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. 2018 Sep 7;9(1):3636.
doi: 10.1038/s41467-018-05428-6.

Variants Associating With Uterine Leiomyoma Highlight Genetic Background Shared by Various Cancers and Hormone-Related Traits

Free PMC article

Variants Associating With Uterine Leiomyoma Highlight Genetic Background Shared by Various Cancers and Hormone-Related Traits

Thorunn Rafnar et al. Nat Commun. .
Free PMC article


Uterine leiomyomas are common benign tumors of the myometrium. We performed a meta-analysis of two genome-wide association studies of leiomyoma in European women (16,595 cases and 523,330 controls), uncovering 21 variants at 16 loci that associate with the disease. Five variants were previously reported to confer risk of various malignant or benign tumors (rs78378222 in TP53, rs10069690 in TERT, rs1800057 and rs1801516 in ATM, and rs7907606 at OBFC1) and four signals are located at established risk loci for hormone-related traits (endometriosis and breast cancer) at 1q36.12 (CDC42/WNT4), 2p25.1 (GREB1), 20p12.3 (MCM8), and 6q26.2 (SYNE1/ESR1). Polygenic score for leiomyoma, computed using UKB data, is significantly correlated with risk of cancer in the Icelandic population. Functional annotation suggests that the non-coding risk variants affect multiple genes, including ESR1. Our results provide insights into the genetic background of leiomyoma that are shared by other benign and malignant tumors and highlight the role of hormones in leiomyoma growth.

Conflict of interest statement

The authors that are affiliated with deCODE are employees of deCODE genetics/Amgen. The remaining authors declare no competing interests.


Fig. 1
Fig. 1
Manhattan plot of the association results of meta-analysis of leiomyoma of the uterus. The Manhattan plot shows variants with P-value < 1.0 × 10−3 in a meta-analysis of GWAS data from 20,621 leiomyoma patients and 280,541 controls of European ancestry. Shown are negative log10-transformed P values (y-axis) over 22 autosomes (x-axis). Red font color indicates leiomyoma loci previously reported in the Japanese population
Fig. 2
Fig. 2
Leiomyoma risk variants intersecting with regulatory regions and their candidate target genes. Two loci on chromosomes 6 (upper panel) and 13 (lower panel) are shown as examples. Acetylation of lysine residue K27 of histone H3 (H3K27ac) and open chromatin (DHS, DNase Hypersensitivity Sites) in the uterus samples are shown as tick marks at the top. At chromosome 6, the lead variant rs58415480 is shown along with the only other variant in the same LD class (r2 > 0.8), rs71575922. At chromosome 13, rs117245733 is in an LD class by itself, i.e., does not have strongly correlated markers. Candidate target genes were identified by the analysis of available chromatin interaction maps, shown on the figure as orange arcs. The shaded regions represent regions found in contact with the regulatory variants

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