Comparative fine-mapping of breast cancer susceptibility loci using summary statistics methods and multinomial regression

Summary statistics fine-mapping methods offer advantages over classical methods, including avoiding data-sharing constraints and improved modelling of correlated variables and sparse effects. However, its performance has not been comprehensively evaluated in breast cancer using real-world data. Previous multinomial stepwise regression (MNR) fine-mapping analyses for breast cancer identified 196 credible sets. Here, we apply summary statistics fine-mapping, compare methods, and assess parameters influencing performance. Using summary statistics from the Breast Cancer Association Consortium, we compared finiMOM, SuSiE, and FINEMAP to published MNR results across 129 regions. Performance was assessed by recall using in-sample and out-of-sample LD. Discordant credible sets were examined for technical factors, and target genes were defined using the INQUISIT pipeline. SuSiE showed the closest agreement with MNR. Results varied across regions depending on the assumed number of causal variants (L), with higher values reducing recall and no single L maximising performance. At optimal L per region, SuSiE identified 8,192 CCVs in 244 credible sets, with recall of 88%, 86%, and 72% for overall, ER-positive, and ER-negative breast cancer. Thirty MNR sets were missed. Discordance was partially explained by allele flips, imputation quality, and array heterogeneity. Fifty-two MNR-identified genes, including BRCA2, WNT7B and CREBBP were not recovered, while additional candidate genes were identified. Using out-of-sample LD reduced recall by 3% but identified novel variants. Fine-mapping results vary across methods, and no single approach is sufficient. The choice of L strongly influences results, and combining analytical approaches with functional validation can improve causal variant identification.