Neuro-Genetic Mechanisms Connecting Brain Structure to Breast Cancer

Abstract Background: Breast cancer incidence has continued to rise over recent decades. Beyond established genetic and hormonal factors, neuropsychiatric conditions including depression, anxiety, and sleep disturbances, have emerged as independent risk factors. Brain structure, as a core neuroendocrine substrate, may share genetic determinants with breast cancer risk; however, this relationship remains insufficiently characterized. Objective: This study investigated the potential genetic correlations between brain imaging-derived phenotypes (IDPs) and breast cancer using genome-wide association study (GWAS) summary statistics via Mendelian randomization (MR) analysis. We hypothesized that shared genetic architecture between neuropsychiatric traits and breast cancer may reveal previously unrecognized biological pathways. Methods: We conducted MR analysis to systematically evaluate potential causal associations between 4,013 IDPs and 14 breast cancer (BC) traits, encompassing overall BC and molecular subtypes. Genetic instruments for IDPs were obtained from the UK Biobank and ENIGMA consortium. Summary-level BC data were sourced from IEU OpenGWAS, FinnGen, and the GWAS Catalog, covering European and African ancestry populations. A combined multi-ancestry linkage disequilibrium (LD) reference panel was constructed to optimize instrument clumping. The inverse-variance weighted (IVW) method served as the primary analysis, supported by sensitivity tests and colocalization to assess robustness and identify shared causal loci. Results: Temporal lobe structure demonstrated the strongest causal associations with estrogen receptor-positive (ER+) breast cancer. Within this region, the fusiform gyrus showed the most consistent negative causal effects across European ancestry datasets: right fusiform volume (IDP: GCST90002807, P -value = 2.23×10 -7 ), right fusiform surface area (IDP: GCST90003180, P -value = 1.11×10 -6 ), and left fusiform surface area (IDP: GCST90003079, P -value = 5.23×10 -6 ). Cross-ancestry analyses highlighted substantial population heterogeneity, as associations identified in European cohorts were not replicated in African ancestry datasets. Colocalization further localized shared genetic signals to chromosomes 17 and 12, implicating genes such as ARL17B and NSFP1 , which are enriched in pathways related to intracellular vesicular transport and membrane dynamics. Conclusion: Our findings reveal a causal relationship between brain structure and breast cancer risk, identifying the fusiform gyrus as a key region associated with ER+ BC. The study uncovers a shared genetic basis underlying this brain-breast axis, centered on genes involved in vesicular transport and membrane regulation. These insights suggest that neural processes may contribute to cancer susceptibility and provide new directions for biomarker development and mechanistic research.