Abstract
BACKGROUND: Uterine fibroids (UFs) are understudied uterus neoplasms, mainly affecting women of reproductive age and often leading to hysterectomy. Clinical series suggest impaired cardiometabolic features in UFs. We investigated potential genetic links between blood pressure (BP), several cardiometabolic traits, and UFs. METHODS AND RESULTS: We used summary statistics of genome-wide association studies for UFs and 18 traits related to BP, obesity, lipids, and main vascular diseases. We applied linkage disequilibrium score regression to estimate genetic correlations and Genome-Wide Complex Trait Analysis-multitrait-based conditional and joint analysis to perform adjusted correlations. Univariate and bidirectional Mendelian randomization verified potential causal associations with UFs. We found UFs to significantly correlate with systolic BP (genetic correlation coefficient [r(g)]=0.08, P=8.7×10(-5)) and diastolic BP (r(g)=0.12, P=8.2×10(-8)), including after adjustment for body mass index. UFs also positively corelated with body mass index (r(g)=0.11, P=4.1×10(-4)), waist-to-hip ratio (r(g)=0.09, P=7.3×10(-3)), type 2 diabetes (r(g)=0.15, P=1.9×10(-5)), and triglycerides (r(g)=0.17, P=7.6×10(-7)). We identified a negative correlation with sex hormone-binding globulin (r(g)=-0.16, P=3×10(-4)), a marker of bioavailability of sex steroids. No evidence for shared genetic basis with vascular diseases was observed, except with migraine (r(g)=0.08, P=5.8×10(-7)). Mendelian randomization analyses confirmed higher body mass index to increase UF risk (beta-per-kg/m(2)=0.033, P=6.1×10(-5)), as did waist-to-hip ratio (beta-per-unit=0.193, P=3.3×10(-5)) and triglycerides (bet-per-mmol/L=0.163, P=1.9×10(-5)). Higher sex hormone-binding globulin decreased UF risk (beta-per-nmol/L=0.005, P=2.5×10(-3)). No causal effect was found for BP. CONCLUSIONS: Our study shows that UFs share substantial genetic basis with traits related to BP, obesity, diabetes, and migraine, a predominantly female vascular disease. We provide Mendelian randomization-based evidence for central obesity, visceral fat traits, and sex-steroid bioavailability as relevant risk factors for UFs.