University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
College Preparatory School, 6100 Broadway, Oakland, CA, 94618, USA.
BMC Genomics. 2022 May 11;23(Suppl 4):360. doi: 10.1186/s12864-022-08576-8.
Genome-wide association studies (GWAS) have uncovered thousands of genetic variants that are associated with complex human traits and diseases. miRNAs are single-stranded non-coding RNAs. In particular, genetic variants located in the 3'UTR region of mRNAs may play an important role in gene regulation through their interaction with miRNAs. Existing studies have not been thoroughly conducted to elucidate 3'UTR variants discovered through GWAS. The goal of this study is to analyze patterns of GWAS functional variants located in 3'UTRs about their relevance in the network between hosting genes and targeting miRNAs, and elucidate the association between the genes harboring these variants and genetic traits.
We employed MIGWAS, ANNOVAR, MEME, and DAVID software packages to annotate the variants obtained from GWAS for 31 traits and elucidate the association between their harboring genes and their related traits. We identified variants that occurred in the motif regions that may be functionally important in affecting miRNA binding. We also conducted pathway analysis and functional annotation on miRNA targeted genes harboring 3'UTR variants for a trait with the highest percentage of 3'UTR variants occurring.
The Child Obesity trait has the highest percentage of 3'UTR variants (75%). Of the 16 genes related to the Child Obesity trait, 5 genes (ETV7, GMEB1, NFIX, ZNF566, ZBTB40) had a significant association with the term DNA-Binding (p < 0.05). EQTL analysis revealed 2 relevant tissues and 10 targeted genes associated with the Child Obesity trait. In addition, Red Blood Cells (RBC), Hemoglobin (HB), and Package Cell Volume (PCV) have overlapping variants. In particular, the PIM1 variant occurred inside the HB Motif region 37,174,641-37,174,660, and LUC7L3 variant occurred inside RBC Motif region 50,753,918-50,753,937.
Variants located in 3'UTR can alter the binding affinity of miRNA and impact gene regulation, thus warranting further annotation and analysis. We have developed a bioinformatics bash pipeline to automatically annotate variants, determine the number of variants in different categories for each given trait, and check common variants across different traits. This is a valuable tool to annotate a large number of GWAS result files.
全基因组关联研究（GWAS）已经发现了数千种与复杂人类特征和疾病相关的遗传变异。miRNA 是单链非编码 RNA。特别是，位于 mRNA 3'UTR 区域的遗传变异可能通过与 miRNA 的相互作用在基因调控中发挥重要作用。现有研究尚未彻底阐明通过 GWAS 发现的 3'UTR 变异。本研究的目的是分析 GWAS 功能变异位于 3'UTR 中的模式，以及它们在宿主基因和靶向 miRNA 之间的网络中的相关性，并阐明携带这些变异的基因与遗传特征之间的关联。
我们使用 MIGWAS、ANNOVAR、MEME 和 DAVID 软件包对从 31 个特征的 GWAS 中获得的变体进行注释，并阐明它们携带的基因与相关特征之间的关联。我们确定了发生在可能对 miRNA 结合有功能重要性的基序区域的变异。我们还对具有最高比例 3'UTR 变异的特征的 miRNA 靶向基因进行了通路分析和功能注释。
儿童肥胖特征的 3'UTR 变异比例最高（75%）。与儿童肥胖特征相关的 16 个基因中，有 5 个基因（ETV7、GMEB1、NFIX、ZNF566、ZBTB40）与 DNA 结合（p < 0.05）有显著关联。eQTL 分析显示，与儿童肥胖特征相关的有 2 个相关组织和 10 个靶向基因。此外，红细胞（RBC）、血红蛋白（HB）和包装细胞体积（PCV）有重叠的变体。特别是，PIM1 变异发生在 HB 基序区域 37,174,641-37,174,660 内，LUC7L3 变异发生在 RBC 基序区域 50,753,918-50,753,937 内。
位于 3'UTR 中的变异可以改变 miRNA 的结合亲和力并影响基因调控，因此需要进一步注释和分析。我们开发了一个生物信息学 bash 管道来自动注释变体，确定每个给定特征的不同类别中的变体数量，并检查不同特征之间的常见变体。这是注释大量 GWAS 结果文件的有价值的工具。
