Cross-tissue transcriptome-wide association and Mendelian randomization identify RALB as a susceptibility gene for breast hypertrophy

Breast hypertrophy is a pathological condition characterized by abnormal enlargement of the breasts due to excessive glandular and adipose tissue proliferation. It is associated with physical discomfort and reduced quality of life. However, its underlying genetic basis remains largely unexplored. We conducted a cross-tissue transcriptome-wide association study (TWAS) using the UTMOST framework, integrating expression quantitative trait locus data from GTEx and GWAS summary statistics from the FinnGen database (7272 cases, 258,508 controls). Additional validation was performed using single-tissue TWAS (FUSION), gene-level association testing (Multi-marker Analysis of GenoMic Annotation (MAGMA)), fine-mapping (FOCUS), and conditional and joint analyses. Key candidate genes were subjected to Mendelian randomization (MR) and Bayesian colocalization analyses to investigate causality. A total of 44 genes were significantly associated with breast hypertrophy in cross-tissue TWAS (false discovery rate < 0.05), and 4 were replicated in whole blood via FUSION. Fine-mapping identified RAS Like Proto-Oncogene B (RALB) as the most probable causal gene (PIP = 0.98), supported by MAGMA, conditional analyses, and colocalization (PPH4 = 0.922). Mendelian randomization confirmed a significant causal relationship between elevated RALB expression and increased risk of breast hypertrophy (odds ratio = 1.26; 95% confidence interval: 1.17-1.35; P < .001). Our integrative genomic analyses identified RALB as a robust susceptibility gene for breast hypertrophy. These findings provide novel insights into the genetic etiology of breast hypertrophy and may facilitate future development of molecular diagnostics or targeted therapies.