GWAS of five gynecologic diseases and cross-trait analysis in Japanese

Tatsuo Masuda, Siew Kee Low, Masato Akiyama, Makoto Hirata, Yutaka Ueda, Koichi Matsuda, Tadashi Kimura, Yoshinori Murakami, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada

Research output: Contribution to journalArticle

Abstract

We performed genome-wide association studies of five gynecologic diseases using data of 46,837 subjects (5236 uterine fibroid, 645 endometriosis, 647 ovarian cancer (OC), 909 uterine endometrial cancer (UEC), and 538 uterine cervical cancer (UCC) cases allowing overlaps, and 39,556 shared female controls) from Biobank Japan Project. We used the population-specific imputation reference panel (n = 3541), yielding 7,645,193 imputed variants. Analyses performed under logistic model, linear mixed model, and model incorporating correlations identified nine significant associations with three gynecologic diseases including four novel findings (rs79219469:C > T, LINC02183, P = 3.3 × 10−8 and rs567534295:C > T, BRCA1, P = 3.1 × 10−8 with OC, rs150806792:C > T, INS-IGF2, P = 4.9 × 10−8 and rs140991990:A > G, SOX9, P = 3.3 × 10−8 with UCC). Random-effect meta-analysis of the five GWASs correcting for the overlapping subjects suggested one novel shared risk locus (rs937380553:A > G, LOC730100, P = 2.0 × 10−8). Reverse regression analysis identified three additional novel associations (rs73494486:C > T, GABBR2, P = 4.8 × 10−8, rs145152209:A > G, SH3GL3/BNC1, P = 3.3 × 10−8, and rs147427629:G > A, LOC107985484, P = 3.8 × 10−8). Estimated heritability ranged from 0.026 for OC to 0.220 for endometriosis. Genetic correlations were relatively strong between OC and UEC, endometriosis and OC, and uterine fibroid and OC (rg > 0.79) compared with relatively weak correlations between UCC and the other four (rg = −0.08 ~ 0.25). We successfully identified genetic associations with gynecologic diseases in the Japanese population. Shared genetic effects among multiple related diseases may help understanding the pathophysiology.

Original languageEnglish
JournalEuropean Journal of Human Genetics
DOIs
Publication statusAccepted/In press - 01-01-2019

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Female Genital Diseases
Genome-Wide Association Study
Ovarian Neoplasms
Uterine Neoplasms
Endometriosis
Uterine Cervical Neoplasms
Leiomyoma
Endometrial Neoplasms
Population
Meta-Analysis
Linear Models
Japan
Logistic Models
Regression Analysis

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Masuda, T., Low, S. K., Akiyama, M., Hirata, M., Ueda, Y., Matsuda, K., ... Okada, Y. (Accepted/In press). GWAS of five gynecologic diseases and cross-trait analysis in Japanese. European Journal of Human Genetics. https://doi.org/10.1038/s41431-019-0495-1
Masuda, Tatsuo ; Low, Siew Kee ; Akiyama, Masato ; Hirata, Makoto ; Ueda, Yutaka ; Matsuda, Koichi ; Kimura, Tadashi ; Murakami, Yoshinori ; Kubo, Michiaki ; Kamatani, Yoichiro ; Okada, Yukinori. / GWAS of five gynecologic diseases and cross-trait analysis in Japanese. In: European Journal of Human Genetics. 2019.
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Masuda, T, Low, SK, Akiyama, M, Hirata, M, Ueda, Y, Matsuda, K, Kimura, T, Murakami, Y, Kubo, M, Kamatani, Y & Okada, Y 2019, 'GWAS of five gynecologic diseases and cross-trait analysis in Japanese', European Journal of Human Genetics. https://doi.org/10.1038/s41431-019-0495-1

GWAS of five gynecologic diseases and cross-trait analysis in Japanese. / Masuda, Tatsuo; Low, Siew Kee; Akiyama, Masato; Hirata, Makoto; Ueda, Yutaka; Matsuda, Koichi; Kimura, Tadashi; Murakami, Yoshinori; Kubo, Michiaki; Kamatani, Yoichiro; Okada, Yukinori.

In: European Journal of Human Genetics, 01.01.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - GWAS of five gynecologic diseases and cross-trait analysis in Japanese

AU - Masuda, Tatsuo

AU - Low, Siew Kee

AU - Akiyama, Masato

AU - Hirata, Makoto

AU - Ueda, Yutaka

AU - Matsuda, Koichi

AU - Kimura, Tadashi

AU - Murakami, Yoshinori

AU - Kubo, Michiaki

AU - Kamatani, Yoichiro

AU - Okada, Yukinori

PY - 2019/1/1

Y1 - 2019/1/1

N2 - We performed genome-wide association studies of five gynecologic diseases using data of 46,837 subjects (5236 uterine fibroid, 645 endometriosis, 647 ovarian cancer (OC), 909 uterine endometrial cancer (UEC), and 538 uterine cervical cancer (UCC) cases allowing overlaps, and 39,556 shared female controls) from Biobank Japan Project. We used the population-specific imputation reference panel (n = 3541), yielding 7,645,193 imputed variants. Analyses performed under logistic model, linear mixed model, and model incorporating correlations identified nine significant associations with three gynecologic diseases including four novel findings (rs79219469:C > T, LINC02183, P = 3.3 × 10−8 and rs567534295:C > T, BRCA1, P = 3.1 × 10−8 with OC, rs150806792:C > T, INS-IGF2, P = 4.9 × 10−8 and rs140991990:A > G, SOX9, P = 3.3 × 10−8 with UCC). Random-effect meta-analysis of the five GWASs correcting for the overlapping subjects suggested one novel shared risk locus (rs937380553:A > G, LOC730100, P = 2.0 × 10−8). Reverse regression analysis identified three additional novel associations (rs73494486:C > T, GABBR2, P = 4.8 × 10−8, rs145152209:A > G, SH3GL3/BNC1, P = 3.3 × 10−8, and rs147427629:G > A, LOC107985484, P = 3.8 × 10−8). Estimated heritability ranged from 0.026 for OC to 0.220 for endometriosis. Genetic correlations were relatively strong between OC and UEC, endometriosis and OC, and uterine fibroid and OC (rg > 0.79) compared with relatively weak correlations between UCC and the other four (rg = −0.08 ~ 0.25). We successfully identified genetic associations with gynecologic diseases in the Japanese population. Shared genetic effects among multiple related diseases may help understanding the pathophysiology.

AB - We performed genome-wide association studies of five gynecologic diseases using data of 46,837 subjects (5236 uterine fibroid, 645 endometriosis, 647 ovarian cancer (OC), 909 uterine endometrial cancer (UEC), and 538 uterine cervical cancer (UCC) cases allowing overlaps, and 39,556 shared female controls) from Biobank Japan Project. We used the population-specific imputation reference panel (n = 3541), yielding 7,645,193 imputed variants. Analyses performed under logistic model, linear mixed model, and model incorporating correlations identified nine significant associations with three gynecologic diseases including four novel findings (rs79219469:C > T, LINC02183, P = 3.3 × 10−8 and rs567534295:C > T, BRCA1, P = 3.1 × 10−8 with OC, rs150806792:C > T, INS-IGF2, P = 4.9 × 10−8 and rs140991990:A > G, SOX9, P = 3.3 × 10−8 with UCC). Random-effect meta-analysis of the five GWASs correcting for the overlapping subjects suggested one novel shared risk locus (rs937380553:A > G, LOC730100, P = 2.0 × 10−8). Reverse regression analysis identified three additional novel associations (rs73494486:C > T, GABBR2, P = 4.8 × 10−8, rs145152209:A > G, SH3GL3/BNC1, P = 3.3 × 10−8, and rs147427629:G > A, LOC107985484, P = 3.8 × 10−8). Estimated heritability ranged from 0.026 for OC to 0.220 for endometriosis. Genetic correlations were relatively strong between OC and UEC, endometriosis and OC, and uterine fibroid and OC (rg > 0.79) compared with relatively weak correlations between UCC and the other four (rg = −0.08 ~ 0.25). We successfully identified genetic associations with gynecologic diseases in the Japanese population. Shared genetic effects among multiple related diseases may help understanding the pathophysiology.

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