Department of Urogynaecology, Imperial College London, UK .
Department of Epidemiology & Biostatistics, Imperial College London, UK.
J Urol. 2021 Sep;206(3):679-687. doi: 10.1097/JU.0000000000001822. Epub 2021 Apr 27.
Genome-wide association studies have not identified replicable genetic risk loci for stress or urgency urinary incontinence.
We carried out a discovery stage, case control, genome-wide association study in 3 independent discovery cohorts of European women (8,979) for stress incontinence, urgency incontinence, and any incontinence phenotypes. We conducted replication in 6 additional studies of European ancestry (4,069). We collected bladder biopsies from women with incontinence (50) to further investigate bladder expression of implicated genes and pathways and used symptom questionnaires for phenotyping. We conducted meta-analyses using inverse variance fixed effects models and whole transcriptome analyses using Affymetrix® arrays with replication with TaqMan® polymerase chain reaction.
In the discovery stage, we identified 16 single nucleotide polymorphisms genotyped or imputed at 5 loci that reached genome-wide significance (p <5×10). In replication, rs138724718 on chromosome 2 near the macrophage receptor with collagenous structure () gene (replication p=0.003) was associated with stress incontinence. In addition, rs34998271 on chromosome 6 near the endothelin 1 () gene (replication p=0.0008) was associated with urgency incontinence. In combined meta-analyses of discovery and replication cohorts, associations with genome-wide significance for these 2 single nucleotide polymorphisms were confirmed. Transcriptomics analyses showed differential expression of 7 of 19 genes in the endothelin pathway between stress and urgency incontinence (p <0.0001).
We uncovered 2 new risk loci near the genes endothelin 1 (), associated with urgency incontinence, and macrophage receptor with collagenous structure (), associated with stress incontinence. These loci are biologically plausible given their roles in smooth muscle contraction and innate host defense, respectively.
全基因组关联研究尚未鉴定出可重复的应激或急迫性尿失禁遗传风险位点。
我们在 3 个独立的欧洲女性发现队列（8979 例）中进行了发现阶段的病例对照全基因组关联研究，用于研究压力性尿失禁、急迫性尿失禁和任何尿失禁表型。我们在另外 6 项具有欧洲血统的研究中进行了复制（4069 例）。我们从有尿失禁的女性中收集膀胱活检，以进一步研究受影响基因和途径在膀胱中的表达，并使用症状问卷进行表型分析。我们使用逆方差固定效应模型进行荟萃分析，并使用 Affymetrix®微阵列进行全转录组分析，并使用 TaqMan®聚合酶链反应进行复制。
在发现阶段，我们在 5 个位点鉴定出 16 个单核苷酸多态性，这些多态性经基因分型或推断达到了全基因组显著性（p<5×10）。在复制中，染色体 2 上靠近巨噬细胞胶原结构受体（）基因的 rs138724718 与压力性尿失禁相关（复制 p=0.003）。此外，染色体 6 上靠近内皮素 1（）基因的 rs34998271 与急迫性尿失禁相关（复制 p=0.0008）。在发现和复制队列的联合荟萃分析中，这 2 个单核苷酸多态性与全基因组显著性的关联得到了确认。转录组学分析显示，在压力性尿失禁和急迫性尿失禁之间，内皮素通路中有 7 个基因的表达存在差异（p<0.0001）。
我们在内皮素 1（）基因附近发现了 2 个新的风险位点，与急迫性尿失禁相关，在巨噬细胞胶原结构受体（）基因附近发现了 1 个新的风险位点，与压力性尿失禁相关。这些位点分别与平滑肌收缩和先天宿主防御有关，其生物学意义是合理的。
