Exome sequencing identifies novel genetic variants associated with varicose veins.

Background: Varicose veins (VV) are one of the common human diseases, but the role of genetics in its development is not fully understood. Methods: We conducted an exome-wide association study of VV using whole-exome sequencing data from the UK Biobank, and focused on common and rare variants using single-variant association analysis and gene-level collapsing analysis. Findings: A total of 13,823,269 autosomal genetic variants were obtained after quality control. We identified 36 VV-related independent common variants mapping to 34 genes by single-variant analysis and three rare variant genes (PIEZO1, ECE1, FBLN7) by collapsing analysis, and most associations between genes and VV were replicated in FinnGen. PIEZO1 was the closest gene associated with VV (P = 5.05 × 10−31), and it was found to reach exome-wide significance in both single-variant and collapsing analyses. Two novel rare variant genes (ECE1 and METTL21A) associated with VV were identified, of which METTL21A was associated only with females. The pleiotropic effects of VV-related genes suggested that body size, inflammation, and pulmonary function are strongly associated with the development of VV. Conclusions: Our findings highlight the importance of causal genes for VV and provide new directions for treatment. Author summary: In this study, whole-exome sequencing data from the UK Biobank were used to explore the effect of genetic variants on varicose veins (VV) and search for new VV-related genes. In contrast to traditional association studies, large-scale whole-exome sequencing analysis is more capable of identifying rare genetic variants (MAF < 1%) in diseases. The current study identified 34 VV-associated common variant genes by single-variant analysis and three rare variant genes (PIEZO1, ECE1, FBLN7) by collapsing analysis, and most associations were validated in FinnGen. In addition to replicating several genes reported in previous genome-wide association studies, we identified 17 novel genes that may be associated with VV. Through subsequent phenome-wide association analyses of identified genes, we found that these genes are also strongly associated with body size, inflammation, and pulmonary function. These findings contribute to understanding the underlying mechanisms of pathogenesis and developing novel therapeutic strategies for VV. [ABSTRACT FROM AUTHOR]