Colocalised genetic associations reveal alternative splicing variants as candidate causal links for breast cancer risk in 10 Loci

Simple Summary Hundreds of common genetic variants have been linked to breast cancer, but their exact mechanisms of action remain unclear. Understanding these mechanisms could lead to better prevention strategies and improved survival rates. Our study focused on how these variants influence splicing-a process by which a gene's coding elements are rearranged to produce different proteins. By analysing data from healthy breast tissue, we identified 43 variants within twelve genes associated with both alternative splicing and breast cancer risk. We then used advanced computational tools and existing experimental data to explore the biological significance of these findings.Abstract Genome-wide association studies (GWASs) have revealed numerous loci associated with breast cancer risk, yet the precise causal variants, their impact on molecular mechanisms, and the affected genes often remain elusive. We hypothesised that specific variants exert their influence by affecting cis-regulatory alternative splice elements. An analysis of splicing quantitative trait loci (sQTL) in healthy breast tissue from female individuals identified multiple variants linked to alterations in splicing ratios. Through colocalisation analysis, we pinpointed 43 variants within twelve genes that serve as candidate causal links between sQTL and GWAS findings. In silico splice analysis highlighted a potential mechanism for three genes-FDPS, SGCE, and MRPL11-where variants in proximity to or on the splice site modulate usage, resulting in alternative splice transcripts. Further in vitro/vivo studies are imperative to fully understand how these identified changes contribute to breast oncogenesis. Moreover, investigating their potential as biomarkers for breast cancer risk could enhance screening strategies and early detection methods for breast cancer.

POCI-01-0145-FEDER-022184; PTDC/MED-GEN/30895/2017; DL 57/2016/CP1361/CT0042;