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

Rafnar, Thorunn; Bjarni Gunnarsson; Ólafur A. Stefánsson; sulem, patrick; Ingason, Andrés; Frigge, Michael L.; Lilja Stefánsdóttir; Jón K. Sigurðsson; Tragante, Vinicius; Steinthorsdottir, Valgerdur; Styrkarsdottir, Unnur; Stacey, Simon N.; Gudmundsson, Julius; Arnadottir, Gudny; Oddsson, Asmundur; Zink, Florian; Halldorsson, Gisli; Sveinbjornsson, Gardar; Kristjansson, Ragnar; Ólafur B. Davíðsson; Anna Þórhildur Salvarsdóttir; Ásgeir Thoroddsen; Elísabet A. Helgadottir; Katrín Kristjánsdóttir; Orri Ingþórsson; Valur Guðmundsson; Geirsson, Reynir T.; Ragnheiður Árnadottir; Gudbjartsson, Daniel; Másson, Gísli; Asselbergs, Folkert W.; Jón Gunnlaugur Jónasson; Karl Ólafsson; Thorsteinsdottir, Unnur; Halldórsson, Bjarni; Thorleifsson, Gudmar; Stefansson, Kari

dc.contributor	Háskólinn í Reykjavík
dc.contributor	Reykjavik University
dc.contributor	Háskóli Íslands
dc.contributor	University of Iceland
dc.contributor.author	orcid.org/0000-0003-0491-7046 Rafnar, Thorunn
dc.contributor.author	Bjarni Gunnarsson
dc.contributor.author	Ólafur A. Stefánsson
dc.contributor.author	orcid.org/0000-0001-7123-6123 sulem, patrick
dc.contributor.author	Ingason, Andrés
dc.contributor.author	Frigge, Michael L.
dc.contributor.author	Lilja Stefánsdóttir
dc.contributor.author	Jón K. Sigurðsson
dc.contributor.author	Tragante, Vinicius
dc.contributor.author	orcid.org/0000-0003-1846-6274 Steinthorsdottir, Valgerdur
dc.contributor.author	orcid.org/0000-0001-8146-8278 Styrkarsdottir, Unnur
dc.contributor.author	Stacey, Simon N.
dc.contributor.author	orcid.org/0000-0003-2517-4763 Gudmundsson, Julius
dc.contributor.author	orcid.org/0000-0001-6571-423X Arnadottir, Gudny
dc.contributor.author	orcid.org/0000-0002-4606-5163 Oddsson, Asmundur
dc.contributor.author	Zink, Florian
dc.contributor.author	orcid.org/0000-0001-7067-9862 Halldorsson, Gisli
dc.contributor.author	orcid.org/0000-0003-2429-9468 Sveinbjornsson, Gardar
dc.contributor.author	orcid.org/0000-0002-3678-5693 Kristjansson, Ragnar
dc.contributor.author	Ólafur B. Davíðsson
dc.contributor.author	Anna Þórhildur Salvarsdóttir
dc.contributor.author	Ásgeir Thoroddsen
dc.contributor.author	Elísabet A. Helgadottir
dc.contributor.author	Katrín Kristjánsdóttir
dc.contributor.author	Orri Ingþórsson
dc.contributor.author	Valur Guðmundsson
dc.contributor.author	Geirsson, Reynir T.
dc.contributor.author	Ragnheiður Árnadottir
dc.contributor.author	Gudbjartsson, Daniel
dc.contributor.author	orcid.org/0000-0003-0493-8242 Másson, Gísli
dc.contributor.author	Asselbergs, Folkert W.
dc.contributor.author	Jón Gunnlaugur Jónasson
dc.contributor.author	Karl Ólafsson
dc.contributor.author	Thorsteinsdottir, Unnur
dc.contributor.author	orcid.org/0000-0003-0756-0767 Halldórsson, Bjarni
dc.contributor.author	orcid.org/0000-0003-4623-9087 Thorleifsson, Gudmar
dc.contributor.author	orcid.org/0000-0003-1676-864X Stefansson, Kari
dc.date.accessioned	2019-11-01T10:31:50Z
dc.date.available	2019-11-01T10:31:50Z
dc.date.issued	2018-09-07
dc.identifier.citation	Rafnar, T., Gunnarsson, B., Stefansson, O.A. et al. Variants associating with uterine leiomyoma highlight genetic background shared by various cancers and hormone-related traits. Nat Commun 9, 3636 (2018) doi:10.1038/s41467-018-05428-6
dc.identifier.issn	2041-1723 (eISSN)
dc.identifier.uri	https://hdl.handle.net/20.500.11815/1328
dc.description	We thank the individuals who participated in the study and whose contribution made this work possible. We acknowledge the Icelandic Cancer Registry for assistance in the ascertainment of the cancer patients. T.R., B.G., P.S., B.V.H., G.T, and K.S. designed the study and interpreted the results. A.S, A.T., E.A.H., K.K., O.I., V.G., R.T.G., R.A., J.G.J., and K.O. carried out the subject ascertainment, recruitment, and collection of clinical data. U.S., V.S., S.N.S., J.G., G.A.A., A.O., F.Z., G.H., R.P.K., O.B.D., G.M., V.T., F.W.A., and U.T. collected, processed, and analyzed the genotype and phenotype data. O.A.S. performed the functional annotations. A.I., M.L.F., L.S., J.K.S., G.S., D.F.G., B.G., and B.V.H., performed the statistical and bioinformatics analyses. T.R., B.G., O.A.S, G.T., and K.S., drafted the manuscript. All authors contributed to the final version of the paper.
dc.description.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.
dc.description.sponsorship	This research has been conducted using the UK Biobank Resource under Application Number ‘24711’.
dc.format.extent	3636
dc.language.iso	en
dc.publisher	Springer Science and Business Media LLC
dc.relation.ispartofseries	Nature Communications;9(1)
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	Genome association
dc.subject	Chronic lymphocytic leukemia
dc.subject	Epithelial ovarian cancer
dc.subject	Bone mineral density
dc.subject	Susceptibility loci
dc.subject	Breast cancer
dc.subject	Risk loci
dc.subject	Sequence variants
dc.subject	Telomere length
dc.subject	Identifies 2
dc.subject	Genamengi
dc.subject	Hvítblæði
dc.subject	Eitlar
dc.subject	Krabbamein
dc.subject	Eggjastokkar
dc.subject	Beinþéttni
dc.subject	Steinefni
dc.subject	Brjóstakrabbamein
dc.subject	Krabbameinsrannsóknir
dc.title	Variants associating with uterine leiomyoma highlight genetic background shared by various cancers and hormone-related traits
dc.type	info:eu-repo/semantics/article
dcterms.license	This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
dc.description.version	Peer reviewed
dc.identifier.journal	Nature Communications
dc.identifier.doi	10.1038/s41467-018-05428-6
dc.contributor.department	Læknadeild (HÍ)
dc.contributor.department	Faculty of Medicine (UI)
dc.contributor.school	School of Science and Engineering (RU)
dc.contributor.school	Heilbrigðisvísindasvið (HÍ)
dc.contributor.school	School of Health Sciences (UI)
dc.contributor.school	Tækni- og verkfræðideild (HR)
dc.contributor.school	Verkfræði- og náttúruvísindasvið (HÍ)
dc.contributor.school	School of Engineering and Natural Sciences (UI)