Assessing Genome-Wide Associations in Women with Urinary Incontinence

Objectives: Understanding genetic determinants of urinary incontinence (UI) is crucial for developing targeted treatments and prevention strategies in predisposed individuals. Our study aim was to carry out a genome-wide association study (GWAS) to explore and identify genetic variants associated with UI subtypes within a well-defined population.

Methods: We conducted an IRB-approved, retrospective GWAS on women older than 18 years of age diagnosed with one of the following UI subtypes [Stress UI (SUI), Urge UI (UUI), or Mixed UI (MUI)] between May 2008-2023. Only women with genetic data available on our institution’s BioBank portal were included. Controls were subjects without a UI diagnosis. The raw data, containing millions of single nucleotide polymorphism (SNP) markers, underwent standard quality control (QC) measures by excluding variants/samples with call rate < 95%, variants with Hardy-Weinberg equilibrium exact p-value < 1x10-6 for controls/cases, samples with discordant sex, samples with abnormal heterozygote rates (>3 standard deviations from mean), non-European ancestry samples, and duplicate/related samples. After QC trimming, the data consisted of 9,453,028 million SNP variants. Minor allele frequency (MAF) cutoffs were applied at 0.5%, 1%, or without MAF checking. The data were subsequently split into three case-control pairs: UUI-control (cases=1,360, controls=19,887), SUI-control (cases=1,755, controls=19,887), MUI-control (cases=1,155, controls=19,887). Logistic regression was performed on the three pairs (using p-value < 5x10-8 to note statistical significance). Manhattan plots were generated for UI subtypes.

Results: Before applying MAF filtering, we identified 5 SNPs significantly associated with MUI (p < 5x10-8) and were distributed accordingly: 1 SNP on chromosome 7 (chr7:19440291:C:A), 1 SNP on chromosome 1 (chr1:93630987:C:T), and 3 SNPs within chromosome 9 (chr9:2308252:T:G, chr9:2326653:T:C, chr9:2419855:G:A). For UUI, 3 SNPs reached statistical significance, including 1 SNP on chromosome 16 (chr16:80222933:A:G) and 2 SNPs on chromosome 15 (chr15:62402783:C:T, chr15:62405785:C:T). No genome-wide significant associations were observed for SUI.

When 0.5% MAF filtering was applied, the total number of SNPs remaining for analysis was 7,992,998, and only 1 SNP, located near the BCAR3 adaptor protein/NSP family member (BCAR3) gene, remained significant on chromosome 1 (1p36.33) for MUI (Fig.1), and 2 SNPs, located near the talin 2 (TLN2) gene, on chromosome 15 (15q22.2) for UUI (Table 1). When a more stringent MAF cutoff (1%) was used, 6,817,980 SNP variants were left for analysis and only the 2 SNPs on chromosome 15 remained statistically significant for UUI (Fig.2).

Conclusions: This study discovered 2 SNPs, near the TLN2 gene, associated with UUI and 1 SNP, near the BCAR3 gene, associated with MUI. These genetic variations associated with the risk of UUI and MUI may explain the heritability of these conditions and their clustering in families. Further research, including combining our data with that of others to increase sample size, is needed in the field to explore other genes associated with UI and its subtypes.