Genome-wide association meta-analyses over one million individuals identify 54 loci associated with urinary incontinence and its subtypes

Urinary incontinence (UI) markedly reduces quality of life, and its genetic basis remains to be elucidated. Here, we performed GWAS meta-analyses of four UI phenotypes, using hospital-based data from 1,045,436 individuals from the Trøndelag Health Study (HUNT), UK Biobank, FinnGen, and the Michigan Genomics Initiative, and self-reported UI from 56,957 females from HUNT and the Nurses' Health Study. We identified 54 (52 novels) genetic loci associated with at least one UI phenotype. Analyses revealed tissue-specific involvement, with connective and muscular tissues for stress UI, and neural tissues for urge UI, and supported key roles of SUI-prioritized genes in the extracellular matrix organization and muscle function. Further, genetic variations contributes to UI through inflammation, immune, and aging pathways. We identified smoking, higher BMI, higher parity, and pelvic organ prolapse as causal risk factors for UI in females, and benign prostatic hyperplasia in males. Our findings identify key genetic factors, tissues, pathways, and causal underlying UI.