Genetic contribution of reproductive traits to risk of uterine leiomyomata: a large-scale, genome-wide, cross-trait analysis

Abstract

BackgroundWhile phenotypic associations between female reproductive characteristics and uterine leiomyomata have long been observed in epidemiological investigations, the shared genetic architecture underlying these complex phenotypes remains unclear. ObjectiveWe aimed to investigate the shared genetic basis, pleiotropic effects, and potential causal relationships underlying reproductive traits (age at menarche, age at natural menopause, and age at first birth) and uterine leiomyomata . Study designUtilizing large-scale genome-wide association studies conducted in women of European ancestry for age at menarche (N = 329,345), age at natural menopause (N = 201,323), age at first birth (N = 418,758), and uterine leiomyomata (Ncases/Ncontrols = 35,474/267,505), we performed a comprehensive genome-wide cross-trait analysis to examine systematically the common genetic influences between reproductive traits and UL. ResultsSignificant global genetic correlations were identified for uterine leiomyomata with age at menarche (rg = –0.17, P = 3.65 × 10–10), age at natural menopause (rg = 0.23, P = 3.26 × 10–07), and age at first birth (rg = –0.16, P = 1.96 × 10–06). Thirteen genomic regions were further revealed as contributing significant local correlations to age at natural menopause and uterine leiomyomata. Cross-trait meta-analysis identified 23 shared loci, three of which were novel. Transcriptome-wide association study found 15 shared genes, targeting tissues of the digestive, exo-/endocrine, nervous, and cardiovascular systems. Mendelian randomization suggested causal relationships of genetically predicted later age at menarche (OR = 0.88, 95% CI = 0.85-0.92, P = 1.50 × 10–10) or later age at first birth (OR = 0.95, 95% CI = 0.90-0.99, P = 0.02) with a reduced risk of uterine leiomyomata, and a causal relationship of genetically predicted later age at natural menopause with an increased risk of uterine leiomyomata (OR = 1.08, 95% CI = 1.06-1.09, P = 2.30 × 10–27). No causal association in the reverse direction was found. ConclusionsOur work highlights substantial shared genetic influences as well as significant causal links underlying reproductive traits and uterine leiomyomata. Findings suggest that early identification of female reproductive risk factors may facilitate the initiation of strategies to modify potential uterine leiomyomata risk.