Abstract PS3-02-05: Shared Genetic Architecture between Breast Cancer and Psychiatric Disorders: Insights from Large-Scale Genome-wide Cross-trait Analysis

Abstract Background: Breast cancer (BC) has been associated with psychiatric disorders. However, the shared genetic determinants underlying these associations remain unevaluated. This study aims to investigate the shared genetic architecture between psychiatric disorders and BC, and to identify the involved shared risk loci, potential key tissues, and underlying genetic mechanisms. Methods: Based on the summary statistics from genome-wide association studies (GWAS), the genetic correlation and overlap between psychiatric disorders and BC were investigated. Furthermore, shared pleiotropic loci and genes were identified through cross-trait analyses. Additionally, a series of functional annotations and tissue-specific enrichments were performed to determine potential associations between each trait pair. Pathway enrichment analysis was conducted to assess possible associated mechanisms. Finally, the causal relationship at the protein level was also evaluated. Results: The results demonstrated shared genetic mechanisms between eight psychiatric disorders and two BC subtypes. After Bonferroni correction,4 of the 16 trait pairs exhibited significant genetic correlations (p < 3.13 × 10-3). A total of 7,274 SNPs were identified at a genome-wide significance threshold of p < 5. 00 × 10-8 threshold. Furthermore, annotation analysis identified 156 genomic risk loci, of which 19 were analyzed using causal colocalization. Gene-level analysis revealed a series of pleiotropic genes, with MTRFA and FGFR2 being identified in the majority of trait pairs. Tissue enrichment analysis indicated that pleiotropic mechanisms play a significant role in the ovary, breast mammary tissue, uterus, and certain brain regions, including the caudate nucleus, cerebellar hemisphere, and putamen. Pathway analysis showed that most trait pairs were enriched for positive regulation of RNA metabolism. Additionally, protein-level causal correlation analysis identified 5 proteins significantly associated with BC risk and 36 proteins significantly associated with the risk of psychiatric disorders. Conclusion: This study explored the shared genetic architecture between psychiatric disorders and BC and identified several potential genetic mechanisms that are critical for the development of novel therapeutic strategies in clinical practice. Citation Format: C. Wang, L. Jing, Y. Lei, Y. Zhang, X. Wang, Y. Wang, H. Jia. Shared Genetic Architecture between Breast Cancer and Psychiatric Disorders: Insights from Large-Scale Genome-wide Cross-trait Analysis [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 PS3-02-05.