Department of Epidemiology and Health Statistics, School of Public Health, Beijing Municipal Key Laboratory of Clinical Epidemiology, Capital Medical University, No.10 Youanmenwai, Beijing, 100069, China.
Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, National Clinical Research Center for Mental Disorders & National Center for Mental Disorders, Capital Medical University, Beijing, 100088, China.
BMC Genomics. 2024 Jun 18;25(1):612. doi: 10.1186/s12864-024-10409-9.
Salt sensitivity of blood pressure (SSBP) is an intermediate phenotype of hypertension and is a predictor of long-term cardiovascular events and death. However, the genetic structures of SSBP are uncertain, and it is difficult to precisely diagnose SSBP in population. So, we aimed to identify genes related to susceptibility to the SSBP, construct a risk evaluation model, and explore the potential functions of these genes.
A genome-wide association study of the systemic epidemiology of salt sensitivity (EpiSS) cohort was performed to obtain summary statistics for SSBP. Then, we conducted a transcriptome-wide association study (TWAS) of 12 tissues using FUSION software to predict the genes associated with SSBP and verified the genes with an mRNA microarray. The potential roles of the genes were explored. Risk evaluation models of SSBP were constructed based on the serial P value thresholds of polygenetic risk scores (PRSs), polygenic transcriptome risk scores (PTRSs) and their combinations of the identified genes and genetic variants from the TWAS. The TWAS revealed that 2605 genes were significantly associated with SSBP. Among these genes, 69 were differentially expressed according to the microarray analysis. The functional analysis showed that the genes identified in the TWAS were enriched in metabolic process pathways. The PRSs were correlated with PTRSs in the heart atrial appendage, adrenal gland, EBV-transformed lymphocytes, pituitary, artery coronary, artery tibial and whole blood. Multiple logistic regression models revealed that a PRS of P < 0.05 had the best predictive ability compared with other PRSs and PTRSs. The combinations of PRSs and PTRSs did not significantly increase the prediction accuracy of SSBP in the training and validation datasets.
Several known and novel susceptibility genes for SSBP were identified via multitissue TWAS analysis. The risk evaluation model constructed with the PRS of susceptibility genes showed better diagnostic performance than the transcript levels, which could be applied to screen for SSBP high-risk individuals.
血压盐敏感性（SSBP）是高血压的中间表型，是预测长期心血管事件和死亡的指标。然而，SSBP 的遗传结构尚不确定，且难以在人群中精确诊断 SSBP。因此，我们旨在鉴定与 SSBP 易感性相关的基因，构建风险评估模型，并探讨这些基因的潜在功能。
对系统性流行病学的盐敏感性研究（EpiSS）队列进行全基因组关联研究，以获得 SSBP 的汇总统计数据。然后，我们使用 FUSION 软件对 12 种组织进行全转录组关联研究（TWAS），以预测与 SSBP 相关的基因，并通过 mRNA 微阵列验证这些基因。探讨了这些基因的潜在作用。根据多基因风险评分（PRSs）、多基因转录组风险评分（PTRSs）及其组合以及 TWAS 中鉴定的基因和遗传变异的串行 P 值阈值，构建了 SSBP 的风险评估模型。TWAS 显示，2605 个基因与 SSBP 显著相关。在这些基因中，根据微阵列分析，有 69 个基因差异表达。功能分析表明，TWAS 中鉴定的基因富集在代谢过程途径中。PRSs 与心耳、肾上腺、EBV 转化的淋巴细胞、垂体、冠状动脉、胫动脉和全血中的 PTRSs 相关。多元逻辑回归模型显示，与其他 PRSs 和 PTRSs 相比，P<0.05 的 PRS 具有最佳的预测能力。在训练和验证数据集中，PRSs 和 PTRSs 的组合并没有显著提高 SSBP 的预测准确性。
通过多组织 TWAS 分析，鉴定了几个与 SSBP 相关的已知和新的易感基因。基于易感基因 PRS 构建的风险评估模型的诊断性能优于转录水平，可用于筛选 SSBP 高危个体。
