Variants associating with uterine leiomyoma highlight genetic background shared by various cancers and hormone-related traits

Thorunn Rafnar; Bjarni Gunnarsson; Olafur A Stefansson; Patrick Sulem; Andres Ingason; Michael L Frigge; Lilja Stefansdottir; Jon K Sigurdsson; Vinicius Tragante; Valgerdur Steinthorsdottir; Unnur Styrkarsdottir; Simon N Stacey; Julius Gudmundsson; Gudny A Arnadottir; Asmundur Oddsson; Florian Zink; Gisli Halldorsson; Gardar Sveinbjornsson; Ragnar P Kristjansson; Olafur B Davidsson; Anna Salvarsdottir; Asgeir Thoroddsen; Elisabet A Helgadottir; Katrin Kristjansdottir; Orri Ingthorsson; Valur Gudmundsson; Reynir T Geirsson; Ragnheidur Arnadottir; Daniel F Gudbjartsson; Gisli Masson; Folkert W Asselbergs; Jon G Jonasson; Karl Olafsson; Unnur Thorsteinsdottir; Bjarni V Halldorsson; Gudmar Thorleifsson; Kari Stefansson

doi:10.1038/s41467-018-05428-6

Variants associating with uterine leiomyoma highlight genetic background shared by various cancers and hormone-related traits

Thorunn Rafnar, Bjarni Gunnarsson, Olafur A Stefansson, Patrick Sulem, Andres Ingason, Michael L Frigge, Lilja Stefansdottir, Jon K Sigurdsson, Vinicius Tragante, Valgerdur Steinthorsdottir, Unnur Styrkarsdottir, Simon N Stacey, Julius Gudmundsson, Gudny A Arnadottir, Asmundur Oddsson, Florian Zink, Gisli Halldorsson, Gardar Sveinbjornsson, Ragnar P Kristjansson, Olafur B DavidssonAnna Salvarsdottir, Asgeir Thoroddsen, Elisabet A Helgadottir, Katrin Kristjansdottir, Orri Ingthorsson, Valur Gudmundsson, Reynir T Geirsson, Ragnheidur Arnadottir, Daniel F Gudbjartsson, Gisli Masson, Folkert W Asselbergs, Jon G Jonasson, Karl Olafsson, Unnur Thorsteinsdottir, Bjarni V Halldorsson, Gudmar Thorleifsson, Kari Stefansson

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Abstract

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.

Original language	English
Article number	3636
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-05428-6
Publication status	Published - 7 Sept 2018

Keywords

Case-Control Studies
Endometriosis/genetics
European Continental Ancestry Group/genetics
Female
Genome-Wide Association Study
Humans
Leiomyoma/genetics
Uterine Neoplasms/genetics

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Rafnar, T., Gunnarsson, B., Stefansson, O. A., Sulem, P., Ingason, A., Frigge, M. L., Stefansdottir, L., Sigurdsson, J. K., Tragante, V., Steinthorsdottir, V., Styrkarsdottir, U., Stacey, S. N., Gudmundsson, J., Arnadottir, G. A., Oddsson, A., Zink, F., Halldorsson, G., Sveinbjornsson, G., Kristjansson, R. P., ... Stefansson, K. (2018). Variants associating with uterine leiomyoma highlight genetic background shared by various cancers and hormone-related traits. Nature Communications, 9(1), Article 3636. https://doi.org/10.1038/s41467-018-05428-6

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title = "Variants associating with uterine leiomyoma highlight genetic background shared by various cancers and hormone-related traits",

abstract = "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.",

keywords = "Case-Control Studies, Endometriosis/genetics, European Continental Ancestry Group/genetics, Female, Genome-Wide Association Study, Humans, Leiomyoma/genetics, Uterine Neoplasms/genetics",

author = "Thorunn Rafnar and Bjarni Gunnarsson and Stefansson, {Olafur A} and Patrick Sulem and Andres Ingason and Frigge, {Michael L} and Lilja Stefansdottir and Sigurdsson, {Jon K} and Vinicius Tragante and Valgerdur Steinthorsdottir and Unnur Styrkarsdottir and Stacey, {Simon N} and Julius Gudmundsson and Arnadottir, {Gudny A} and Asmundur Oddsson and Florian Zink and Gisli Halldorsson and Gardar Sveinbjornsson and Kristjansson, {Ragnar P} and Davidsson, {Olafur B} and Anna Salvarsdottir and Asgeir Thoroddsen and Helgadottir, {Elisabet A} and Katrin Kristjansdottir and Orri Ingthorsson and Valur Gudmundsson and Geirsson, {Reynir T} and Ragnheidur Arnadottir and Gudbjartsson, {Daniel F} and Gisli Masson and Asselbergs, {Folkert W} and Jonasson, {Jon G} and Karl Olafsson and Unnur Thorsteinsdottir and Halldorsson, {Bjarni V} and Gudmar Thorleifsson and Kari Stefansson",

note = "Publisher Copyright: {\textcopyright} 2018, The Author(s).",

year = "2018",

month = sep,

day = "7",

doi = "10.1038/s41467-018-05428-6",

language = "English",

volume = "9",

journal = "Nature Communications",

issn = "2041-1723",

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Rafnar, T, Gunnarsson, B, Stefansson, OA, Sulem, P, Ingason, A, Frigge, ML, Stefansdottir, L, Sigurdsson, JK, Tragante, V, Steinthorsdottir, V, Styrkarsdottir, U, Stacey, SN, Gudmundsson, J, Arnadottir, GA, Oddsson, A, Zink, F, Halldorsson, G, Sveinbjornsson, G, Kristjansson, RP, Davidsson, OB, Salvarsdottir, A, Thoroddsen, A, Helgadottir, EA, Kristjansdottir, K, Ingthorsson, O, Gudmundsson, V, Geirsson, RT, Arnadottir, R, Gudbjartsson, DF, Masson, G, Asselbergs, FW, Jonasson, JG, Olafsson, K, Thorsteinsdottir, U, Halldorsson, BV, Thorleifsson, G & Stefansson, K 2018, 'Variants associating with uterine leiomyoma highlight genetic background shared by various cancers and hormone-related traits', Nature Communications, vol. 9, no. 1, 3636. https://doi.org/10.1038/s41467-018-05428-6

TY - JOUR

T1 - Variants associating with uterine leiomyoma highlight genetic background shared by various cancers and hormone-related traits

AU - Rafnar, Thorunn

AU - Gunnarsson, Bjarni

AU - Stefansson, Olafur A

AU - Sulem, Patrick

AU - Ingason, Andres

AU - Frigge, Michael L

AU - Stefansdottir, Lilja

AU - Sigurdsson, Jon K

AU - Tragante, Vinicius

AU - Steinthorsdottir, Valgerdur

AU - Styrkarsdottir, Unnur

AU - Stacey, Simon N

AU - Gudmundsson, Julius

AU - Arnadottir, Gudny A

AU - Oddsson, Asmundur

AU - Zink, Florian

AU - Halldorsson, Gisli

AU - Sveinbjornsson, Gardar

AU - Kristjansson, Ragnar P

AU - Davidsson, Olafur B

AU - Salvarsdottir, Anna

AU - Thoroddsen, Asgeir

AU - Helgadottir, Elisabet A

AU - Kristjansdottir, Katrin

AU - Ingthorsson, Orri

AU - Gudmundsson, Valur

AU - Geirsson, Reynir T

AU - Arnadottir, Ragnheidur

AU - Gudbjartsson, Daniel F

AU - Masson, Gisli

AU - Asselbergs, Folkert W

AU - Jonasson, Jon G

AU - Olafsson, Karl

AU - Thorsteinsdottir, Unnur

AU - Halldorsson, Bjarni V

AU - Thorleifsson, Gudmar

AU - Stefansson, Kari

PY - 2018/9/7

Y1 - 2018/9/7

N2 - 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.

AB - 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.

KW - Case-Control Studies

KW - Endometriosis/genetics

KW - European Continental Ancestry Group/genetics

KW - Female

KW - Genome-Wide Association Study

KW - Humans

KW - Leiomyoma/genetics

KW - Uterine Neoplasms/genetics

U2 - 10.1038/s41467-018-05428-6

DO - 10.1038/s41467-018-05428-6

M3 - Article

C2 - 30194396

SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3636

ER -

Variants associating with uterine leiomyoma highlight genetic background shared by various cancers and hormone-related traits

Abstract

Keywords

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