Bellaire High School, 5100 Maple St, Bellaire, TX, 77401, USA.
Northville High School, 45700 Six Mile Road, Northville, MI, 48168, USA.
BMC Med Genomics. 2020 Dec 28;13(Suppl 11):191. doi: 10.1186/s12920-020-00830-w.
Understanding gene regulation is important but difficult. Elucidating tissue-specific gene regulation mechanism is even more challenging and requires gene co-expression network assembled from protein-protein interaction, transcription factor and gene binding, and post-transcriptional regulation (e.g., miRNA targeting) information. The miRNA binding affinity could therefore be changed by SNP(s) located at the 3' untranslated regions (3'UTR) of the target messenger RNA (mRNA) which miRNA(s) interacts with. Genome-wide association study (GWAS) has reported significant numbers of loci hosting SNPs associated with many traits. The goal of this study is to pinpoint GWAS functional variants located in 3'UTRs and elucidate if the genes harboring these variants along with their targeting miRNAs are associated with genetic traits relevant to certain tissues.
By applying MIGWAS, CoCoNet, ANNOVAR, and DAVID bioinformatics software and utilizing the gene expression database (e.g. GTEx data) to study GWAS summary statistics for 43 traits from 28 GWAS studies, we have identified a list of miRNAs and targeted genes harboring 3'UTR variants, which could contribute to trait-relevant tissue over miRNA-target gene network.
Our result demonstrated that strong association between traits and tissues exists, and in particular, the Primary Biliary Cirrhosis (PBC) trait has the most significant p-value for all 180 tissues among all 43 traits used for this study. We reported SNPs located in 3'UTR regions of genes (SFMBT2, ZC3HAV1, and UGT3A1) targeted by miRNAs for PBC trait and its tissue association network. After employing Gene Ontology (GO) analysis for PBC trait, we have also identified a very important miRNA targeted gene over miRNA-target gene network, PFKL, which encodes the liver subunit of an enzyme.
The non-coding variants identified from GWAS studies are casually assumed to be not critical to translated protein product. However, 3' untranslated regions (3'UTRs) of genes harbor variants can often change the binding affinity of targeting miRNAs playing important roles in protein translation degree. Our study has shown that GWAS variants could play important roles on miRNA-target gene networks by contributing the association between traits and tissues. Our analysis expands our knowledge on trait-relevant tissue network and paves way for future human disease studies.
理解基因调控非常重要，但也极具挑战性。阐明组织特异性基因调控机制更加具有挑战性，需要组装来自蛋白质-蛋白质相互作用、转录因子和基因结合以及转录后调控（例如 miRNA 靶向）信息的基因共表达网络。因此，miRNA 结合亲和力可能会因位于目标信使 RNA (mRNA) 的 3'非翻译区 (3'UTR) 的 SNP(s) 而改变 miRNA(s) 与之相互作用的情况。全基因组关联研究 (GWAS) 已经报道了大量与许多性状相关的 SNP 所在的基因座。本研究的目的是确定位于 3'UTR 中的 GWAS 功能变体，并阐明是否这些变体与它们携带的基因以及靶向这些基因的 miRNA 与特定组织相关的遗传特征相关。
通过应用 MIGWAS、CoCoNet、ANNOVAR 和 DAVID 生物信息学软件，并利用基因表达数据库（例如 GTEx 数据）研究 28 项 GWAS 研究中 43 项性状的 GWAS 汇总统计数据，我们确定了一组 miRNA 和靶向基因，这些基因包含 3'UTR 变体，这些变体可能与与组织相关的 miRNA 靶向基因网络有关。
我们的研究结果表明，性状和组织之间存在很强的关联，特别是原发性胆汁性肝硬化 (PBC) 性状在用于本研究的所有 43 项性状的 180 个组织中具有最高的 p 值。我们报告了位于 miRNA 靶向 PBC 性状及其组织关联网络的基因 (SFMBT2、ZC3HAV1 和 UGT3A1) 3'UTR 区域的 SNPs。在对 PBC 性状进行基因本体论 (GO) 分析后，我们还在 miRNA 靶向基因网络中发现了一个非常重要的 miRNA 靶向基因 PFKL，它编码酶的肝脏亚基。
GWAS 研究中鉴定的非编码变体通常被认为对翻译蛋白产物不重要。然而，基因的 3'非翻译区 (3'UTR) 中的变体通常可以改变靶向 miRNA 的结合亲和力，从而在蛋白质翻译程度中发挥重要作用。我们的研究表明，GWAS 变体可以通过在性状和组织之间建立关联，在 miRNA 靶向基因网络中发挥重要作用。我们的分析扩展了我们对与组织相关的性状网络的认识，并为未来的人类疾病研究铺平了道路。
