Major depressive disorder causally increases breast cancer risk with OR 1.27 (95% CI: 1.11-1.46, P=5.90×10⁻⁴) and significant shared genetic architecture.
Is there a shared genetic architecture and causal relationship between breast cancer and major depressive disorder?
There is a shared genetic basis between breast cancer and major depressive disorder, with MDD showing a causal effect on increased breast cancer risk.
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Abstract Background: An increasing body of epidemiological evidence has suggested that breast cancer (BC) and major depressive disorder (MDD) are frequently comorbid, with MDD being particularly prevalent among BC patients during diagnosis and treatment. However, whether this relationship reflects a shared genetic predisposition or a causal biological link remains unclear. Here, we aimed to comprehensively investigate the shared genetic architecture and potential causal associations between BC and MDD using large-scale genome-wide association study (GWAS) data. Methods: We obtained publicly available GWAS summary statistics for BC and MDD. First, linkage disequilibrium score regression (LDSC) was used to estimate the genome-wide genetic correlation between the two traits. To identify shared genetic variants (pleiotropic loci), we conducted multiple cross-trait GWAS analyses including multi-trait analysis of GWAS (MTAG), cross-phenotype association (CPASSOC), and pleiotropic analysis under composite null hypothesis (PLACO). We then functionally annotated PLACO-identified SNPs using Functional Mapping and Annotation (FUMA) to identify lead variants and genomic risk loci. Gene-level associations were further evaluated using MAGMA to uncover shared susceptibility genes. Finally, we used both Generalized Summary-data-based Mendelian Randomization (GSMR) and two-sample Mendelian Randomization (TSMR) approaches to assess the direction and magnitude of potential causal effects between MDD and BC. Results: LDSC revealed a significant positive genetic correlation between BC and MDD (rg = 0.0545, SE = 0.0151, P = 3.0 × 10-4), indicating a modest but meaningful shared genetic basis. MTAG analysis identified 17 pleiotropic SNPs reaching genome-wide significance. CPASSOC and PLACO analyses revealed 16,470 and 775 pleiotropic SNPs, respectively, suggesting widespread cross-trait genetic overlap. FUMA-based annotation of PLACO hits yielded 22 independent genomic loci and MAGMA further identified 130 pleiotropic genes, highlighting biological convergence between psychiatric and oncologic pathways. GSMR (OR = 1.27, 95% CI: 1.11-1.46, P = 5.90 × 10-4) and TSMR (OR = 1.12, 95% CI: 1.02-1.22, P = 1.43 × 10-2) demonstrated significant causal effects of MDD on increased BC risk. The sensitivity analysis suggested that the results of TSMR were not affected by horizontal pleiotropy (P = 0.75). Conclusions: Our study charted the shared genetic architecture between BC and MDD and explored their potential causal relationship. The findings enhanced the understanding of the genetic pathways commonly involved in both BC and MDD, highlighting their complex interconnections. This research provided valuable insights for experimental studies aimed at developing new preventive measures and therapeutic interventions for BC and MDD. Citation Format: Y. Lin, J. She, R. Zhao, Y. Zhang, A. Qiu, L. Zhang, Q. Yang. Charting the shared genetic architecture between breast cancer and major depressive disorder based on genome-wide association study abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-03-09.
Lin et al. (Tue,) reported a other. Major depressive disorder causally increases breast cancer risk with OR 1.27 (95% CI: 1.11-1.46, P=5.90×10⁻⁴) and significant shared genetic architecture.