Investigation of common genetic risk factors between thyroid traits and breast cancer

Elise A. Lucotte; Yazdan Asgari; Pierre-Emmanuel Sugier; Mojgan Karimi; Cloé Domenighetti; Fabienne Lesueur; Anne Boland-Augé; Evgenia Ostroumova; Florent de Vathaire; Monia Zidane; Pascal Guénel; Jean-François Deleuze; Marie-Christine Boutron-Ruault; Gianluca Severi; Benoît Liquet; Thérèse Truong

doi:10.1093/hmg/ddad159

Investigation of common genetic risk factors between thyroid traits and breast cancer

Elise A. Lucotte, Yazdan Asgari, Pierre-Emmanuel Sugier, Mojgan Karimi, Cloé Domenighetti, Fabienne Lesueur, Anne Boland-Augé, Evgenia Ostroumova, Florent de Vathaire, Monia Zidane, Pascal Guénel, Jean-François Deleuze, Marie-Christine Boutron-Ruault, Gianluca Severi, Benoît Liquet, Thérèse Truong

School of Mathematical and Physical Sciences

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

1 Citation (Scopus)

87 Downloads (Pure)

Abstract

Breast cancer (BC) risk is suspected to be linked to thyroid disorders, however observational studies exploring the association between BC and thyroid disorders gave conflicting results. We proposed an alternative approach by investigating the shared genetic risk factors between BC and several thyroid traits. We report a positive genetic correlation between BC and thyroxine (FT4) levels (corr = 0.13, p-value = 2.0 x 10^-4) and a negative genetic correlation between BC and thyroid-stimulating hormone (TSH) levels (corr = -0.09, p-value = 0.03). These associations are more striking when restricting the analysis to estrogen receptor-positive BC. Moreover, the polygenic risk scores (PRS) for FT4 and hyperthyroidism are positively associated to BC risk (OR = 1.07, 95%CI: 1.00-1.13, p-value = 2.8 x 10^-2 and OR = 1.04, 95%CI: 1.00-1.08, p-value = 3.8 x 10^-2, respectively), while the PRS for TSH is inversely associated to BC risk (OR = 0.93, 95%CI: 0.89-0.97, p-value = 2.0 x 10^-3). Using the PLACO method, we detected 49 loci associated to both BC and thyroid traits (p-value < 5 x 10^-8), in the vicinity of 130 genes. An additional colocalization and gene-set enrichment analyses showed a convincing causal role for a known pleiotropic locus at 2q35 and revealed an additional one at 8q22.1 associated to both BC and thyroid cancer. We also found two new pleiotropic loci at 14q32.33 and 17q21.31 that were associated to both TSH levels and BC risk. Enrichment analyses and evidence of regulatory signals also highlighted brain tissues and immune system as candidates for obtaining associations between BC and TSH levels. Overall, our study sheds light on the complex interplay between BC and thyroid traits and provides evidence of shared genetic risk between those conditions.

Original language	English
Pages (from-to)	38-47
Number of pages	10
Journal	Human Molecular Genetics
Volume	33
Issue number	1
Early online date	Sept 2023
DOIs	https://doi.org/10.1093/hmg/ddad159
Publication status	Published - 1 Jan 2024

Bibliographical note

© The Author(s) 2023. Published by Oxford University Press. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

breast cancer
thyroid cancer
cross phenotype association
pleiotropy
thyroid traits

Access to Document

10.1093/hmg/ddad159Licence: CC BY-NC

Publisher version (open access)Final published version, 562 KBLicence: CC BY-NC

Cite this

Lucotte, E. A., Asgari, Y., Sugier, P.-E., Karimi, M., Domenighetti, C., Lesueur, F., Boland-Augé, A., Ostroumova, E., de Vathaire, F., Zidane, M., Guénel, P., Deleuze, J.-F., Boutron-Ruault, M.-C., Severi, G., Liquet, B., & Truong, T. (2024). Investigation of common genetic risk factors between thyroid traits and breast cancer. Human Molecular Genetics, 33(1), 38-47. https://doi.org/10.1093/hmg/ddad159

@article{10b8dc207b38489eb442b41d44363672,

title = "Investigation of common genetic risk factors between thyroid traits and breast cancer",

abstract = "Breast cancer (BC) risk is suspected to be linked to thyroid disorders, however observational studies exploring the association between BC and thyroid disorders gave conflicting results. We proposed an alternative approach by investigating the shared genetic risk factors between BC and several thyroid traits. We report a positive genetic correlation between BC and thyroxine (FT4) levels (corr = 0.13, p-value = 2.0 x 10-4) and a negative genetic correlation between BC and thyroid-stimulating hormone (TSH) levels (corr = -0.09, p-value = 0.03). These associations are more striking when restricting the analysis to estrogen receptor-positive BC. Moreover, the polygenic risk scores (PRS) for FT4 and hyperthyroidism are positively associated to BC risk (OR = 1.07, 95%CI: 1.00-1.13, p-value = 2.8 x 10-2 and OR = 1.04, 95%CI: 1.00-1.08, p-value = 3.8 x 10-2, respectively), while the PRS for TSH is inversely associated to BC risk (OR = 0.93, 95%CI: 0.89-0.97, p-value = 2.0 x 10-3). Using the PLACO method, we detected 49 loci associated to both BC and thyroid traits (p-value < 5 x 10-8), in the vicinity of 130 genes. An additional colocalization and gene-set enrichment analyses showed a convincing causal role for a known pleiotropic locus at 2q35 and revealed an additional one at 8q22.1 associated to both BC and thyroid cancer. We also found two new pleiotropic loci at 14q32.33 and 17q21.31 that were associated to both TSH levels and BC risk. Enrichment analyses and evidence of regulatory signals also highlighted brain tissues and immune system as candidates for obtaining associations between BC and TSH levels. Overall, our study sheds light on the complex interplay between BC and thyroid traits and provides evidence of shared genetic risk between those conditions.",

keywords = "breast cancer, thyroid cancer, cross phenotype association, pleiotropy, thyroid traits",

author = "Lucotte, {Elise A.} and Yazdan Asgari and Pierre-Emmanuel Sugier and Mojgan Karimi and Clo{\'e} Domenighetti and Fabienne Lesueur and Anne Boland-Aug{\'e} and Evgenia Ostroumova and {de Vathaire}, Florent and Monia Zidane and Pascal Gu{\'e}nel and Jean-Fran{\c c}ois Deleuze and Marie-Christine Boutron-Ruault and Gianluca Severi and Beno{\^i}t Liquet and Th{\'e}r{\`e}se Truong",

note = "{\textcopyright} The Author(s) 2023. Published by Oxford University Press. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.",

year = "2024",

month = jan,

day = "1",

doi = "10.1093/hmg/ddad159",

language = "English",

volume = "33",

pages = "38--47",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "1",

}

Lucotte, EA, Asgari, Y, Sugier, P-E, Karimi, M, Domenighetti, C, Lesueur, F, Boland-Augé, A, Ostroumova, E, de Vathaire, F, Zidane, M, Guénel, P, Deleuze, J-F, Boutron-Ruault, M-C, Severi, G, Liquet, B & Truong, T 2024, 'Investigation of common genetic risk factors between thyroid traits and breast cancer', Human Molecular Genetics, vol. 33, no. 1, pp. 38-47. https://doi.org/10.1093/hmg/ddad159

TY - JOUR

T1 - Investigation of common genetic risk factors between thyroid traits and breast cancer

AU - Lucotte, Elise A.

AU - Asgari, Yazdan

AU - Sugier, Pierre-Emmanuel

AU - Karimi, Mojgan

AU - Domenighetti, Cloé

AU - Lesueur, Fabienne

AU - Boland-Augé, Anne

AU - Ostroumova, Evgenia

AU - de Vathaire, Florent

AU - Zidane, Monia

AU - Guénel, Pascal

AU - Deleuze, Jean-François

AU - Boutron-Ruault, Marie-Christine

AU - Severi, Gianluca

AU - Liquet, Benoît

AU - Truong, Thérèse

N1 - © The Author(s) 2023. Published by Oxford University Press. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2024/1/1

Y1 - 2024/1/1

N2 - Breast cancer (BC) risk is suspected to be linked to thyroid disorders, however observational studies exploring the association between BC and thyroid disorders gave conflicting results. We proposed an alternative approach by investigating the shared genetic risk factors between BC and several thyroid traits. We report a positive genetic correlation between BC and thyroxine (FT4) levels (corr = 0.13, p-value = 2.0 x 10-4) and a negative genetic correlation between BC and thyroid-stimulating hormone (TSH) levels (corr = -0.09, p-value = 0.03). These associations are more striking when restricting the analysis to estrogen receptor-positive BC. Moreover, the polygenic risk scores (PRS) for FT4 and hyperthyroidism are positively associated to BC risk (OR = 1.07, 95%CI: 1.00-1.13, p-value = 2.8 x 10-2 and OR = 1.04, 95%CI: 1.00-1.08, p-value = 3.8 x 10-2, respectively), while the PRS for TSH is inversely associated to BC risk (OR = 0.93, 95%CI: 0.89-0.97, p-value = 2.0 x 10-3). Using the PLACO method, we detected 49 loci associated to both BC and thyroid traits (p-value < 5 x 10-8), in the vicinity of 130 genes. An additional colocalization and gene-set enrichment analyses showed a convincing causal role for a known pleiotropic locus at 2q35 and revealed an additional one at 8q22.1 associated to both BC and thyroid cancer. We also found two new pleiotropic loci at 14q32.33 and 17q21.31 that were associated to both TSH levels and BC risk. Enrichment analyses and evidence of regulatory signals also highlighted brain tissues and immune system as candidates for obtaining associations between BC and TSH levels. Overall, our study sheds light on the complex interplay between BC and thyroid traits and provides evidence of shared genetic risk between those conditions.

AB - Breast cancer (BC) risk is suspected to be linked to thyroid disorders, however observational studies exploring the association between BC and thyroid disorders gave conflicting results. We proposed an alternative approach by investigating the shared genetic risk factors between BC and several thyroid traits. We report a positive genetic correlation between BC and thyroxine (FT4) levels (corr = 0.13, p-value = 2.0 x 10-4) and a negative genetic correlation between BC and thyroid-stimulating hormone (TSH) levels (corr = -0.09, p-value = 0.03). These associations are more striking when restricting the analysis to estrogen receptor-positive BC. Moreover, the polygenic risk scores (PRS) for FT4 and hyperthyroidism are positively associated to BC risk (OR = 1.07, 95%CI: 1.00-1.13, p-value = 2.8 x 10-2 and OR = 1.04, 95%CI: 1.00-1.08, p-value = 3.8 x 10-2, respectively), while the PRS for TSH is inversely associated to BC risk (OR = 0.93, 95%CI: 0.89-0.97, p-value = 2.0 x 10-3). Using the PLACO method, we detected 49 loci associated to both BC and thyroid traits (p-value < 5 x 10-8), in the vicinity of 130 genes. An additional colocalization and gene-set enrichment analyses showed a convincing causal role for a known pleiotropic locus at 2q35 and revealed an additional one at 8q22.1 associated to both BC and thyroid cancer. We also found two new pleiotropic loci at 14q32.33 and 17q21.31 that were associated to both TSH levels and BC risk. Enrichment analyses and evidence of regulatory signals also highlighted brain tissues and immune system as candidates for obtaining associations between BC and TSH levels. Overall, our study sheds light on the complex interplay between BC and thyroid traits and provides evidence of shared genetic risk between those conditions.

KW - breast cancer

KW - thyroid cancer

KW - cross phenotype association

KW - pleiotropy

KW - thyroid traits

UR - http://www.scopus.com/inward/record.url?scp=85180414508&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddad159

DO - 10.1093/hmg/ddad159

M3 - Article

C2 - 37740403

SN - 0964-6906

VL - 33

SP - 38

EP - 47

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 1

ER -

Investigation of common genetic risk factors between thyroid traits and breast cancer

Abstract

Bibliographical note

Keywords

Access to Document

Other files and links

Fingerprint

Cite this