Genome-wide association study of 398,238 women unveils seven loci associated with high-grade serous ovarian cancer

Daniel R. Barnes; Jonathan P. Tyrer; Joe Dennis; Goska Leslie; Manjeet K. Bolla; Michael Lush; Amber M. Aeilts; Kristiina Aittomäki; Nadine Andrieu; Irene L. Andrulis; Hoda Anton-Culver; Adalgeir Arason; Banu K. Arun; Judith Balmaña; Elisa V. Bandera; Rosa B. Barkardottir; Lieke P.V. Berger; Amy Berrington de Gonzalez; Pascaline Berthet; Katarzyna Bialkowska; Line Bjørge; Amie M. Blanco; Marinus J. Blok; Kristie A. Bobolis; Natalia V. Bogdanova; James D. Brenton; Henriett Butz; Saundra S. Buys; Maria A. Caligo; Ian Campbell; Carmen Castillo; Kathleen B.M. Claes; Sarah V. Colonna; Linda S. Cook; Mary B. Daly; Agnieszka Dansonka-Mieszkowska; Miguel de la Hoya; Anna deFazio; Allison DePersia; Yuan Chun Ding; Jennifer A. Doherty; Susan M. Domchek; Thilo Dörk; Zakaria Einbeigi; Christoph Engel; D. Gareth Evans; Lenka Foretova; Renée T. Fortner; Florentia Fostira; Maria Cristina Foti; Et al.

doi:10.1038/s41525-025-00529-w

Genome-wide association study of 398,238 women unveils seven loci associated with high-grade serous ovarian cancer

Daniel R. Barnes^*
, Jonathan P. Tyrer
, Joe Dennis
, Goska Leslie
, Manjeet K. Bolla
, Michael Lush
, Amber M. Aeilts
, Kristiina Aittomäki
, Nadine Andrieu
, Irene L. Andrulis
, Hoda Anton-Culver
, Adalgeir Arason
, Banu K. Arun
, Judith Balmaña
, Elisa V. Bandera
, Rosa B. Barkardottir
, Lieke P.V. Berger
, Amy Berrington de Gonzalez
, Pascaline Berthet
, Katarzyna Bialkowska

Line Bjørge, Amie M. Blanco, Marinus J. Blok, Kristie A. Bobolis, Natalia V. Bogdanova, James D. Brenton, Henriett Butz, Saundra S. Buys, Maria A. Caligo, Ian Campbell, Carmen Castillo, Kathleen B.M. Claes, Sarah V. Colonna, Linda S. Cook, Mary B. Daly, Agnieszka Dansonka-Mieszkowska, Miguel de la Hoya, Anna deFazio, Allison DePersia, Yuan Chun Ding, Jennifer A. Doherty, Susan M. Domchek, Thilo Dörk, Zakaria Einbeigi, Christoph Engel, D. Gareth Evans, Lenka Foretova, Renée T. Fortner, Florentia Fostira, Maria Cristina Foti, Et al.

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We meta-analyzed >22 million variants for 398,238 women from the Ovarian Cancer Association Consortium (OCAC), UK Biobank (UKBB) and Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA) to identify novel HGSOC susceptibility loci. Eight novel variants were associated with HGSOC risk. An interesting discovery biologically was TP53 3’-UTR SNP rs78378222-T’s association with HGSOC (per-T-allele relative risk (RR) = 1.44, 95% CI:1.28–1.62, P = 1.76 × 10^-9). Polygenic scores (PGS) were developed using OCAC and CIMBA data and trained on FinnGen data. The optimal PGS included 64,518 variants and was associated with an odds ratio of 1.46 (95% CI:1.37–1.54) per standard deviation when validated in the UKBB. This study represents the largest HGSOC GWAS to date – demonstrating that improvements in imputation reference panels and increased sample sizes help to identify HGSOC associated variants that previously went undetected, ultimately improving PGS which can improve personalized HGSOC risk prediction.

Original language	English
Article number	73
Number of pages	21
Journal	npj Genomic Medicine
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41525-025-00529-w
Publication status	Published - 1 Dec 2025

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Barnes, D. R., Tyrer, J. P., Dennis, J., Leslie, G., Bolla, M. K., Lush, M., Aeilts, A. M., Aittomäki, K., Andrieu, N., Andrulis, I. L., Anton-Culver, H., Arason, A., Arun, B. K., Balmaña, J., Bandera, E. V., Barkardottir, R. B., Berger, L. P. V., Berrington de Gonzalez, A., Berthet, P., ... Et al. (2025). Genome-wide association study of 398,238 women unveils seven loci associated with high-grade serous ovarian cancer. npj Genomic Medicine, 10(1), Article 73. https://doi.org/10.1038/s41525-025-00529-w

@article{87696e9c80694b5f84d7879f6d5e14c6,

title = "Genome-wide association study of 398,238 women unveils seven loci associated with high-grade serous ovarian cancer",

abstract = "Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We meta-analyzed >22 million variants for 398,238 women from the Ovarian Cancer Association Consortium (OCAC), UK Biobank (UKBB) and Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA) to identify novel HGSOC susceptibility loci. Eight novel variants were associated with HGSOC risk. An interesting discovery biologically was TP53 3{\textquoteright}-UTR SNP rs78378222-T{\textquoteright}s association with HGSOC (per-T-allele relative risk (RR) = 1.44, 95\% CI:1.28–1.62, P = 1.76 × 10-9). Polygenic scores (PGS) were developed using OCAC and CIMBA data and trained on FinnGen data. The optimal PGS included 64,518 variants and was associated with an odds ratio of 1.46 (95\% CI:1.37–1.54) per standard deviation when validated in the UKBB. This study represents the largest HGSOC GWAS to date – demonstrating that improvements in imputation reference panels and increased sample sizes help to identify HGSOC associated variants that previously went undetected, ultimately improving PGS which can improve personalized HGSOC risk prediction.",

author = "Barnes, \{Daniel R.\} and Tyrer, \{Jonathan P.\} and Joe Dennis and Goska Leslie and Bolla, \{Manjeet K.\} and Michael Lush and Aeilts, \{Amber M.\} and Kristiina Aittom{\"a}ki and Nadine Andrieu and Andrulis, \{Irene L.\} and Hoda Anton-Culver and Adalgeir Arason and Arun, \{Banu K.\} and Judith Balma{\~n}a and Bandera, \{Elisa V.\} and Barkardottir, \{Rosa B.\} and Berger, \{Lieke P.V.\} and \{Berrington de Gonzalez\}, Amy and Pascaline Berthet and Katarzyna Bialkowska and Line Bj{\o}rge and Blanco, \{Amie M.\} and Blok, \{Marinus J.\} and Bobolis, \{Kristie A.\} and Bogdanova, \{Natalia V.\} and Brenton, \{James D.\} and Henriett Butz and Buys, \{Saundra S.\} and Caligo, \{Maria A.\} and Ian Campbell and Carmen Castillo and Claes, \{Kathleen B.M.\} and Colonna, \{Sarah V.\} and Cook, \{Linda S.\} and Daly, \{Mary B.\} and Agnieszka Dansonka-Mieszkowska and \{de la Hoya\}, Miguel and Anna deFazio and Allison DePersia and Ding, \{Yuan Chun\} and Doherty, \{Jennifer A.\} and Domchek, \{Susan M.\} and Thilo D{\"o}rk and Zakaria Einbeigi and Christoph Engel and Evans, \{D. Gareth\} and Lenka Foretova and Fortner, \{Ren{\'e}e T.\} and Florentia Fostira and Foti, \{Maria Cristina\} and \{Et al.\}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = dec,

day = "1",

doi = "10.1038/s41525-025-00529-w",

language = "English",

volume = "10",

journal = "npj Genomic Medicine",

issn = "2056-7944",

publisher = "Nature Publishing Group",

number = "1",

}

Barnes, DR, Tyrer, JP, Dennis, J, Leslie, G, Bolla, MK, Lush, M, Aeilts, AM, Aittomäki, K, Andrieu, N, Andrulis, IL, Anton-Culver, H, Arason, A, Arun, BK, Balmaña, J, Bandera, EV, Barkardottir, RB, Berger, LPV, Berrington de Gonzalez, A, Berthet, P, Bialkowska, K, Bjørge, L, Blanco, AM, Blok, MJ, Bobolis, KA, Bogdanova, NV, Brenton, JD, Butz, H, Buys, SS, Caligo, MA, Campbell, I, Castillo, C, Claes, KBM, Colonna, SV, Cook, LS, Daly, MB, Dansonka-Mieszkowska, A, de la Hoya, M, deFazio, A, DePersia, A, Ding, YC, Doherty, JA, Domchek, SM, Dörk, T, Einbeigi, Z, Engel, C, Evans, DG, Foretova, L, Fortner, RT, Fostira, F, Foti, MC & Et al. 2025, 'Genome-wide association study of 398,238 women unveils seven loci associated with high-grade serous ovarian cancer', npj Genomic Medicine, vol. 10, no. 1, 73. https://doi.org/10.1038/s41525-025-00529-w

TY - JOUR

T1 - Genome-wide association study of 398,238 women unveils seven loci associated with high-grade serous ovarian cancer

AU - Barnes, Daniel R.

AU - Tyrer, Jonathan P.

AU - Dennis, Joe

AU - Leslie, Goska

AU - Bolla, Manjeet K.

AU - Lush, Michael

AU - Aeilts, Amber M.

AU - Aittomäki, Kristiina

AU - Andrieu, Nadine

AU - Andrulis, Irene L.

AU - Anton-Culver, Hoda

AU - Arason, Adalgeir

AU - Arun, Banu K.

AU - Balmaña, Judith

AU - Bandera, Elisa V.

AU - Barkardottir, Rosa B.

AU - Berger, Lieke P.V.

AU - Berrington de Gonzalez, Amy

AU - Berthet, Pascaline

AU - Bialkowska, Katarzyna

AU - Bjørge, Line

AU - Blanco, Amie M.

AU - Blok, Marinus J.

AU - Bobolis, Kristie A.

AU - Bogdanova, Natalia V.

AU - Brenton, James D.

AU - Butz, Henriett

AU - Buys, Saundra S.

AU - Caligo, Maria A.

AU - Campbell, Ian

AU - Castillo, Carmen

AU - Claes, Kathleen B.M.

AU - Colonna, Sarah V.

AU - Cook, Linda S.

AU - Daly, Mary B.

AU - Dansonka-Mieszkowska, Agnieszka

AU - de la Hoya, Miguel

AU - deFazio, Anna

AU - DePersia, Allison

AU - Ding, Yuan Chun

AU - Doherty, Jennifer A.

AU - Domchek, Susan M.

AU - Dörk, Thilo

AU - Einbeigi, Zakaria

AU - Engel, Christoph

AU - Evans, D. Gareth

AU - Foretova, Lenka

AU - Fortner, Renée T.

AU - Fostira, Florentia

AU - Foti, Maria Cristina

AU - Et al.

PY - 2025/12/1

Y1 - 2025/12/1

N2 - Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We meta-analyzed >22 million variants for 398,238 women from the Ovarian Cancer Association Consortium (OCAC), UK Biobank (UKBB) and Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA) to identify novel HGSOC susceptibility loci. Eight novel variants were associated with HGSOC risk. An interesting discovery biologically was TP53 3’-UTR SNP rs78378222-T’s association with HGSOC (per-T-allele relative risk (RR) = 1.44, 95% CI:1.28–1.62, P = 1.76 × 10-9). Polygenic scores (PGS) were developed using OCAC and CIMBA data and trained on FinnGen data. The optimal PGS included 64,518 variants and was associated with an odds ratio of 1.46 (95% CI:1.37–1.54) per standard deviation when validated in the UKBB. This study represents the largest HGSOC GWAS to date – demonstrating that improvements in imputation reference panels and increased sample sizes help to identify HGSOC associated variants that previously went undetected, ultimately improving PGS which can improve personalized HGSOC risk prediction.

AB - Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We meta-analyzed >22 million variants for 398,238 women from the Ovarian Cancer Association Consortium (OCAC), UK Biobank (UKBB) and Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA) to identify novel HGSOC susceptibility loci. Eight novel variants were associated with HGSOC risk. An interesting discovery biologically was TP53 3’-UTR SNP rs78378222-T’s association with HGSOC (per-T-allele relative risk (RR) = 1.44, 95% CI:1.28–1.62, P = 1.76 × 10-9). Polygenic scores (PGS) were developed using OCAC and CIMBA data and trained on FinnGen data. The optimal PGS included 64,518 variants and was associated with an odds ratio of 1.46 (95% CI:1.37–1.54) per standard deviation when validated in the UKBB. This study represents the largest HGSOC GWAS to date – demonstrating that improvements in imputation reference panels and increased sample sizes help to identify HGSOC associated variants that previously went undetected, ultimately improving PGS which can improve personalized HGSOC risk prediction.

U2 - 10.1038/s41525-025-00529-w

DO - 10.1038/s41525-025-00529-w

M3 - Article

SN - 2056-7944

VL - 10

JO - npj Genomic Medicine

JF - npj Genomic Medicine

IS - 1

M1 - 73

ER -

Genome-wide association study of 398,238 women unveils seven loci associated with high-grade serous ovarian cancer

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