Extended Data Fig. 1: Overview of the analytic strategy and results from the investigation of breast cancer susceptibility variants in women of European descent.

Analyses included investigating for susceptibility variants for overall breast cancer (invasive, in-situ or unknown invasiveness) and for susceptibility variants accounting for tumor heterogeneity according to the estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and grade, and specifically investigating for variants that predispose for risk of the triple-negative subtype. 1) Genotyping data from two Illumina genome-wide custom arrays, the iCOGS and Oncoarray, and imputed to the 1000 Genomes Project (Phase 3). (2) Overall breast cancer (invasive, in-situ, or unknown invasiveness) analyses included 82 studies from the Breast Cancer Association Consortium (BCAC; 118,474 cases and 96,201 controls) and summary level data from 11 other breast cancer GWAS (14,910 cases and 17,588 controls; Supplementary Table 1). (3) Analyses accounting for tumor marker heterogeneity according to ER, PR, HER2 and grade included 81 studies from BCAC (106,278 invasive cases and 91,477 controls). (4) Analyses investigating triple-negative susceptibility variants included 91,477 controls and 8,602 triple-negative TN (effective sample, see Supplementary Note) cases from BCAC and 9,414 affected and 9,494 unaffected BRCA1/2 carriers from 60 studies from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA; Supplementary Table 3). (5) Variants excluded following conditional analyses showing the identified variants to not be independent (P>1x10-6) of 178 known susceptibility variants (see Methods). (6) See Supplementary Fig. 6 for results of country-specific sensitivity analyses. (7) See Supplementary Table 5 for the 22 independent susceptibility variants identified in overall breast cancer analyses. (8) See Supplementary Table 6 for the 16 independent susceptibility variants identified using two-stage polytomous regression, accounting for tumor markers heterogeneity according to ER, PR, HER2, and grade. Note that 8 of the 16 variants were also detected in the overall breast cancer analysis (9) See Supplementary Table 7 for the 3 independent susceptibility variants identified in the CIMBA/BCAC- triple-negative TN meta-analysis. Note that rs78378222 was detected in both the analyses using the two-stage polytomous regression and in CIMBA/BCAC- triple-negative TN.