乳腺癌（BC）风险被怀疑与甲状腺疾病相关联，然而，观察性研究探讨了BC和甲状腺疾病之间的关联却得出了矛盾的结果。我们提出了一种替代方法，通过研究BC和几种甲状腺特征之间的共享遗传风险因素来探讨这种关联。我们报告了BC和甲状腺素（FT4）水平之间的正遗传相关（相关系数=0.13，p值=2.0x10-4），以及BC和促甲状腺激素（TSH）水平之间的负遗传相关（相关系数=-0.09，p值=0.03）。当限制分析范围为雌激素受体阳性BC时，这些关联更加明显。此外，对于FT4和甲状腺功能亢进的多基因风险评分（PRS），它们与BC风险呈正相关关系（OR=1.07，95%CI: 1.00-1.13，p值=2.8x10-2和OR=1.04，95%CI: 1.00-1.08，p值=3.8x10-2），而对于TSH的PRS则与BC风险呈负相关关系（OR=0.93，95%CI: 0.89-0.97，p值=2.0x10-3）。使用PLACO方法，我们检测到与BC和甲状腺特征（p值<5x10-8）相关的49个位点，在130个基因附近。额外的共定位和基因集富集分析显示了已知的2q35位置上的一个离散性位点的确凿因果作用，并且还发现了一个与BC和甲状腺癌相关的8q22.1位置上的额外离散性位点。我们还发现了两个与TSH水平和BC风险都相关的新的离散性位点，分别位于14q32.33和17q21.31位置。富集分析和调控信号的证据还突出了大脑组织和免疫系统作为获取BC与TSH水平之间关联的候选人。总体而言，我们的研究揭示了BC和甲状腺特征之间复杂的相互作用，并提供了这些疾病之间共享遗传风险的证据。© 作者 2023。由牛津大学出版。版权所有。如需获得权限，请发送电子邮件至：journals.permissions@oup.com。

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 = 2.0x10-4) 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 = 2.8x10-2 and OR = 1.04, 95%CI: 1.00-1.08, p-value = 3.8x10-2, respectively), while the PRS for TSH is inversely associated to bc risk (OR = 0.93, 95%CI: 0.89-0.97, p-value = 2.0x10-3). Using the PLACO method, we detected 49 loci associated to both bc and thyroid traits (p-value<5x10-8), 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.© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.