Genetic predisposition to uterine leiomyoma is determined by loci for genitourinary development and genome stability

  1. Niko Välimäki
  2. Heli Kuisma
  3. Annukka Pasanen
  4. Oskari Heikinheimo
  5. Jari Sjöberg
  6. Ralf Bützow
  7. Nanna Sarvilinna
  8. Hanna-Riikka Heinonen
  9. Jaana Tolvanen
  10. Simona Bramante
  11. Tomas Tanskanen
  12. Juha Auvinen
  13. Terhi Piltonen
  14. Amjad Alkodsi
  15. Rainer Lehtonen
  16. Eevi Kaasinen
  17. Kimmo Palin
  18. Lauri A Aaltonen  Is a corresponding author
  1. University of Helsinki, Finland
  2. University of Helsinki and Helsinki University Hospital, Finland
  3. University of Oulu, Finland
  4. Oulu University Hospital, Finland
  5. University Of Helsinki, Finland

Abstract

Uterine leiomyomas (ULs) are benign tumors that are a major burden to women's health. A genome-wide association study on 15,453 UL cases and 392,628 controls was performed, followed by replication of the genomic risk in six cohorts. Effects of the risk alleles were evaluated in view of molecular and clinical characteristics. 22 loci displayed a genome-wide significant association. The likely predisposition genes could be grouped to two biological processes. Genes involved in genome stability were represented by TERT, TERC, OBFC1 - highlighting the role of telomere maintenance - TP53 and ATM. Genes involved in genitourinary development, WNT4, WT1, SALL1, MED12, ESR1, GREB1, FOXO1, DMRT1 and uterine stem cell marker antigen CD44, formed another strong subgroup. The combined risk contributed by the 22 loci was associated with MED12 mutation-positive tumors. The findings link genes for uterine development and genetic stability to leiomyomagenesis, and in part explain the more frequent occurrence of UL in women of African origin.

Data availability

The UKBB data is available through the UK Biobank (http://www.ukbiobank.ac.uk). The NFBC data can be requested from the Northern Finland Birth Cohorts' Project Center at the Medical Faculty, University of Oulu (http://www.oulu.fi/nfbc/). The summary statistics that support the findings presented in this work are included in Supplementary Tables and Supplementary Data.

The following previously published data sets were used

Article and author information

Author details

  1. Niko Välimäki

    Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9200-9560
  2. Heli Kuisma

    Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
  3. Annukka Pasanen

    Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0079-9807
  4. Oskari Heikinheimo

    Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
  5. Jari Sjöberg

    Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
  6. Ralf Bützow

    Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
  7. Nanna Sarvilinna

    Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
  8. Hanna-Riikka Heinonen

    Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
  9. Jaana Tolvanen

    Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1183-4943
  10. Simona Bramante

    Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
  11. Tomas Tanskanen

    Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
  12. Juha Auvinen

    Northern Finland Birth Cohort Studies and Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland
    Competing interests
    The authors declare that no competing interests exist.
  13. Terhi Piltonen

    Department of Obstetrics and Gynecology, PEDEGO Research Unit, Medical Research Center Oulu, Oulu University Hospital, Oulu, Finland
    Competing interests
    The authors declare that no competing interests exist.
  14. Amjad Alkodsi

    Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3528-4683
  15. Rainer Lehtonen

    Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
  16. Eevi Kaasinen

    Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
  17. Kimmo Palin

    Department of Medical and Clinical Genetics, University Of Helsinki, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4621-6128
  18. Lauri A Aaltonen

    Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
    For correspondence
    lauri.aaltonen@helsinki.fi
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6839-4286

Funding

Terveyden Tutkimuksen Toimikunta (1250345)

  • Lauri A Aaltonen

European Research Council (695727)

  • Lauri A Aaltonen

Cancer Society of Finland

  • Lauri A Aaltonen

Sigrid Juséliuksen Säätiö

  • Lauri A Aaltonen

Jane ja Aatos Erkon Säätiö

  • Lauri A Aaltonen

Luonnontieteiden ja Tekniikan Tutkimuksen Toimikunta (287665)

  • Niko Välimäki

NordForsk (62721)

  • Kimmo Palin

Terveyden Tutkimuksen Toimikunta (312041)

  • Lauri A Aaltonen

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: The anonymous patient samples (65) were collected according to Finnish laws and regulations by permission of the director of the health care unit. For the rest of the patients, an informed consent was obtained. This study was conducted in accordance with the Declaration of Helsinki and approved by the Finnish National Supervisory Authority for Welfare and Health, National Institute for Health and Welfare (THL/151/5.05.00/2017), and the Ethics Committee of the Hospital District of Helsinki and Uusimaa (HUS/177/13/03/03/2016).

Reviewing Editor

  1. Eduardo Franco, McGill University, Canada

Publication history

  1. Received: March 29, 2018
  2. Accepted: September 17, 2018
  3. Accepted Manuscript published: September 18, 2018 (version 1)
  4. Version of Record published: October 26, 2018 (version 2)

Copyright

© 2018, Välimäki et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Niko Välimäki
  2. Heli Kuisma
  3. Annukka Pasanen
  4. Oskari Heikinheimo
  5. Jari Sjöberg
  6. Ralf Bützow
  7. Nanna Sarvilinna
  8. Hanna-Riikka Heinonen
  9. Jaana Tolvanen
  10. Simona Bramante
  11. Tomas Tanskanen
  12. Juha Auvinen
  13. Terhi Piltonen
  14. Amjad Alkodsi
  15. Rainer Lehtonen
  16. Eevi Kaasinen
  17. Kimmo Palin
  18. Lauri A Aaltonen
(2018)
Genetic predisposition to uterine leiomyoma is determined by loci for genitourinary development and genome stability
eLife 7:e37110.
https://doi.org/10.7554/eLife.37110

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