For the potentially novel SNP modifiers the risk ratio of BC applicable to mutation carriers was assumed to be equal to the OR estimate from the case-only analysis (with the hypothesis that their relative risk equals 1 in the general population, given that none of them was found to be associated with BC in BCAC)55.

For the known BC susceptibility SNPs, a significant association in the case-only analysis implies that the magnitude of association is different for BRCA1 or BRCA2 mutation carriers than for the general population. Therefore, the risk ratio of BC for mutation carriers was computed as the product of OR × ORBCAC where OR was obtained from the case-only analysis, and ORBCAC was the odds ratio of association obtained from either Michailidou et al.35 for the SNPs associated with overall BC risk and from Milne et al.48 for the SNPs associated with ER-negative BC.

For all associated SNPs in case-only analyses, heterogeneity by country was assessed using likelihood ratio tests that compared models with and without an SNP by country interaction term. When the heterogeneity test was significant at P < 0.05, a leave-one-out analysis was performed, by excluding each country in turn to assess the influence of a data from a specific country on the overall association.

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