背景:尽管全基因组关联研究(GWAS)已经确定了14个与虚弱指数(FI)易感性相关的基因座,潜在的致病基因和生物学机制仍然难以捉摸。方法:使用分子标记统一测试(UTMOST)进行跨组织转录组关联研究(TWAS),它整合了来自164,610名欧洲血统个人和10,616名瑞典参与者的GWAS汇总统计数据,与来自基因型-组织表达(GTEx)项目的基因表达矩阵一起。通过三种不同的方法对重要基因进行验证:FUSION,重点,全基因组注释的多重标记分析(MAGMA)。使用MAGMA进行FI相关SNP的组织和功能富集的探索。条件和联合分析,随着精细映射,被用来加强我们对FI基因结构的理解。孟德尔随机化被用来确定显著基因和FI之间的因果关系,并利用共定位分析来研究显著基因和FI之间的共享SNP。结果:在这项研究中,通过应用4种TWAS方法,鉴定出2种与FI风险相关的新易感基因.孟德尔随机化表明,HTT可能会增加发育脆弱的风险,而LRPPRC可以提供预防虚弱发作的保护。此外,共定位分析确定了LRPPRC和FI之间的共有SNP。组织富集分析显示,与虚弱相关的SNP相关的基因组区域主要富集在不同的大脑区域,包括额叶皮层,大脑皮层,和小脑半球。有条件的,综合分析,精细作图共同确定了两个与脆弱相关的遗传区域:2p21和4q16.3。功能富集分析显示,与虚弱相关的途径主要与MHC复合体有关,PD-1信号,认知,对抗原刺激的炎症反应,和第二信使分子的产生。结论:这项研究发现了两个新鉴定的基因,其预测表达水平与FI风险相关,为FI背后的遗传结构提供了新的视角。
Background: Although genome-wide association studies (GWAS) have identified 14 loci associated with frailty index (FI) susceptibility, the underlying causative genes and biological mechanisms remain elusive. Methods: A cross-tissue transcriptome-wide association study (
TWAS) was conducted utilizing the Unified Test for Molecular Markers (UTMOST), which integrates GWAS summary statistics from 164,610 individuals of European ancestry and 10,616 Swedish participants, alongside gene expression matrices from the Genotype-Tissue Expression (GTEx) Project. Validation of the significant genes was performed through three distinct methods: FUSION, FOCUS, and Multiple Marker Analysis of Genome-wide Annotation (MAGMA). Exploration of tissue and functional enrichment for FI-associated SNPs was conducted using MAGMA. Conditional and joint analyses, along with fine mapping, were employed to enhance our understanding of FI\'s genetic architecture. Mendelian randomization was employed to ascertain causal relationships between significant genes and FI, and co-localization analysis was utilized to investigate shared SNPs between significant genes and FI. Results: In this study, two novel susceptibility genes associated with the risk of FI were identified through the application of four
TWAS methods. Mendelian randomization demonstrated that HTT may elevate the risk of developing frailty, whereas LRPPRC could offer protection against the onset of frailty. Additionally, co-localization analysis identified a shared SNP between LRPPRC and FI. Tissue enrichment analyses revealed that genomic regions linked to SNPs associated with frailty were predominantly enriched in various brain regions, including the frontal cortex, cerebral cortex, and cerebellar hemispheres. Conditional, combined analyses, and fine mapping collectively identified two genetic regions associated with frailty: 2p21 and 4q16.3. Functional enrichment analyses revealed that the pathways associated with frailty were primarily related to the MHC complex, PD-1 signaling, cognition, inflammatory response to antigenic stimuli, and the production of second messenger molecules. Conclusion: This investigation uncovers two newly identified genes with forecasted expression levels associated with the risk of FI, offering new perspectives on the genetic architecture underlying FI.