Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China.
Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China.
PLoS Genet. 2024 Jul 9;20(7):e1011339. doi: 10.1371/journal.pgen.1011339. eCollection 2024 Jul.
Varicose veins (VV) are one of the common human diseases, but the role of genetics in its development is not fully understood.
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.
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.
Our findings highlight the importance of causal genes for VV and provide new directions for treatment.
静脉曲张（VV）是一种常见的人类疾病，但遗传因素在其发病机制中的作用尚未完全阐明。
我们使用英国生物库的全外显子组测序数据，对 VV 进行了外显子组全关联研究，通过单变体关联分析和基因水平合并分析，重点关注常见和罕见变异。
经过质量控制后，共获得 13823269 个常染色体遗传变异。我们通过单变量分析鉴定了 36 个与 VV 相关的独立常见变异基因，映射到 34 个基因，通过合并分析鉴定了三个罕见变异基因（PIEZO1、ECE1、FBLN7），并且基因与 VV 之间的大多数关联在 FinnGen 中得到了复制。PIEZO1 是与 VV 最接近的基因（P=5.05×10-31），在单变量和合并分析中均达到外显子组全关联显著性。发现了两个与 VV 相关的新的罕见变异基因（ECE1 和 METTL21A），其中 METTL21A 仅与女性相关。VV 相关基因的多效性效应表明，体型、炎症和肺功能与 VV 的发生密切相关。
我们的研究结果强调了 VV 相关因果基因的重要性，并为治疗提供了新的方向。
