SNPs and in the opposite direction for 4,750 SNPs. Assuming that SNPs with effects in opposite directions are not associated with risk, an estimated 1,168 loci selected from the GWAS are associated with risk. However, this is an underestimate because weakly associated SNPs might have effects in opposite directions in the two stages. As an alternative approach, we fitted the distribution of z scores for the iCOGS stage, aligned to the direction of the effect in the GWAS, as a mixture of two normal distributions representing those SNPs that were or were not associated with disease (Fig. 2 and Online Methods)58. On the basis of the posterior probabilities from this analysis, an estimated 92% of loci (n = 9,815) were associated with breast cancer risk (95% CI = 85–100%), and these contributed approximately 18% of the familial risk of breast cancer. It should be noted, however, that the large majority of the loci had very small individual effects on risk: for example, the estimated OR was >1.05 for only 10 loci, and 920 loci had an estimated OR of >1.02. When taking into account effects from the previously known loci, these analyses suggest that ~28% of familial risk is explained
