Figshare · Apr 10, 2026
Integrative TWAS of a Large Breast Cancer GWAS Reveals Subtype-Specific NAD+ Homeostasis, Senescence, and Apoptosis Pathways
By Cheung N
Breast cancer is molecularly heterogeneous, but most genome-wide association studies have long treated it as a single disease. Zhang et al. (2020) moved beyond that limitation by applying a two-stage polytomous regression model to summary statistics from 133,384 cases and 113,789 controls, while accounting for correlations among estrogen receptor, progesterone receptor, HER2, and grade. That analysis identified 32 novel susceptibility loci, including 15 with significant heterogeneity across tumor features and 5 with opposite-direction effects between luminal-like and triple-negative disease. Candidate causal variants at those opposite-direction loci overlapped cell-type-specific enhancers whose activity differs between basal and luminal mammary cells.Using those summary statistics, we carried out a multi-tissue transcriptome-wide association study with S-PrediXcan and GTEx v8 cis-eQTL models from breast mammary tissue, spleen, visceral adipose, uterus, and whole blood. Cross-tissue signals were combined with Stouffer’s method, and pathway-level significance was assessed with 10,000 label-swapping permutations. The resulting patterns were strongly subtype specific. NAD+-binding and NAD+ metabolism gene sets were enriched in overall breast cancer but not in triple-negative breast cancer, with GOMF NADPLUS BINDING ALL showing a meta-Z of +7.63 and a permutation P value of 0.019, and WP NAD METABOLISM ALL showing a meta-Z of +6.22 and a permutation P value of 0.047. Senescence-related genes followed the same overall pattern, with REACTOME SENESCENCE ALL enriched in overall disease, with a meta-Z of +6.60 and a permutation P value of 0.030, but showing a negative trend in triple-negative disease. By contrast, BCL-2 family apoptosis complexes were enriched only in triple-negative breast cancer, where GOCC BCL 2 FAMILY PROTEIN COMPLEX ALL reached a meta-Z of +6.40 and a permutation P value of 0.034. Triple-negative disease also showed positive trends in mitochondrial and oxidative phosphorylation pathways.These findings fit closely with the subtype heterogeneity reported by Zhang et al. (2020). Taken together, the data suggest that common susceptibility variants may shape luminal and triple-negative risk through partly distinct metabolic, senescence, and apoptotic programs. The results are correlative and still need functional validation, but they point to coherent biological axes that may be useful for subtype-specific risk modeling and, eventually, more targeted prevention and treatment strategies.