Abstract
Background: 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. Methods: 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. Results: 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; p = 3.05 × 10-8), rs62206790 (OR = 2.780; 95% CI, 1.864 to 4.146; p = 2.02 × 10-7), rs879176184 (OR = 2.724; 95% CI, 1.822 to 4.073; p = 4.30 × 10-7) and rs13115019 (OR = 2.437; 95% CI, 1.702 to 3.488; p = 5.80 × 10-7) as high-risk variants for PFO, while rs57922961 (OR = 0.5081; 95% CI, 0.388 to 0.666; p = 6.82 × 10-7) was identified as protective variant. These variations were replicated in the validation cohort (111 cases and 152 controls). Single-cell sequencing showed that CNOT2, KCNMB4, MLLT10, IGBP1, and FRG1 were highly expressed with significant changes during heart development. Conclusion: The identification of susceptible loci for PFO might provide insights into the pathogenesis of PFO and contribute to understanding heart development. Clinical trial registration: https://www.chictr.org.cn/showproj.html?proj=40590, identifier ChiCTR1900024623.