Dong Bosi, Li Yajiao, Ai Fandi, Geng Jia, Tang Ting, Peng Wan, Tang Yusha, Wang Hui, Tian Zixuan, Bu Fengxiao, Chen Lei
Department of Neurology, West China Hospital of Sichuan University, Chengdu, China.
Department of Cardiology, West China Hospital of Sichuan University, Chengdu, China.
Front Genet. 2025 Jan 13;15:1523304. doi: 10.3389/fgene.2024.1523304. eCollection 2024.
Patent foramen ovale (PFO) is a congenital defect between the atria, resulting in abnormal hemodynamics. We conducted a genome-wide association study (GWAS) to identify common genetic variants associated with PFO.
We performed a whole genome sequencing in a discovery cohort of 3,227 unrelated Chinese participants screened for PFO via contrast transthoracic echocardiography (cTTE). Single-nucleotide polymorphisms (SNPs) associated with PFO were further validated by Sanger sequencing and subsequently were evaluated in a validation cohort. Expression quantitative trait loci (eQTL) analysis was conducted using the GTEx database. Single-cell sequencing analyses with pseudotime trajectory modeling were employed to evaluate their expression in human fetal hearts.
The case-control GWAS of discovery cohort ultimately included 517 cases and 517 demographically matched controls. Of the 7,040,407 variants assessed, we identified rs1227675732 (OR = 2.903; 95% CI, 1.961 to 4.297; = 3.05 × 10), rs62206790 (OR = 2.780; 95% CI, 1.864 to 4.146; = 2.02 × 10), rs879176184 (OR = 2.724; 95% CI, 1.822 to 4.073; = 4.30 × 10) and rs13115019 (OR = 2.437; 95% CI, 1.702 to 3.488; = 5.80 × 10) as high-risk variants for PFO, while rs57922961 (OR = 0.5081; 95% CI, 0.388 to 0.666; = 6.82 × 10) was identified as protective variant. These variations were replicated in the validation cohort (111 cases and 152 controls). Single-cell sequencing showed that , , , , and were highly expressed with significant changes during heart development.
The identification of susceptible loci for PFO might provide insights into the pathogenesis of PFO and contribute to understanding heart development.
https://www.chictr.org.cn/showproj.html?proj=40590, identifier ChiCTR1900024623.
卵圆孔未闭（PFO）是心房之间的先天性缺陷，导致异常血流动力学。我们进行了一项全基因组关联研究（GWAS），以鉴定与PFO相关的常见基因变异。
我们对3227名通过经胸超声心动图造影（cTTE）筛查PFO的无血缘关系的中国参与者的发现队列进行了全基因组测序。通过桑格测序进一步验证与PFO相关的单核苷酸多态性（SNP），随后在验证队列中进行评估。使用GTEx数据库进行表达定量性状位点（eQTL）分析。采用单细胞测序分析和伪时间轨迹建模来评估它们在人类胎儿心脏中的表达。
发现队列的病例对照GWAS最终纳入了517例病例和517名人口统计学匹配的对照。在评估的7040407个变异中，我们将rs1227675732（OR = 2.903；95%CI，1.961至4.297；= 3.05×10）、rs62206790（OR = 2.780；95%CI，1.864至4.146；= 2.02×10）、rs879176184（OR = 2.724；95%CI，1.822至4.073；= 4.30×10）和rs13115019（OR = 2.437；95%CI，1.702至3.488；= 5.80×10）鉴定为PFO的高风险变异，而rs57922961（OR = 0.5081；95%CI，0.388至0.666；= 6.82×10）被鉴定为保护变异。这些变异在验证队列（111例病例和152名对照）中得到了重复验证。单细胞测序显示， 、 、 、 和 在心脏发育过程中高表达且有显著变化。
PFO易感位点的鉴定可能为PFO的发病机制提供见解，并有助于理解心脏发育。
https://www.chictr.org.cn/showproj.html?proj=40590，标识符ChiCTR1900024623。
