genome molecular interaction network can be used to inform the search for multigene inheritance. Using a set of nine previously published genome wide association studies (GWAS) of AuD genes, we generated AuD-specific molecular interaction networks to identify networks of associated genes. We show that all nine "seed genes" can be connected within a 35-member network via interactions with 26 connecting genes. We show that this network is more connected than expected by chance, and 13 of the connecting genes showed association with multiple AuD upon GWAS reanalysis. Furthermore, we report association of SNPs in five new genes (IL10RA, DGKA, GRB2, STAT5A, and NFATC2) which were not previously considered as AuD candidates, and show significant association in novel disease samples of Crohn's disease and systemic lupus erythematosus. Furthermore, we show that the connecting genes show no association in four non-AuD GWAS. Finally, we test the connecting genes in psoriasis GWAS, and show association to previously identified loci and report new loci. These findings support the hypothesis that molecular interaction networks can be used to inform the search for multigene disease etiology, especially for disorders with overlapping etiology.
来自多个独立遗传学研究的汇聚证据表明，少数基因使个体易患多种自身免疫性疾病 (AuD)。这些相交的基因座强化了这样一种假说，即具有重叠病因的疾病在整个基因组分子相互作用网络中聚集在一组密切相关的基因中。我们检验了这样一个假设，即在整个基因组分子相互作用网络内的“生物网络接近度”可以用于告知多基因遗传的搜索。我们使用一组先前发表的九项自身免疫性疾病基因的全基因组关联研究 (GWAS)，生成了自身免疫性疾病特异性分子相互作用网络，以鉴定相关基因的网络。我们表明，所有九个“种子基因”都可以通过与 26 个连接基因的相互作用在一个 35 个成员的网络中连接。我们表明，这个网络比随机连接更紧密，并且连接基因中的 13 个在 GWAS 重新分析时与多种自身免疫性疾病有关。此外，我们报告了五个新基因 (IL10RA、DGKA、GRB2、STAT5A 和 NFATC2) 中 SNP 的关联，这些基因以前不被认为是自身免疫性疾病候选基因，并且在新的克罗恩病和系统性红斑狼疮疾病样本中显示出显著关联。此外，我们表明连接基因在四项非自身免疫性疾病 GWAS 中没有关联。最后，我们在银屑病 GWAS 中测试了连接基因，显示与先前确定的基因座有关联，并报告了新的基因座。这些发现支持了这样一种假说，即分子相互作用网络可以用于告知多基因疾病病因的搜索，特别是对于具有重叠病因的疾病。
