A Mendelian randomization study identified obesity as a causal risk factor of uterine endometrial cancer in Japanese

Abstract

Causal inference is one of the challenges in epidemiologic studies. Gynecologic diseases have been reported to have association with obesity, however the causality remained controversial except for uterine endometrial cancer. We conducted two-sample Mendelian randomization (MR) analysis using the large-scale genome-wide association study (GWAS) results of gynecologic diseases and body mass index (BMI) in the Japanese population to assess causal effect of BMI on gynecologic diseases. We first conducted GWAS of ovarian cancer, uterine endometrial cancer, uterine cervical cancer, endometriosis, and uterine fibroid (n = 647, 909, 538, 5236, and 645 cases, respectively, and 39 556 shared female controls), and BMI (81 610 males and non-overlapping 23 924 females). We then applied two-sample MR using 74 BMI-associated variants as instrumental variables. We observed significant causal effect of increased BMI on uterine endometrial cancer (β = 0.735, P = .0010 in inverse variance-weighted analysis), which is concordant with results of European studies. Causal effect of obesity was not apparent in the other gynecologic diseases tested. Our MR analyses provided strong evidence of the causal role of obesity in gynecologic diseases etiology, and suggested a possible preventive effect of intervention for obesity.

Keywords: BMI; GWAS; Mendelian randomization; gynecologic diseases; obesity.

FIGURE 1

Scatter plots of Mendelian randomization (MR) tests assessing the effect of body mass index (BMI) on each gynecologic disease. Each dot represents effect sizes of each single nucleotide polymorphism (SNP) on BMI (x‐axis) and gynecologic diseases (y‐axis), and regression slopes show the estimated causal effect of BMI on gynecologic diseases. For all plots, inverse variance‐weighted (IVW) results are shown in blue and MR‐Egger regression results are shown in red