Paris-Saclay University, UVSQ, Gustave Roussy, Inserm, CESP, Team "Exposome and Heredity", 94807 Villejuif, France.
Laboratoire de Mathématiques et de leurs Applications de Pau, Université de Pau et des Pays de l'Adour, UMR CNRS 5142, E2S-UPPA, 64013 Pau, France.
Hum Mol Genet. 2023 Dec 12;33(1):38-47. doi: 10.1093/hmg/ddad159.
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 × 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 × 10-2 and OR = 1.04, 95%CI: 1.00-1.08, p-value = 3.8 × 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 × 10-3). Using the PLACO method, we detected 49 loci associated to both BC and thyroid traits (p-value < 5 × 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.
乳腺癌（BC）风险被怀疑与甲状腺疾病有关，但探索 BC 与甲状腺疾病之间关联的观察性研究结果存在矛盾。我们通过研究 BC 和几种甲状腺特征之间的共同遗传风险因素，提出了一种替代方法。我们报告了 BC 与甲状腺素（FT4）水平之间存在正遗传相关性（corr=0.13，p 值=2.0×10-4），BC 与促甲状腺激素（TSH）水平之间存在负遗传相关性（corr=-0.09，p 值=0.03）。当将分析仅限于雌激素受体阳性 BC 时，这些关联更加明显。此外，FT4 和甲状腺功能亢进的多基因风险评分（PRS）与 BC 风险呈正相关（OR=1.07，95%CI：1.00-1.13，p 值=2.8×10-2 和 OR=1.04，95%CI：1.00-1.08，p 值=3.8×10-2），而 TSH 的 PRS 与 BC 风险呈负相关（OR=0.93，95%CI：0.89-0.97，p 值=2.0×10-3）。使用 PLACO 方法，我们在 130 个基因附近检测到 49 个与 BC 和甲状腺特征都相关的位点（p 值<5×10-8）。进一步的 colocalization 和基因集富集分析显示，在 2q35 附近的一个已知的多效性位点以及在 8q22.1 附近的一个新的多效性位点与 BC 和甲状腺癌都有关。我们还发现了两个新的多效性位点 14q32.33 和 17q21.31，它们与 TSH 水平和 BC 风险都有关。富集分析和调控信号的证据也突出了脑组织和免疫系统作为获得 BC 和 TSH 水平之间关联的候选者。总的来说，我们的研究揭示了 BC 和甲状腺特征之间的复杂相互作用，并提供了这些疾病之间存在共同遗传风险的证据。
