Richter Holly E, Whitehead Nedra, Arya Lily, Ridgeway Beri, Allen-Brady Kristina, Norton Peggy, Sung Vivian, Shepherd Jonathan P, Komesu Yuko, Gaddis Nathan, Fraser Matthew O, Tan-Kim Jasmine, Meikle Susan, Page Grier P
University of Alabama at Birmingham, Birmingham, Alabama.
Research Triangle International, Research Triangle Park, North Carolina.
J Urol. 2015 Jun;193(6):2020-7. doi: 10.1016/j.juro.2014.12.023. Epub 2014 Dec 15.
We identify genetic variants associated with urgency urinary incontinence in postmenopausal women.
A 2-stage genome-wide association analysis was conducted to identify variants associated with urgency urinary incontinence. The WHI GARNET substudy with 4,894 genotyped post-reproductive white women was randomly split into independent discovery and replication cohorts. Genome-wide imputation was performed using IMPUTE2 with the 1000 Genomes ALL Phase I integrated variant set as a reference. Controls reported no urgency urinary incontinence at enrollment or followup. Cases reported monthly or greater urgency urinary incontinence and leaked sufficiently to wet/soak underpants/clothes. Logistic regression models were used to predict urgency urinary incontinence case vs control status based on genotype, assuming additive inheritance. Age, obesity, diabetes and depression were included in the models as covariates.
Following quality control, 975,508 single nucleotide polymorphisms in 2,241 cases (discovery 1,102; replication 1,133) and 776 controls (discovery 405, replication 371) remained. Genotype imputation resulted in 9,077,347 single nucleotide polymorphisms and insertions/deletions with minor allele frequency greater than 0.01 available for analysis. Meta-analysis of the discovery and replication samples identified 6 loci on chromosomes 5, 10, 11, 12 and 18 associated with urgency urinary incontinence at p <10(-6). Of the loci 3 were within genes, the zinc finger protein 521 (ZFP521) gene on chromosome 18q11, the ADAMTS16 gene on chromosome 5p15 and the CIT gene on chromosome 12q24. The other 3 loci were intergenic.
Although environmental factors also likely contribute, this first exploratory genome-wide association study for urgency urinary incontinence suggests that genetic variants in the ZFP521, CIT and ADAMTS16 genes might account for some of the observed heritability of the condition.
我们旨在识别绝经后女性急迫性尿失禁相关的基因变异。
进行了两阶段全基因组关联分析，以识别与急迫性尿失禁相关的变异。女性健康倡议（WHI）石榴石子研究中4894名已进行基因分型的绝经后白人女性被随机分为独立的发现队列和复制队列。使用IMPUTE2软件，以千人基因组计划第一阶段整合变异集作为参考进行全基因组插补。对照组在入组或随访时均未报告急迫性尿失禁。病例报告每月或更频繁出现急迫性尿失禁，且漏尿严重到浸湿内裤或衣物。采用逻辑回归模型，基于基因型预测急迫性尿失禁病例与对照状态，假设为加性遗传。模型中纳入年龄、肥胖、糖尿病和抑郁作为协变量。
经过质量控制后，2241例（发现队列1102例；复制队列1133例）和776例对照（发现队列405例，复制队列371例）中保留了975508个单核苷酸多态性。基因型插补后得到9077347个单核苷酸多态性以及插入/缺失变异，其小等位基因频率大于0.01，可供分析。对发现队列和复制队列样本进行荟萃分析，在染色体5、10、11、12和18上确定了6个与急迫性尿失禁相关的位点，p值<10⁻⁶。其中3个位点位于基因内，分别是18q11染色体上的锌指蛋白521（ZFP521）基因、5p15染色体上的ADAMTS16基因和12q24染色体上的CIT基因。另外3个位点为基因间区域。
尽管环境因素可能也起作用，但这项针对急迫性尿失禁的首次探索性全基因组关联研究表明，ZFP521、CIT和ADAMTS16基因中的遗传变异可能是该疾病部分可观察到的遗传度的原因。
