primary genotype data were obtained for nine breast cancer gwas in populations of european ancestry ( supplementary table 6 ) . we excluded all individuals with low call rate ( < 95% ) , extreme high or low heterozygosity ( p<10 ) , and all individuals evaluated to be of non - european ancestry ( > 15% non - european component , by multidimensional scaling using the three hapmap2 populations as a reference ) . we excluded snps with : call rate < 95% ; call rate < 99% and maf<5% , all snps with maf<1% , and snps whose genotype frequencies departed from hardy - weinberg equilibrium at p<10 in controls or p<10 in cases . for highly significant snps the genotype intensity cluster plots were examined manually to judge reliability , either centrally or by contacting the original investigators . data were imputed for all scans for ~2.6 m snps using hapmap version 2 ceu as a reference , using the program mach v1.0 . estimated per - allele ors and standard errors were generated from the imputed genotypes using probabel . for two studies ( uk2 and hebcs ) , estimates were adjusted by the first three principal components , since this was found to materially reduce the inflation . residual inflation was then adjusted for by multiplying the variance by a genomic control adjustment factor , based on the ratio of the median chi - squared test statistic to its expected value . bbcs and uk2 used the same control data ( wtccc2 ) but different genotyping platforms . these studies were imputed separately . for the combined analysis , the control set was divided randomly between the two studies , in proportion to the size of case series , to provide disjoint strata . for a limited subset of snps that could not be imputed ( including rs2532348 and rs199523 on 17q21 ) , genotype data from the original scan(s ) snps for replication were genotyped in 46 studies , of which 4 were case - only studies that did not contribute to the current analysis ( supplementary table 7 ) . seven studies ( habcs , hmbcs , hubcs , karbac , rbcs , search and sebcs ) were analysed by fluidigm for 72 snps ( supplementary table 2 ) . we selected 63 snps selected from uk2 : one replaced by a better surrogate , and one failed , so only data were available for 61 snps . ten snps were selected from bbcs and one snp was selected from both scans ( the original snp , rs1975930 , also referred to as rs56003999 , did not work by fluidigm and in some iplex analyses and was replaced by a surrogate rs10771399 , r=0.95 , which was typed in all studies ) . samples from 27 studies were genotyped by iplex for 29 snps that showed the strongest associations . seven additional studies ( abcfs , cgps , mccs , nc - bcfr , ofbcr , pbcs , ukbgs ) were genotyped by taqman for up to 4 snps that showed association after the fluidigm and iplex genotyping , including all three 3 snps discussed in detail here . we restricted the analysis to individuals of european or east asian ancestry , since the sample size for other ethnicities was too small to give meaningful results . all studies complied with bcac genotyping qc standards by including at least 2% of samples in duplicate and a common set of 93 ceph dnas used by the hapmap consortium ( hapmappt01 , coriell institute for medical research , cambden , nj ) . genotype data were excluded for : any sample that consistently failed genotyping for > 20% of the snps typed ; all samples on any one plate that had a snp call rate < 90% ; all genotype data for any snp where overall call rate was < 95% ; and all genotype data for any snp where duplicate concordance was < 98% ( based on 2% of samples genotyped in duplicate ) . in addition , for any snp for which the p - value for departure from hardy - weinberg equilibrium for controls was < 0.005 , clustering of the intensity plots was reviewed manually and the data excluded if clustering was judged to be poor . after qc exclusions we analysed data on 54,588 cases of invasive breast cancer , 2,401 cases of dcis and 58,098 controls . per - allele and genotype - specific odds ratios for the replication stage were estimated using logistic regression , adjusted for study . nc - bcfr contributed cases and controls to both european and asian analyses ; for the remaining studies the subjects were either predominantly european or predominantly asian , and subjects from other minority ethnicities were excluded . statistical significance levels from the gwas and bcac replication phases were obtained by combining the logor estimates and standard errors as in a fixed effect meta - analysis . heterogeneity in the or association with each snp by er status was evaluated using a case - only analysis , by logistic regression . primary genotype data were obtained for nine breast cancer gwas in populations of european ancestry ( supplementary table 6 ) . we excluded all individuals with low call rate ( < 95% ) , extreme high or low heterozygosity ( p<10 ) , and all individuals evaluated to be of non - european ancestry ( > 15% non - european component , by multidimensional scaling using the three hapmap2 populations as a reference ) . we excluded snps with : call rate < 95% ; call rate < 99% and maf<5% , all snps with maf<1% , and snps whose genotype frequencies departed from hardy - weinberg equilibrium at p<10 in controls or p<10 in cases . for highly significant snps the genotype intensity cluster plots were examined manually to judge reliability , either centrally or by contacting the original investigators . data were imputed for all scans for ~2.6 m snps using hapmap version 2 ceu as a reference , using the program mach v1.0 . estimated per - allele ors and standard errors were generated from the imputed genotypes using probabel . for two studies ( uk2 and hebcs ) , estimates were adjusted by the first three principal components , since this was found to materially reduce the inflation . residual inflation was then adjusted for by multiplying the variance by a genomic control adjustment factor , based on the ratio of the median chi - squared test statistic to its expected value . bbcs and uk2 used the same control data ( wtccc2 ) but different genotyping platforms . these studies were imputed separately . for the combined analysis , the control set was divided randomly between the two studies , in proportion to the size of case series , to provide disjoint strata . for a limited subset of snps that could not be imputed ( including rs2532348 and rs199523 on 17q21 ) , genotype data from the original scan(s ) snps for replication were genotyped in 46 studies , of which 4 were case - only studies that did not contribute to the current analysis ( supplementary table 7 ) . seven studies ( habcs , hmbcs , hubcs , karbac , rbcs , search and sebcs ) were analysed by fluidigm for 72 snps ( supplementary table 2 ) . we selected 63 snps selected from uk2 : one replaced by a better surrogate , and one failed , so only data were available for 61 snps . ten snps were selected from bbcs and one snp was selected from both scans ( the original snp , rs1975930 , also referred to as rs56003999 , did not work by fluidigm and in some iplex analyses and was replaced by a surrogate rs10771399 , r=0.95 , which was typed in all studies ) . samples from 27 studies were genotyped by iplex for 29 snps that showed the strongest associations . seven additional studies ( abcfs , cgps , mccs , nc - bcfr , ofbcr , pbcs , ukbgs ) were genotyped by taqman for up to 4 snps that showed association after the fluidigm and iplex genotyping , including all three 3 snps discussed in detail here . we restricted the analysis to individuals of european or east asian ancestry , since the sample size for other ethnicities was too small to give meaningful results . all studies complied with bcac genotyping qc standards by including at least 2% of samples in duplicate and a common set of 93 ceph dnas used by the hapmap consortium ( hapmappt01 , coriell institute for medical research , cambden , nj ) . genotype data were excluded for : any sample that consistently failed genotyping for > 20% of the snps typed ; all samples on any one plate that had a snp call rate < 90% ; all genotype data for any snp where overall call rate was < 95% ; and all genotype data for any snp where duplicate concordance was < 98% ( based on 2% of samples genotyped in duplicate ) . in addition , for any snp for which the p - value for departure from hardy - weinberg equilibrium for controls was < 0.005 , clustering of the intensity plots was reviewed manually and the data excluded if clustering was judged to be poor . after qc exclusions we analysed data on 54,588 cases of invasive breast cancer , 2,401 cases of dcis and 58,098 controls . per - allele and genotype - specific odds ratios for the replication stage were estimated using logistic regression , adjusted for study . nc - bcfr contributed cases and controls to both european and asian analyses ; for the remaining studies the subjects were either predominantly european or predominantly asian , and subjects from other minority ethnicities were excluded . statistical significance levels from the gwas and bcac replication phases were obtained by combining the logor estimates and standard errors as in a fixed effect meta - analysis . heterogeneity in the or association with each snp by er status was evaluated using a case - only analysis , by logistic regression .
breast cancer is the most common cancer among women . to date , 22 common breast cancer susceptibility loci have been identified accounting for ~ 8% of the heritability of the disease . 
 we followed up 72 promising associations from two independent genome wide association studies ( gwas ) in ~70,000 cases and ~68,000 controls from 41 case - control studies and nine breast cancer gwas . 
 we identified three new breast cancer risk loci on 12p11 ( rs10771399 ; p=2.7  1035 ) , 12q24 ( rs1292011 ; p=4.31019 ) and 21q21 ( rs2823093 ; p=1.11012 ) . 
 snp rs10771399 was associated with similar relative risks for both estrogen receptor ( er)-negative and er - positive breast cancer , whereas the other two loci were associated only with er - positive disease . 
 two of the loci lie in regions that contain strong plausible candidate genes : pthlh ( 12p11 ) plays a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer , while nrip1 ( 21q21 ) encodes an er co - factor and has a role in the regulation of breast cancer cell growth .