Identification of a novel uterine leiomyoma GWAS locus in a Japanese population

Kensuke Sakai,Atsushi Shimizu,Kokichi Arisawa,Akira Hirasawa,Nobuo Fuse,Yoichiro Kamatani,Shoichiro Tsugane,Wataru Yamagami,Hiroaki Ikezaki,Michiaki Kubo,Chizu Tanikawa,Nobuyuki Susumu,Kenji Wakai,Fumio Kataoka,Aya Kadota,Motoki Iwasaki,Takako Toda ,Taiki Yamaji,Atsushi Takahashi,Akimune Fukushima,Tatsuyuki Chiyoda,Daisuke Aoki,Norie Sawada,Makoto Hirata,Chikashi Terao,Yukihide Momozawa,Koichi Matsuda

doi:10.1038/s41598-020-58066-8

Abstract

Uterine leiomyoma is one of the most common gynaecologic benign tumours, but its genetic basis remains largely unknown. Six previous GWAS identified 33 genetic factors in total. Here, we performed a two-staged GWAS using 13,746 cases and 70,316 controls from the Japanese population, followed by a replication analysis using 3,483 cases and 4,795 controls. The analysis identified 9 significant loci, including a novel locus on 12q23.2 (rs17033114, P = 6.12 × 10−25 with an OR of 1.177 (1.141-1.213), LINC00485). Subgroup analysis indicated that 5 loci (3q26.2, 5p15.33, 10q24.33, 11p15.5, 13q14.11) exhibited a statistically significant effect among multiple leiomyomas, and 2 loci (3q26.2, 10q24.33) exhibited a significant effect among submucous leiomyomas. Pleiotropic analysis indicated that all 9 loci were associated with at least one proliferative disease, suggesting the role of these loci in the common neoplastic pathway. Furthermore, the risk T allele of rs2251795 (3q26.2) was associated with longer telomere length in both normal and tumour tissues. Our findings elucidated the significance of genetic factors in the pathogenesis of leiomyoma.

Highlights

Uterine leiomyoma is one of the most common gynaecologic benign tumours, but its genetic basis remains largely unknown
A total of DNA samples from 5,720 uterine leiomyoma patients and 17,492 controls were analysed in stage 1 (GWAS screening stage 1)
We reported 9 regions that were significantly associated with uterine leiomyoma in the Japanese population

Summary

Introduction

Uterine leiomyoma is one of the most common gynaecologic benign tumours, but its genetic basis remains largely unknown. Six previous GWAS identified 33 genetic factors in total. We performed a two-staged GWAS using 13,746 cases and 70,316 controls from the Japanese population, followed by a replication analysis using 3,483 cases and 4,795 controls. Pleiotropic analysis indicated that all 9 loci were associated with at least one proliferative disease, suggesting the role of these loci in the common neoplastic pathway. Our findings elucidated the significance of genetic factors in the pathogenesis of leiomyoma. Uterine leiomyoma is one of the most common gynaecologic benign tumours. We reported that a positive family history is associated with a higher leiomyoma risk among Japanese individuals (odds ratio of 5.496 (5.061–5.969))[13]

Methods

Results

Conclusion