Uterine leiomyomas (ULs) are benign tumors that are a major burden to women's health. A genome-wide association study on 5,417 UL cases and 331,791 controls was performed, followed by replication of the genomic risk in two cohorts. Effects of the identified risk alleles were evaluated in view of molecular and clinical features. Five loci displayed a genome-wide significant association; the previously reported TNRC6B, and four novel loci ESR1 (ERα), WT1, WNT4, and ATM. The sixth hit TERT is also a conceivable target. The combined polygenic risk contributed by these loci was associated with MED12 mutation-positive tumors. The findings link genes for uterine development and genetic stability to leiomyomagenesis. While the fundamental role of sex hormones in UL aetiology has been clear, this work reveals a connection to estrogen receptor alpha on genetic level and suggests that determinants of UL growth associated with estrogen exposure have an inherited component.

ESR1, WT1, WNT4, ATM and TERT loci are major contributors to uterine leiomyoma predisposition