■全基因组关联研究(GWAS)已经确定了38个与溃疡性结肠炎(UC)易感性相关的基因座,但是风险基因及其生物学机制仍有待全面阐明。
■使用基因组注释(MAGMA)软件在FinnGen数据库的UC的GWAS汇总统计上注释基因。进行遗传分析以鉴定风险基因。进行使用分子特征统一测试(UTMOST)的跨组织转录组范围关联研究(TWAS),以将GWAS汇总统计与基因表达矩阵(来自基因型-组织表达项目)进行数据整合。随后,我们使用FUSION软件从个体组织中选择关键基因.此外,进行了条件分析和联合分析,以提高我们对UC的理解。使用因果基因集(FOCUS)软件进行精细定位以准确定位风险基因。四项遗传分析的结果(MAGMA,UMOST,FUSION和FOCUS)组合获得一组UC风险基因。最后,进行孟德尔随机化(MR)分析和贝叶斯共定位分析以确定风险基因与UC之间的因果关系。为了测试我们发现的稳健性,采用相同的方法验证UC在IEU上的GWAS数据.
■多次校正测试将PIM3筛选为UC的风险基因。贝叶斯共定位分析结果表明,假设4的后验概率在验证数据集中分别为0.997和0.954。使用逆方差加权方法和两个单核苷酸多态性(SNP,rs28645887和rs62231924)包括在分析中(p<0.001,95CI:1.45-1.89)。在验证数据集中,MR结果为p<0.001,95CI:1.19-1.72,表明PIM3与UC之间存在明显的因果关系。
■我们的研究验证了PIM3是UC的关键风险基因,其表达水平可能与UC的风险有关,为进一步提高目前对UC遗传结构的认识提供了新的参考。
UNASSIGNED: Genome-wide association studies (GWASs) have identified 38 loci associated with ulcerative colitis (UC) susceptibility, but the risk genes and their biological mechanisms remained to be comprehensively elucidated.
UNASSIGNED: Multi-marker analysis of genomic annotation (MAGMA) software was used to annotate genes on GWAS summary statistics of UC from FinnGen database. Genetic analysis was performed to identify risk genes. Cross-tissue transcriptome-wide association study (TWAS) using the unified test for molecular signatures (UTMOST) was performed to compare GWAS summary statistics with gene expression matrix (from Genotype-Tissue Expression Project) for data integration. Subsequently, we used FUSION software to select key genes from the individual tissues. Additionally, conditional and joint analysis was conducted to improve our understanding on UC. Fine-mapping of causal gene sets (FOCUS) software was employed to accurately locate risk genes. The results of the four genetic analyses (MAGMA, UTMOST, FUSION and FOCUS) were combined to obtain a set of UC risk genes. Finally, Mendelian randomization (MR) analysis and Bayesian colocalization analysis were conducted to determine the causal relationship between the risk genes and UC. To test the robustness of our findings, the same approaches were taken to verify the GWAS data of UC on IEU.
UNASSIGNED: Multiple correction tests screened PIM3 as a risk gene for UC. The results of Bayesian colocalization analysis showed that the posterior probability of hypothesis 4 was 0.997 and 0.954 in the validation dataset. MR was conducted using the inverse variance weighting method and two single nucleotide polymorphisms (SNPs, rs28645887 and rs62231924) were included in the analysis (p < 0.001, 95%CI: 1.45-1.89). In the validation dataset, MR result was p < 0.001, 95%CI: 1.19-1.72, indicating a clear causal relationship between PIM3 and UC.
UNASSIGNED: Our study validated PIM3 as a key risk gene for UC and its expression level may be related to the risk of UC, providing a novel reference for further improving the current understanding on the genetic structure of UC.