text:
Fine-mapping of breast cancer susceptibility loci characterizes genetic risk in African Americans.
Fang Chen, Gary K Chen, Robert C Millikan, Esther M John, Christine B Ambrosone, Leslie Bernstein, Wei Zheng, Jennifer J Hu, Regina G Ziegler, Sandra L Deming, Elisa V Bandera, Sarah Nyante, Julie R Palmer, Timothy R Rebbeck, Sue A Ingles, Michael F Press, Jorge L Rodriguez-Gil, Stephen J Chanock, Loïc Le Marchand, Laurence N Kolonel, Brian E Henderson, Daniel O Stram, Christopher A Haiman
ABSTRACT Genome-wide association studies (GWAS) have revealed 19 common genetic variants that are associated with breast cancer risk. Testing of the index signals found through GWAS and fine-mapping of each locus in diverse populations will be necessary for characterizing the role of these risk regions in contributing to inherited susceptibility. In this large study of breast cancer in African-American women (3016 cases and 2745 controls), we tested the 19 known risk variants identified by GWAS and replicated associations (P < 0.05) with only 4 variants. Through fine-mapping, we identified markers in four regions that better capture the association with breast cancer risk in African Americans as defined by the index signal (2q35, 5q11, 10q26 and 19p13). We also identified statistically significant associations with markers in four separate regions (8q24, 10q22, 11q13 and 16q12) that are independent of the index signals and may represent putative novel risk variants. In aggregate, the more informative markers found in the study enhance the association of these risk regions with breast cancer in African Americans [per allele odds ratio (OR) = 1.18, P = 2.8 × 10(-24) versus OR = 1.04, P = 6.1 × 10(-5)]. In this detailed analysis of the known breast cancer risk loci, we have validated and improved upon markers of risk that better characterize their association with breast cancer in women of African ancestry.
- Douglas F Easton, Karen A Pooley, Alison M Dunning, Georgia Chenevix-Trench, Amanda B Spurdle, Jonathan Beesley, Xiaoqing Chen, Melissa Brown, Margaret Cummings, Sunil Lakhani, et al, SEARCH Collaborators, kConFab, AOCS Management Group01/2007;
- SourceAvailable from: Qiuyin Cai
Article: Genome-wide association study identifies a new breast cancer susceptibility locus at 6q25.1.
Wei Zheng, Jirong Long, Yu-Tang Gao, Chun Li, Ying Zheng, Yong-Bin Xiang, Wanqing Wen, Shawn Levy, Sandra L Deming, Jonathan L Haines, Kai Gu, Alecia Malin Fair, Qiuyin Cai, Wei Lu, Xiao-Ou Shu[show abstract] [hide abstract]
ABSTRACT: We carried out a genome-wide association study among Chinese women to identify risk variants for breast cancer. After analyzing 607,728 SNPs in 1,505 cases and 1,522 controls, we selected 29 SNPs for a fast-track replication in an independent set of 1,554 cases and 1,576 controls. We further investigated four replicated loci in a third set of samples comprising 3,472 cases and 900 controls. SNP rs2046210 at 6q25.1, located upstream of the gene encoding estrogen receptor alpha (ESR1), showed strong and consistent association with breast cancer across all three stages. Adjusted odds ratio (95% CI) were 1.36 (1.24-1.49) and 1.59 (1.40-1.82), respectively, for genotypes A/G and A/A versus G/G (P for trend 2.0 x 10(-15)) in the pooled analysis of samples from all three stages. We also found a similar, albeit weaker, association in an independent study comprising 1,591 cases and 1,466 controls of European ancestry (P(trend) = 0.01). These results strongly implicate 6q25.1 as a susceptibility locus for breast cancer.Nature Genetics 04/2009; 41(3):324-8. · 35.21 Impact Factor - C. Turnbull, S. Ahmed, J. Morrison, D. Pernet, A. Renwick, M. Maranian, S. Seal, M. Ghoussaini, S. Hines, C.S. Healey, [......], M. Schutte, Ouweland A. van den, R. Houlston, G. Ross, C. Langford, P.D. Pharoah, M.R. Stratton, A.M. Dunning, N. Rahman, D.F. Easton[show abstract] [hide abstract]
ABSTRACT: Breast cancer is the most common cancer in women in developed countries. To identify common breast cancer susceptibility alleles, we conducted a genome-wide association study in which 582,886 SNPs were genotyped in 3,659 cases with a family history of the disease and 4,897 controls. Promising associations were evaluated in a second stage, comprising 12,576 cases and 12,223 controls. We identified five new susceptibility loci, on chromosomes 9, 10 and 11 (P = 4.6 x 10(-7) to P = 3.2 x 10(-15)). We also identified SNPs in the 6q25.1 (rs3757318, P = 2.9 x 10(-6)), 8q24 (rs1562430, P = 5.8 x 10(-7)) and LSP1 (rs909116, P = 7.3 x 10(-7)) regions that showed more significant association with risk than those reported previously. Previously identified breast cancer susceptibility loci were also found to show larger effect sizes in this study of familial breast cancer cases than in previous population-based studies, consistent with polygenic susceptibility to the diseaseNat.Genet. 01/2010; 42(6):504-507.
Page 1
Fine-mapping of breast cancer susceptibility loci
characterizes genetic risk in African Americans
Fang Chen1, Gary K. Chen1, Robert C. Millikan3, Esther M. John4,5, Christine B. Ambrosone6,
Leslie Bernstein7, Wei Zheng8, Jennifer J. Hu9, Regina G. Ziegler10, Sandra L. Deming8,
Elisa V. Bandera11, Sarah Nyante3, Julie R. Palmer12, Timothy R. Rebbeck13, Sue A. Ingles1,
Michael F. Press2, Jorge L. Rodriguez-Gil9, Stephen J. Chanock10, Loı ¨c Le Marchand14,
Laurence N. Kolonel14, Brian E. Henderson1, Daniel O. Stram1and Christopher A. Haiman1,∗
1Department of Preventive Medicine and2Department of Pathology, Keck School of Medicine and Norris
Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA,3Department of
Epidemiology, Gillings School of Global Public Health, and Lineberger Comprehensive Cancer Center, University of
North Carolina, Chapel Hill, NC, USA,4Northern California Cancer Center, Fremont, CA, USA,5Stanford University
School of Medicine and Stanford Cancer Center, Stanford, CA, USA,6Department of Cancer Prevention and
Control, Roswell Park Cancer Institute, Buffalo, NY, USA,7Division of Cancer Etiology, Department of Population
Science, Beckman Research Institute, City of Hope, CA, USA,8Division of Epidemiology, Department of Medicine,
Vanderbilt Epidemiology Center, and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine,
Nashville, TN, USA,9Department of Epidemiology and Public Health, and Sylvester Comprehensive Cancer Center,
University of Miami Miller School of Medicine, Miami, FL, USA,10Division of Cancer Epidemiology and Genetics,
National Cancer Institute, Bethesda, MD, USA,11The Cancer Institute of New Jersey, New Brunswick, NJ, USA,
12Slone Epidemiology Center at Boston University, Boston, MA, USA,13University of Pennsylvania School of
Medicine, Philadelphia, PA, USA and14Epidemiology Program, Cancer Research Center, University of Hawaii,
Honolulu, HI, USA
Received May 4, 2011; Revised July 15, 2011; Accepted August 15, 2011
Genome-wide association studies (GWAS) have revealed 19 common genetic variants that are associated with
populations will be necessary for characterizing the role of these risk regions in contributing to inherited
susceptibility. In this large study of breast cancer in African-American women (3016 cases and 2745 controls),
we tested the 19 known risk variants identified by GWAS and replicated associations (P < 0.05) with only 4
variants. Through fine-mapping, we identified markers in four regions that better capture the association
with breast cancer risk in African Americans as defined by the index signal (2q35, 5q11, 10q26 and 19p13).
We also identified statistically significant associations with markers in four separate regions (8q24, 10q22,
11q13 and 16q12) that are independent of the index signals and may represent putative novel risk variants.
In aggregate, the more informative markers found in the study enhance the association of these risk regions
with breast cancer in African Americans [per allele odds ratio (OR) 5 1.18, P 5 2.8 3 10224versus OR 5
1.04, P 5 6.1 3 1025]. In this detailed analysis of the known breast cancer risk loci, we have validated and
improved upon markers of risk that better characterize their association with breast cancer in women of
African ancestry.
∗To whom correspondence should be addressed at: Harlyne Norris Research Tower, 1450 Biggy Street, Room 1504, Los Angeles, CA 90033, USA,
Tel: +1 3234427755; Fax: +1 3234427749; E-mail: email@example.com
# The Author 2011. Published by Oxford University Press. All rights reserved.
For Permissions, please email: email@example.com
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Genome-wide association studies (GWAS) of breast cancer
have identified at least 19 chromosomal regions that harbor
common alleles that contribute to genetic susceptibility
(1–10). These discoveries have allowed for improved under-
standing of genetic risk for this common cancer, although it
is argued that many more markers will be needed to elucidate
disease heritability, and in the clinical setting for disease pre-
diction (11–13). Except for the breast cancer risk locus at
6q25 identified in a GWAS of Chinese women, the risk loci
for breast cancer have been revealed in studies in women of
European ancestry. We have recently shown in a multiethnic
study that a summary score comprised of the index variants
at many of these risk loci is statistically significantly asso-
ciated with breast cancer risk in multiple populations [odds
ratio (OR) per allele of .1.10], but not in African Americans
(14). Similar studies in African-American women have also
reported lack of replication with many of the reported index
signals (15–17). Limited statistical power of these initial
reports as well as variation in both allele frequency and pat-
terns of linkage disequilibrium (LD) across populations may
be contributing factors as to why the associations found in
the GWAS populations may not be generalizable to African
Americans. Association testing of the risk variants as well as
fine-mapping in a sufficiently large sample of African Amer-
icans will be needed to identify and localize the subset of
markers that best define risk of the functional allele(s)
within known risk regions.
In the present study, we tested common genetic variation at
the breast cancer risk loci identified in women of European
and Asian descent in a large sample comprised of 3016
African-American breast cancer cases and 2745 controls to
identify markers of risk that are relevant to this population.
More specifically, we examined the index variants and con-
ducted fine-mapping of the locus to both improve the current
set of risk markers in African Americans as well as to identify
new risk variants for breast cancer. We then applied this infor-
mation to model breast cancer risk in African-American
women in an attempt to characterize the spectrum of genetic
risk in this population defined by common variants at the
known risk loci.
The ages of cases and controls ranged from 22 to 87 years and
23 to 86 years, respectively, with cases and controls having
similar mean ages (55 and 58 years, respectively; Supplemen-
tary Material, Table S1).
We tested 19 validated breast cancer risk variants (referred
to as 'index variants' throughout the paper) at 1p11, 2q35,
3p24, 5p12, 5q11, 6q25, 8q24, 9p21, 9q31, 10p15, 10q21,
10q22, 10q26, 11p15, 11q13, 14q24, 16q12, 17q23 and
19p13 in models adjusted for age, study, global ancestry (the
first 10 eigenvectors) and local ancestry (Table 1; Supplemen-
tary Material, Table S2) (1–10); 17 SNPs were directly geno-
typed, whereas 2 were imputed (r2. 0.98; see Materials and
Methods). All 19 variants were common (≥0.05) in African
Americans, with 11 variants being more common in
Europeans than in African Americans (Table 1, Fig. 1). In
previous GWAS, the index signals had modest ORs (1.05–
1.29 per copy of the risk allele) and our sample size provided
≥70% statistical power to detect the reported effects for 12 of
the 19 variants (at P , 0.05; Supplementary Material,
Table S2).
We observed positive associations with 11 of the 19 variants
(OR . 1); however, only 4 were statistically significant
(P , 0.05 at 2q35, 9q31, 10q26 and 19p13; Table 1). Of the
15 variants that were not replicated at P , 0.05, statistical
power was ,70% for only 7 of the variants. Although
power was more limited, we also evaluated associations by
estrogen receptor (ER) status as some risk variants have
been found to be more strongly associated with ER-positive
(ER+) or ER-negative (ER2) breast cancer (2,18). We
observed positive associations with 12 variants (2 at
P , 0.05) for ER+ disease (n ¼ 1520) and with 9 variants
for ER2 (3 at P , 0.05; n ¼ 988) (Supplementary Material,
Table S3). For only one variant did we observe statistically
significant risk heterogeneity by ER status (rs13387042 at
2q35, P ¼ 0.013) (Supplementary Material, Table S3).
Local ancestry was included in all models, as it was found
to be associated with breast cancer risk in many regions (Sup-
plementary Material, Table S4). We observed nominally sig-
nificant associations between local ancestry and overall
breast cancer, ER+ or ER2 disease risk at 5 loci (5p12,
6q25, 8q24, 10p15, 10q26). The most statistically significant
association was between European ancestry and ER+ breast
cancer risk at 6q25 (OR per European allele chromosome ¼
1.19, P ¼ 6.2 × 1023). The inverse association observed
between European ancestry and ER+ disease risk at 10q26
(OR per European chromosome ¼ 0.85, P ¼ 0.011) is consist-
ent with previous reports of over-representation of African
ancestry at this locus in many of these same cases (19,20).
Aside from statistical power, the lack of a statistically
significant association with an index variant (OR . 1 and
P , 0.05) suggests that the particular variant revealed in the
GWAS populations may not be adequately correlated with
the biologically relevant allele in African Americans. In an
attempt to identify a better genetic marker of risk in African
Americans, we conducted fine-mapping across all risk
regions, using genotyped SNPs on the Illumina 1M array
and imputed SNPs to Phase 2 HapMap populations (see
Materials and Methods). If a marker associated with risk in
African Americans represents the same signal as that reported
in the initial GWAS, then it should be correlated to some
degree with the index signal in the GWAS population.
Using HapMap data for the populations in which the risk
variant was identified [Utah residents with ancestry from
northern and western Europe (CEU), or Han Chinese in
Beijing, China (CHB)], we catalogued and tested all SNPs
that were correlated (r2≥ 0.2) with the index signal (within
250 kb), applying an aaof 3.2 × 1023which was estimated
to be 0.05 divided by the average number of tags needed to
capture (r2≥ 0.8) the common risk alleles correlated with
the index allele in each region in the Yoruba HapMap popula-
tion [in Ibadan, Nigeria (YRI); Supplementary Material,
Table S5]. We also tested for novel independent associations,
focusing on SNPs that were uncorrelated with the index signal
in the initial GWAS populations. Here, we applied a Bonfer-
roni correction for defining novel associations as statistically
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Table 1. Associations with common variants at known breast cancer risk regions in African Americans
Chr., nearest genesIndex SNP from GWAS (3016 cases, 2745 controls)
Marker, position, alleles
Best marker in African Americans (3016 cases, 2745 controls)
Marker, position, alleles
RAF in CEU/AAa, OR (95% CI),
RAF in CEU/AAa, OR (95% CI),
Ptrendfrom stepwise analysis
r2with index in
3p24, NEK10
5p12, MRPS30
5q11, MAP3K1
6q25, C6orf97
9p21, CDKN2B
10p15, ANKRD16
10q21, ZNF365
10q22, ZMIZ1
10q26, FGFR2
11p15, LSP1
14q24, RAD51L1
16q12, TNRC9
17q23, COX11
19p13, ANKLE1
rs11249433, 120982136, G/A
rs13387042, 217614077, A/G
rs4973768, 27391017, T/C
rs4415084, 44698272, T/C
rs889312, 56067641, C/A
rs2046210c,d, 151990059, A/G
rs13281615, 128424800, G/A
rs1011970, 22052134, T/G
rs865686, 109928199, T/G
rs2380205, 5926740, C/T
rs10995190, 63948688, G/A
rs704010, 80511154, T/C
rs2981582, 123342307, A/G
rs3817198, 1865582, C/T
rs614367, 69037945, T/C
rs999737, 68104435, T/C
rs3803662, 51143842, A/G
rs6504950c, 50411470, G/A
rs2363956, 17255124, T/G
0.43/0.13, 1.01 (0.90–1.14), 0.84
0.56/0.72, 1.12 (1.03–1.21), 7.5 × 1023
0.44/0.36, 1.04 (0.96–1.13), 0.32
0.38/0.63, 1.02 (0.95–1.11), 0.54
0.30/0.34, 1.07 (0.99–1.18), 0.084
0.38/0.60, 1.00 (0.93–1.09), 0.88
0.45/0.43, 1.05 (0.97–1.13), 0.20
0.17/0.33, 1.05 (0.97–1.14), 0.24
0.61/0.52, 1.08 (1.01–1.17), 0.034
0.52/0.42, 0.98 (0.91–1.06), 0.60
0.87/0.83, 0.97 (0.88–1.08), 0.57
0.43/0.11, 0.99 (0.87–1.12), 0.83
0.46/0.46, 1.11 (1.03–1.19), 8.6 × 1023
0.33/0.17, 0.98 (0.88–1.08), 0.63
0.18/0.13, 0.96 (0.86–1.07), 0.45
0.26/0.051, 0.98 (0.82–1.17), 0.80
0.25/0.51, 0.99 (0.92–1.08), 0.85
0.70/0.66, 1.05 (0.97–1.14), 0.19
0.45/0.49, 1.14 (1.05–1.22), 8.0 × 1024
rs13000023c, 217632639, G/A 0.82/0.83, 1.20 (1.09–1.33), 5.8 × 1024
rs16886165, 56058840, G/T 0.16/0.31, 1.15 (1.06–1.25), 6.5 × 1024
rs12355688, 80725632, T/C
rs2981578c, 123330301, C/T
0.090/0.20, 1.24 (1.13–1.36), 6.8 × 1026
0.46/0.81, 1.24 (1.11–1.39), 1.7 × 1024
1.00/0.59, 1.20 (1.11–1.30), 1.0 × 1025
0.020/0.20, 1.18 (1.08–1.30), 3.9 × 1024
0.52/0.75, 1.20 (1.10–1.32), 3.7 × 1025
rs609275c, 69112096, C/TNA/,0.01
rs3112572, 51157948, A/G
rs3745185, 17245267, G/A 0.57/0.19
SNP positions are based on NCBI build 36.
ORs are per allele odds ratios adjusted for age, study, the first 10 eigenvectors and local ancestry at each risk locus.
Ptrendvalues are based on test of trend (1 d.f.).
aRAF, risk allele frequencies in the original GWAS population (HapMap CEU, or CHB for rs2046210) and AA (African American) controls in this study. Risk allele is the allele associated with increased risk
in previous GWAS.
bPairwise correlations (r2) between the index signal and the best marker are from the CEU (CHB for rs2046210) and YRI populations in the 1000 Genomes Project (March 2010 release).
cImputed SNPs.
dIndex signal reported in Han Chinese. RAFs based on HapMap CHB and r2based on CHB in the 1000 Genomes Project (March 2010 release).
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significant in each region, with abestimated to be 0.05 divided
by the total number of tags needed to capture (r2≥ 0.8) all
common risk alleles in the 19 regions in the YRI population
(ab¼ 1.0 × 1025; similar to the genome-wide-type correction
of 5 × 1028, which accounts for the number of tags needed to
capture all common alleles in the genome; Supplementary Ma-
terial, Table S5). For each region, stepwise logistic regression
was used with SNPs kept in the final model based on aaor ab
(results for each model are provided in Supplementary Mater-
ial, Tables S6 and S7). These procedures were applied to all
cases and controls as well as in hypothesis-generating analyses
stratified by ER status.
At nine loci, we detected variants that were statistically sig-
nificantly associated with breast cancer risk in African
Americans. These regions include 9q31, where the sole
marker of risk was the index signal (rs865686: OR ¼ 1.08,
P ¼ 0.034; Table 1). In five of these nine regions, the index
marker itself was not statistically significantly associated
with disease risk. Through fine-mapping, we revealed
markers in four regions that were more significantly associated
with risk than the index signal (.1 order of magnitude change
in the P-value) and are likely to capture the same signal (2q35,
5q11, 10q26 and 19p13). We also identified markers in four
regions that are not correlated with the index signal in the
GWAS populations (8q24, 10q22, 11q13 and 16q12) and
may represent putative novel risk variants, with one being spe-
cific for ER+ disease (8q24) (Table 1, Fig. 2 and Supplemen-
tary Material, Table S8). These regions are discussed in what
Risk variants that better define the index signal
in African Americans
2q35. The index signal at 2q35 was statistically significantly
associated with risk of overall breast cancer (rs13387042:
OR ¼ 1.12, P ¼ 7.5 × 1023; Table 1) and ER+ disease
P ¼ 2.6 × 1024; SupplementaryMaterial,
Table S3). However, we found stronger associations with
two markers that are each modestly correlated with the
index signal in CEU and YRI: rs13000023 with overall
breast cancer (OR ¼ 1.20, P ¼ 5.8 × 1024) and rs12998806
with ER+ disease (OR ¼ 1.39, P ¼ 3.3 × 1026) (Table 1
and Supplementary Material, Table S8). As shown in Supple-
mentary Material, Figure S1, the signal in this region appeared
limited to ER+ breast cancer, which is consistent with the
initial report of this risk locus (2) but not with subsequent
large-scale replication efforts in European populations (21).
5q11. We found a positive non-significant association with the
index signal at 5q11, which is located 79 kb centromeric of the
MAP3K1 gene (rs889312: OR ¼ 1.07, P ¼ 0.084; Table 1).
Fine-mapping revealed statistically significant associations
with markers, rs16886165 for overall breast cancer (OR ¼
1.15, P ¼ 6.5 × 1024) and rs832529 for ER2 disease
(OR ¼ 1.22, P ¼ 1.3 × 1023; Table 1 and Supplementary Ma-
terial, Table S8). These SNPs show greater correlation with
the index signal in Europeans (CEU, r2¼ 0.40 and 0.46)
than in Africans (YRI, r2, 0.01 and r2¼ 0.09), which
suggests that they may be better markers of the biologically
functional variant in African Americans (Table 1, Fig. 2).
10q26. Both the index signal, rs2981582 (OR ¼ 1.11,
P ¼ 8.6 × 1023; Table 1) and rs2981578, which was identified
previously through fine-mapping in African Americans (which
some of these studies contributed to) (22), were statistically
significantly associated with risk (OR ¼ 1.24, P ¼ 1.7 ×
1024, Table 1). Variant rs2981578 was the most strongly asso-
ciated marker in the region for overall breast cancer and for
ER+ disease, which is consistent with previous reports of
variation in this region being more strongly associated with
ER+ breast cancer (Supplementary Material, Table S8) (18).
In fine-mapping the locus, we observed a suggestive associ-
ation with a correlated marker and ER2 disease (rs2912774:
OR ¼ 1.19, P ¼ 2.1 × 1023; Supplementary Material, Table
Figure 1. RAFs in Europeans and African Americans. The distribution of RAFs for the 19 index SNPs (from Table 1) in HapMap CEU (CHB for rs2046210)
and African Americans (AA). The variants are sorted based on the RAF in the GWAS population.
4494Human Molecular Genetics, 2011, Vol. 20, No. 22
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Figure 2. –Log P plots for common alleles at eight breast cancer risk loci in African Americans. –Log P-values for risk-associated alleles in African Americans
from logistic regression models adjusted for age, study, global ancestry (the first 10 eigenvectors) and local ancestry. P-values are for overall breast cancer risk
except for 8q24, which is for ER+ breast cancer. Pairwise correlations (r2) in the HapMap CEU population are shown in relation to markers identified through
fine-mapping in African Americans (diamond), except for 11q13, where r2is shown in HapMap YRI as the marker is monomorphic in CEU. Squares denote
genotyped SNPs; circles, imputed SNPs. Gray squares and circles denote that r2cannot be estimated (not in HapMap or monomorphic in CEU). Red
arrows denote markers identified in African Americans; yellow arrows, GWAS index variants. Each panel shows a –log P plot for common alleles for
regions: (A) 2q35; (B) 5q11; (C) 8q24; (D) 10q22; (E)10q26; (F) 11q13; (G) 16q12; (H) 19p13. The plots were generated using LocusZoom (55).
Human Molecular Genetics, 2011, Vol. 20, No. 224495
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S8); however, the association was also noted with ER+
disease (OR ¼ 1.10, P ¼ 0.041; Supplementary Material,
Table S9) and is likely to capture the same signal as
19p13. 19p13 was the first risk locus reported to harbor a
variant that may be specific for ER2 disease (9). In African
Americans, the index variant was statistically significantly
associated with risk of overall breast cancer (rs2363956:
OR ¼ 1.14, P ¼ 8.0 × 1024), as well as ER+ (OR ¼ 1.12,
Table 1 and Supplementary Material, Table S3). The most sig-
nificant association in the region for overall breast cancer
and ER+ disease was with rs3745185 (P ¼ 3.7 × 1025and
P ¼ 8.2 × 1024, respectively), which is likely to capture the
same functional variant (r2¼ 0.57 in CEU and 0.19 in YRI;
Table 1 and Supplementary Material, Table S8). The most sig-
nificant marker for ER2 breast cancer was correlated with
both rs2363956 and rs3745185 (rs11668840: OR ¼ 1.25,
P ¼ 5.1 × 1025; Supplementary Material, Tables S8 and S10).
disease (OR ¼ 1.14,
Novel risk-associated markers at breast cancer
susceptibility loci
8q24. Given the importance of the 8q24 locus in cancer, we
conducted association testing across the entire cancer risk
region(126.0–130.0 Mb)(23–25).
(rs13281615) was not statistically significantly associated
with risk in African Americans (Table 1 and Supplementary
Material, Table S3), nor did we identify significant associa-
tions with correlated SNPs. However, we did detect a signifi-
cant association with rs16902056 and ER+ breast cancer [risk
allele frequency (RAF) 0.95; P ¼ 6.7 × 1026; ER2: P ¼
0.66; Supplementary Material, Table S8]. This SNP is
located 78 kb centromeric of the index variant and is not cor-
related with the index variant (r2, 0.01 in CEU and r2¼
0.027 in YRI). No statistically significant associations were
observed with variants found previously in association with
cancers of the bladder and ovary, or leukemia (rs9642880:
OR ¼ 1.03, P ¼ 0.58; rs10088218: OR ¼ 1.02, P ¼ 0.62;
rs2456449: OR ¼ 1.07, P ¼ 0.14) (26–28). Of the known
risk variants for prostate cancer (29–35), we found a single
nominally significant (P , 0.05) association with the same
risk allele of rs1016343 (P ¼ 0.015) which is located
.260 kb centromeric of the breast cancer risk region and is
not correlated with rs13281615 or rs16902056.
Theindex signal
10q22. We observed no association with the index signal at
10q22 (rs704010) which is located in intron 1 of the gene
ZMIZ1, or with any correlated markers. However, we did
detect strong evidence of a second signal located 215 kb telo-
meric in intron 12 of the gene ZMIZ1 (rs12355688: OR ¼
1.24, P ¼ 6.8 × 1026). As is shown in Table 1 and Figure 2,
this putative novel risk variant is not correlated with the
index variant in the CEU or YRI populations (r2, 0.01).
11q13. No positive association was noted with the index
variant at 11q13. However, we did detect evidence of a
second independent signal (rs609275: OR ¼ 1.20, P ¼ 1.0 ×
1025), located 74 kb telomeric, and 53 kb centromeric of
CCND1. The variant is monomorphic and uncorrelated with
the index signal in the CEU population; and r2with the
index signal in the YRI population is ,0.01 (Table 1).
16q12. As in previous studies of African Americans, we were
not able to replicate the association signal defined by the index
variant rs3803662 (Table 1) (15,16). A recent study of African
Americans reported a suggestive association with SNP
rs3104746, which is located 15 kb telomeric of rs3803662
(16). This SNP has a minor allele frequency (MAF) of 0.04
in the HapMap CEU population, 0.19 in our African-American
controls, and is modestly correlated with rs3803662 in
Africans (r2¼ 0.31 in YRI), but not in Europeans (r2¼
0.038; Supplementary Material, Table S10). Fine-mapping
around this putative signal revealed a perfect proxy (r2¼ 1)
for rs3104746, rs3112572, which is significantly associated
with breast cancer risk in African Americans (OR ¼ 1.18,
P ¼ 3.9 × 1024), with the association noted to be stronger
for ER+
Table 1 and Supplementary Material, Table S8).
For index SNPs found to be nominally associated with
breast cancer risk, as well as risk-associated markers identified
through fine-mapping, we also tested for associations by geno-
type. Results from the genotype-specific model were consist-
ent with log-additive associations (Supplementary Material,
Tables S9 and S11). Risk variants at 2q35 and 8q24 were
also found to have significantly stronger associations with
ER+ breast cancer than ER2 disease (Supplementary Mater-
ial, Table S7), which is consistent with previous studies (2,18).
We observed no statistically significant associations with
common variation at 10 risk loci on 1p11, 3p24, 5p12, 6q25,
9p21, 10p15, 10q21, 11p15, 14q24 and 17q23 (Supplementary
Material, Fig. S2). We also could not replicate the association
with the recently identified SNP rs9397435 at 6q25 that was
found through fine-mapping in European, African and Asian
population samples (17) (P ¼ 0.26 for overall breast cancer,
P ¼ 0.71 for ER+ and P ¼ 0.36 for ER2 tumor subtypes).
Neither could we replicate the association with SNP
rs4784227 at 16q12, which was identified by a recent multi-
stage GWAS in women of Asian ancestry (36) in our
African-American sample (P ¼ 0.51 overall, P ¼ 0.35 and
P ¼ 0.65 for ER+ and ER2 subtypes, respectively).
breast cancer(OR ¼ 1.27,
Risk modeling
We next estimated the cumulative effect of all breast cancer
risk variants, and compared a summary risk score comprised
of unweighted counts of all GWAS-reported risk variants
with a risk score that included variants we identified as
being associated with risk in African Americans (Table 2).
Using the 19 index signals from GWAS (see Materials and
Methods), the risk per allele was 1.04 [95% confidence inter-
val (CI) 1.02–1.06; P ¼ 6.1 × 1025], and individuals in the
top quintile of the risk allele distribution were at 1.4-fold
greater risk (P ¼ 7.4 × 1025) of breast cancer compared
with those in the lowest quintile (Table 2). As expected, the
risk score was improved when utilizing the markers that we
identified at the known risk loci as being more relevant to
African Americans (eight markers for overall breast cancer:
2q35, 5q11, 9q31, 10q22, 10q26, 11q13, 16q12 and 19p13;
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OR ¼ 1.18; 95% CI 1.14–1.22; P ¼ 2.8 × 10224), with risk
for those in the top quartile being 2.2 times that observed in
the lowest quintile (P ¼ 3.6 × 10217). This score was signifi-
cantly associated with risk of both ER+ (OR ¼ 1.20, P ¼
1.7 × 10219)
disease (Phet¼ 0.12) (Supplementary Material, Table S12).
Stratifying by first-degree family history of breast cancer
differentiated risk further with those with a family history
and in the top quintile of the risk score distribution (4% of
the population) having a 3.4-fold greater risk (P ¼ 9.9 ×
10214) compared with those without a family history and in
the lowest quintile of the risk score (Table 2).
In hypothesis-generating analyses, we also developed risk
scores for ER+ and ER2 breast tumor subtypes, utilizing the
most informative markers revealed through fine-mapping of
each phenotype. These phenotype-specific scores were highly
significant (ER+: OR ¼ 1.30, P ¼ 6.0 × 10218; ER2: OR ¼
1.20, P ¼ 2.3 × 10210) with statistically significant heterogen-
eity noted when the scores were applied to the other subtype
(Phet¼ 1.7 × 1025and 5.0 × 1023for ER+ and ER2 scores,
respectively) (Supplementary Material, Table S12).
In this large study of breast cancer in African-American
women, we were able to replicate associations with 4 of the
19 index variants (at P , 0.05). Through fine-mapping, we
observed that overall breast cancer risk was statistically sig-
nificantly associated with markers in four regions which are
likely to capture the GWAS-reported signal and to serve as
better markers of the functional allele and risk in African
Americans. We also detected putative novel associations that
are independent of the index signals in three regions for
overall breast cancer (10q22, 11q13 and 16q12) and in one
region for ER+ disease (8q24). In 10 of the risk regions,
however, we were not able to replicate the GWAS index
signals, nor did we detect statistically significant associations
of common SNPs with breast cancer risk at the levels of statis-
tical significance we set for fine-mapping. The inability to repli-
cate associations with the index signals despite adequate
statistical power (.70% power for 12 of 19 variants) suggests
that they are unlikely to be functional variants or capture the
functional variants as efficiently in this population. Our ability
to find associated markers in five regions where index signals
were not significantly associated with risk also demonstrates
the value of testing common variation at GWAS-identified
risk loci in additional populations (14,16,17,22,37,38).
In four regions, we observed risk markers that are correlated
with, and in the same LD block as the index markers in CEU
(rs13000023 at 2q35, rs16886165 at 5q11, rs2981578 at 10q26
and rs3745185 at 19p13). It is likely that these risk markers
capture the same signal as defined by the index markers
Table 2. The association of the total risk score with breast cancer risk in African Americans
Index markers from
GWAS (19 markers)
Risk-associated best markers in African Americansa
(8 markers)
Mean number of risk alleles in controls (range)
Per allele OR (95% CI)
15.7 (6–25)
1.04 (1.02–1.06)
6.1 × 1025
8.4 (3–14)
1.18 (1.14–1.22)
2.8 × 10224
First-degree family
history negativeb
First-degree family
history positiveb
554/303 Subjects, n cases/n controls
Risk quintilesc
n cases/n controls
n cases/n controls
n cases/n controls
n cases/n controls
n cases/n controls
3016/2745 3016/2745
1.00 (ref.)
1.00 (ref.)
1.00 (ref.)
1.58 (1.06–2.37)
0.99 (0.84–1.16)
1.17 (0.96–1.42)
1.15 (0.93–1.43)
2.18 (1.46–3.26)
1.5 × 1024
1.15 (0.96–1.39)
1.37 (1.14–1.64)
7.2 × 1024
1.31 (1.07–1.60)
8.0 × 1023
3.14 (2.17–4.53)
1.2 × 1029
1.16 (0.98–1.36)
1.56 (1.30–1.87)
2.3 × 1026
1.51 (1.24–1.86)
6.2 × 1025
2.52 (1.81–3.52)
4.0 × 1028
1.44 (1.20–1.72)
7.4 × 1025
2.16 (1.80–2.58)
3.6 × 10217
2.11 (1.73–2.56)
1.3 × 10213
3.44 (2.47–4.77)
9.9 × 10214
ORs are adjusted for age, study and the first 10 eigenvectors.
Ptrendvalues are based on test of trend (1 d.f.).
aThe most significant markers from the stepwise analysis for overall breast cancer in each region from Table 1.
bInformation about first-degree family history of breast cancer is available on 97.5% of cases and 96.6% of controls.
cBased on distribution in controls (cut points for index markers aggregate: 13.3, 15, 16, 18; cut points for best markers aggregate: 7, 8, 9, 10).
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based on the r2values between these markers and the index
markers (≥0.35). We cannot rule out the possibility, though,
that some of them may represent a second, independent
signal in the same region.
In the four regions where we observed independent signals,
the risk alleles (rs16902056 at 8q24, rs12355688 at 10q22,
rs609275 at 11q13 and rs3112572 at 16q12) were uncorrelated
with, and not in, the same LD block as the index variant in
Europeans (CEU, r2, 0.04)) (distances from the index
signal ranged from 14 kb at 16q12 to 215 kb at 10q22) (Sup-
plementary Material, Fig. S3). Therefore, these variants are
likely to pick up a novel signal independent of the index
signal. However, because of different LD patterns in European
and African ancestry populations, they may each mark the
same functional variant, and if the functional variant is less
common it may not be well captured by either common
marker alone. At 10q22, both the index SNP and the novel
variant are located within introns of the ZMIZ1 gene. ZMIZ1
encodes zinc finger MIZ-type containing 1, which regulates
the activity of various transcription factors (39–41). At
11q13, rs609275 lies 74 kb telomeric of the index signal and
in closer proximity to a number of candidate genes, including
CCND1 (encoding cyclin D1, a protein crucial for cell-cycle
control), ORAOV1 (encoding oral cancer overexpressed 1)
and FGF19 (encoding fibroblast growth factor 19). The asso-
ciation at 16q12 confirms the findings of a previous, smaller
study of African Americans (16), and is consistent with a pre-
vious fine-mapping study suggesting that African Americans
may harbor a separate causal variant in this region (42).
Whether this variant is influencing the same genes/pathways
as the index variant rs3803662 is not known; however, the
stronger associations noted for both variants with ER+
disease (2,18) suggest that they may affect the same biological
Notably, at region 19p13, which was originally reported in
association with ER2 breast cancer (9), the index signal was
statistically significantly associated with both ER+ and
ER2 subtypes in African Americans. In addition, we
found a stronger marker in this region (rs3745185) for
ER+ as well as overall breast cancer risk (Table 1 and Sup-
plementary Material, Table S8). We also found stronger
associations with ER+ than ER2 disease for variants in
many regions, including 2q35, 8q24, 10q26 and 16q12,
which is consistent with previous reports (2,18). In the
study, we also found strong signals for ER2 disease in
regions 5q11, 10q26 and 19p13. It is possible that these
signals may explain some of the excess risk for ER2
disease in African Americans, since these risk alleles have
higher frequencies in this population than they do in
European-ancestry populations. However, our understanding
of their contribution to racial and ethnic differences in
disease incidence will only be determined once the functional
variants have been identified and tested across populations.
Unfortunately, we were not able to assess associations with
receptor; HER2, human epidermal growth factor receptor 2)
breast cancer, since HER2 status was available for only a
limited number of cases. However, in a large study of
women of European ancestry which tested many of these
same index variants, further stratification on tumor subtype
PR, progesterone
using HER2 status was not additionally informative for
ER/PR-negative breast cancer (43).
The observation of secondary signals at many loci, and
associations of variants with different tumor subtypes that
have not yet been reported in European-ancestry populations
could indicate a different genetic architecture of breast
cancer across populations. For example, the index signal at
TNRC9 does not replicate in African Americans, but there
appears to be a second risk variant that is unique to this popu-
lation. At FGFR2, which was originally reported to be asso-
ciated with ER+ disease in women of European ancestry,
we found a signal for ER2 disease with a marker correlated
with the index variant. Similarly, for chromosome 19p13,
which was reported as an ER2 locus, we observed an associ-
ation with ER+ breast cancer. However, these findings and
their implications require further validation.
We investigated local ancestry as a potential confounding
factor in the analysis of each risk locus. At five loci, we
observed nominally significant evidence of association
between local ancestry and breast cancer risk, with the most
statistically significant association observed at 6q25 between
European ancestry and ER+ breast cancer risk. Although
the association of local ancestry and breast cancer risk needs
to be validated in additional large studies, the inability to iden-
tify a risk variant that is differentiated in frequency between
populations of European and African ancestry implies that
either the association with local ancestry at many regions is
a false-positive signal and/or we have not tested an adequate
surrogate of the functional alleles.
The majority of the variants identified by GWAS for
common cancers are of low risk (relative risks ,1.30) and
in aggregate are not yet informative for risk prediction
(11–13). Until the functional alleles at each susceptibility
locus are identified and their effects are accurately estimated,
modeling of the genetic risk will rely on markers that best
capture risk for a given population. Many of the markers we
identified at these risk loci appear to have stronger associations
with breast cancer risk compared with the GWAS-identified
variants in African-American women. The risk score for
overall breast cancer was also equally efficient for ER+ and
ER2 tumors. However, our hypothesis-generating model
suggests that identification of tumor subtype-specific variants
will improve the fit of these models.
While this is the largest study of African Americans to date
to investigate genetic risk at known breast cancer susceptibil-
ity loci, statistical power was still limited. We had only 35%
power to detect an OR of 1.10 for a risk allele of 0.10 fre-
quency which may account for our inability to replicate
GWAS signals or risk-associated markers in 10 of the
regions. While attempting to apply a strict threshold for
declaring significance through fine-mapping, we did not take
into account testing for multiple phenotypes (overall breast
as well as ER+ and ER2 disease). As a result, the a-levels
used as selection criteria may be too liberal. However, our
risk modeling focused on the variants revealed for overall
breast cancer, whereas we consider the associations observed
for markers identified for ER+ or ER2 disease and used in
the subtype-specific risk modeling as hypothesis-generating.
Since allof the casesand
mapping/discovery were also included in the risk modeling,
controlsusedfor fine-
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the risk model is likely to over-estimate the level of associ-
ation due to winner's curse. Instead of partitioning the
sample into test and validation sets, we felt it was necessary
to use all of the subjects in the association testing of known
variants and in fine-mapping to increase the statistical power
to detect associations in each region. Therefore, other
studies with reasonable power in African Americans must be
performed in the future to test the model presented.
In summary, through fine-mapping of the breast cancer sus-
ceptibility regions in a large sample of African-American
women, we identified markers with enhanced association
with breast cancer in this population. Validation and augmen-
tation of this model are needed before risk modeling based on
genetic variants of low risk can be implemented in the clinical
Ethics statement
The Institutional Review Board at the University of Southern
California approved the study protocol.
Study populations
This study included 9 epidemiological studies of breast cancer
among African-American women, which comprise a total of
3153 cases and 2831 controls. Sample size and selected char-
acteristics for these studies are summarized in Supplementary
Material, Table S1. What follows is a brief description of these
The Multiethnic Cohort Study (MEC). The MEC is a prospect-
ive cohort study of 215 000 men and women in Hawaii and
Los Angeles (44) between the ages of 45 and 75 years at base-
line (1993–1996). Through 31 December 2007, a nested
breast cancer case–control study in the MEC included
556 African-American cases (544 invasive and 12 in situ)
and 1003 African-American controls. An additional 178
African-American breast cancer cases (ages: 50–84) diag-
nosed between 1 June 2006 and 31 December 2007 in
Los Angeles County (but outside of the MEC) were included
in the study.
The Los Angeles component of The Women's Contraceptive
and Reproductive Experiences (CARE) Study. The CARE
Study is a large multi-center, population-based case–control
study that was designed to examine the effects of oral contra-
African-American women and white women aged 35–64
years in five US locations (45). Cases in Los Angeles
County were diagnosed from 1 July 1994 through 30 April
1998, and controls were sampled by random-digit dialing
(RDD) from the same population and time period; 380
African-American cases and 224 African-American controls
were included in the study.
breastcancer riskamong
The Women's Circle of Health Study (WCHS). The WCHS is
an ongoing case–control study of breast cancer among
European women and African-American women in the
New York City boroughs and in seven counties in New
Jersey (46). Eligible cases included women with invasive
breast cancer between 20 and 74 years of age; controls were
identified through RDD. The WCHS contributed 272 invasive
African-American cases and 240 African-American controls.
The San Francisco Bay Area Breast Cancer Study (SFBCS).
The SFBCS is a population-based case–control study of inva-
sive breast cancer in Hispanic, African-American and non-
Hispanic white women conducted between 1995 and 2003 in
the San Francisco Bay Area (47). African-American cases,
aged 35–79 years, were diagnosed between 1 April 1995
and 30 April 1999, with controls identified through RDD.
Included from this study were 172 invasive African-American
cases and 231 African-American controls.
The Northern California Breast Cancer Family Registry
(NC-BCFR). The NC-BCFR is a population-based family
study conducted in the Greater San Francisco Bay Area, and
one of six sites of the Breast Cancer Family Registry
(BCFR) (48). African-American breast cancer cases in
NC-BCFR were diagnosed after 1 January 1995 and
between the ages of 18 and 64 years; population controls
were identified through RDD. Genotyping was conducted
for 440 invasiveAfrican-American
African-American controls.
The Carolina Breast Cancer Study (CBCS). The CBCS is a
population-based case–control study conducted between
1993 and 2001 in 24 counties of central and eastern North
Carolina (49). Cases were identified by rapid case ascertain-
ment system in cooperation with the North Carolina Central
Cancer Registry, and controls were selected from the North
Carolina Division of Motor Vehicle and United States
Health Care Financing Administration beneficiary lists. Parti-
cipants' ages ranged from 20 to 74 years. DNA samples were
provided from 656 African-American cases with invasive
breast cancer and 608 African-American controls.
The Prostate, Lung, Colorectal, and Ovarian Cancer Screen-
ing Trial (PLCO) Cohort. PLCO, coordinated by the US
National Cancer Institute (NCI) in 10 US centers, enrolled
approximately 155 000 men and women aged 55–74 years
during 1993–2001 in a randomized, two-arm trial to evaluate
the efficacy of screening for these four cancers (50). A total of
64 African-American invasive breast cancer cases and 133
African-American controls contributed to this study.
The Nashville Breast Health Study (NBHS). The NBHS is a
population-based case–control study of incident breast
cancer conducted in Tennessee (15). The study was initiated
in 2001 to recruit patients with invasive breast cancer or
ductal carcinoma in situ, and controls, recruited through
RDD between the ages of 25 and 75 years. NBHS contributed
310 African-Americancases
African-American controls.
insitu) and186
Wake Forest University Breast Cancer Study (WFBC).
African-American breast cancer cases and controls in WFBC
were recruited at Wake Forest University Health Sciences
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from November 1998 through December 2008 (51). Controls
were recruited from the patient population receiving routine
mammography at the Breast Screening and Diagnostic
Center. Age range of participants was 30–86 years. WFBC
contributed 125 cases (116 invasive and 9 in situ) and 153
controls to the analysis.
Genotyping and quality control
Genotyping in stage 1 was conducted using the Illumina
Human1M-Duo BeadChip. Of the 5984 samples from these
studies (3153 cases and 2831 controls), we attempted genotyp-
ing of 5932, removing samples (n ¼ 52) with DNA concentra-
tions ,20 ng/ml. Following genotyping, we removed samples
based on the following exclusion criteria: (i) unknown repli-
cates (≥98.9% genetically identical) that we were able to
confirm (only one of each duplicate was removed, n ¼ 15);
(ii) unknown replicates that we were not able to confirm
through discussions with study investigators (pair or triplicate
removed, n ¼ 14); (iii) samples with call rates ,95% after a
second attempt (n ¼ 100); (iv) samples with ≤5% African
ancestry (n ¼ 36) (discussed in what follows); and (v)
samples with ,15% mean heterozygosity of SNPs on the X
chromosome and/or similar mean allele intensities of SNPs
on the X and Y chromosomes (n ¼ 6) (these are likely to be
In the analysis, we removed SNPs with ,95% call rates
(n ¼ 21 732) or MAFs ,1% (n ¼ 80 193). To assess genotyp-
ing reproducibility, we included 138 replicate samples; the
average concordance rate was 99.95% (.99.93% for all
pairs). We also eliminated SNPs with genotyping concordance
rates ,98% based on the replicates (n ¼ 11 701). The final
analysis data set included 1 043 036 SNPs genotyped on
3016 cases (1520 ER+, 988 ER2 and the remaining 508
cases with unknown ER status) and 2745 controls, with an
average SNP call rate of 99.7% and average sample call rate
of 99.8%.
Statistical analysis
Ancestry estimation. We used principal components analysis
(52) to estimate global ancestry among the 5761 individuals,
using 2546 ancestry informative markers. Eigenvector 1 was
highly correlated (r ¼ 0.997, P , 1 × 10216) with percentage
of European ancestry, estimated in HAPMIX (53), and
accounted for 10.1% of the variation between subjects; subse-
quent eigenvectors accounted for no more than 0.5%. At each
locus and for each participant, we also estimated local ancestry
[i.e. the number of European chromosomes (continuous
between 0 and 2) carried by the participant], using the
HAPMIX program (53). To summarize local ancestry at
each region, for each individual we averaged across all local
ancestry estimates that were within the start and end points
of the region (Supplementary Material, Table S5). To
address the potential for confounding by genetic ancestry,
we adjusted for both global and local ancestry in all analyses.
SNP imputation. In order to generate a data set suitable for
fine-mapping, we carried out genome-wide imputation using
the software MACH (54). Phased haplotype data from the
founders of the CEU and YRI HapMap Phase 2 samples
were used to infer LD patterns in order to impute ungenotyped
markers. The r2metric, defined as the observed variance
divided by the expected variance, provides a measure of the
quality of the imputation at any SNP, and was used as a thresh-
old in determining which SNPs to filter from analysis
(r2, 0.3). Of the 1539 328 common SNPs (MAF ≥ 0.05) in
the YRI population in HapMap Phase 2, we could impute
1392 294 (90%) with r2≥ 0.8. For all the imputed SNPs
presented in Results and the tables reported herein, the
average r2was 0.92 (estimated in MACH).
Association testing. For each typed and imputed SNP, ORs
and 95% CIs were estimated using unconditional logistic
regression adjusting for age at diagnosis (or age at the
reference date for controls), study, the first 10 eigenvalues
and local ancestry. For each SNP, we tested for allele
dosage effects through a 1 d.f. Wald x2trend test.
We fine-mapped each risk locus using the combined
genotyped and imputed SNPs in search of (i) an SNP that is
more associated with risk in African Americans than the
index signal; and (ii) a novel signal that is independent of
the index signal. As some risk loci have been found to be
more strongly associated with breast cancer subtypes, we
investigated three outcomes: (i) overall breast cancer, (ii)
ER+ breast cancer, and (iii) ER2 breast cancer, with the
latter two being hypothesis-generating.
included SNPs (genotyped and imputed) spanning 250 kb
upstream and 250 kb downstream of each index signal. If
the index signal was contained within an LD block (based
on the D′statistic) of .250 kb, then the region was extended
to include the entire region of LD.
Stepwise regression was performed by region to select the
most informative risk variants as discussed in what follows,
in models adjusted for age, study, global ancestry (the first
10 eigenvectors) and local ancestry. In the stepwise regression,
we preserved the original sample size by using the mean geno-
type of typed subjects in place of 'no-calls' for SNPs with
,100% genotyping completion rate.
Within each known risk locus, it is expected that markers
that are associated with risk in African Americans will be cor-
related with the index signal reported in Europeans. Thus, we
identified and tested SNPs that are correlated (r2. 0.2) with
the index signals in the GWAS populations (HapMap CEU
or CHB for 6q25). For each region, we determined the
number of tags needed to capture all the SNPs correlated
with the index signal in the YRI population (Phase 2
HapMap). The average number of tags in each region was
then used as the correction factor for Bonferroni correction.
An a-level of 0.05 divided by average number of tags
needed in each region was applied in the stepwise regression
process. For all of the remaining markers that were not corre-
lated with the index signal (in Europeans), we applied a more
stringent a-level for defining statistical significance. In each
risk region, we determined the number of tag SNPs needed
to capture all common alleles (MAF . 0.05, with r2. 0.8)
in the YRI HapMap population. The total number of tags
across the 19 regions was then used as a correction factor,
as they define the number of independent tests in each
region. An a of 0.05 divided by the number of tags was
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applied to assess statistical significance for any putative novel,
independent signal in each region. For correlated SNPs that
were selected to be better markers, we also assessed phase
to ensure that the new risk allele is on the same haplotype
as the GWAS-reported risk allele in the HapMap CEU
Risk modeling. We modeled the cumulative genetic risk of
breast cancer using the risk variants reported in previous
GWAS (total ¼ 19). We compared the results with a model
of the SNPs found to be significantly associated with risk in
African Americans, which included SNPs identified from the
stepwise procedures at all loci for overall breast cancer risk
(presented in Table 1). More specifically, in each case we
summed the number of risk alleles for each individual and
estimated the OR per allele for this aggregate-unweighted
allele count variable as an approximate risk score appropriate
for unlinked variants with independent effects of approximate-
ly the same magnitude for each allele. We then applied this
risk score to overall breast cancer as well as ER+/
ER2 breast cancer subtypes. We also constructed risk
scores based on risk alleles for ER+ and ER2 tumor subtypes
separately, and, as hypothesis-generating, applied both risk
scores to overall and ER+/ER2 breast cancer subtypes.
Supplementary Material is available at HMG online.
We thank the women who volunteered to participate in each
study. We also thank Madhavi Eranti, Andrea Holbrook,
Paul Poznaik, Loreall Pooler, Xin Sheng and David Wong
from the University of Southern California for their technical
support. We would also like to acknowledge co-investigators
from the WCHS study: Dana H. Bovbjerg (University of Pitts-
burgh), Lina Jandorf (Mount Sinai School of Medicine) and
Gregory Ciupak, Warren Davis, Gary Zirpoli, Song Yao and
Michelle Roberts from Roswell Park Cancer Institute.
Conflict of Interest statement. None declared.
This work was supported by a Department of Defense Breast
Cancer Research Program Era of Hope Scholar Award to
Health grant to C.A.H. (R01-CA132839), the Norris Founda-
tion, and a grant from the California Breast Cancer Research
Program to D.O.S. (15UB-8402). Each of the participating
studies was supported by the following grants: MEC: by
NationalInstitutesof Health
R37-CA54281); CARE: by National Institute for Child
Health and Development (NO1-HD-3-3175), WCHS: by
USArmy Medical Research
(USAMRMC) (DAMD-17-01-0-0334); the National Institutes
of Health (R01-CA100598); and the Breast Cancer Research
Foundation; SFBCS:by National
a NationalInstituteof
(R01-CA63464 and
andMaterial Command
Institutes ofHealth
(R01-CA77305) and United States Army Medical Research
Program (DAMD17-96-6071); NC-BCFR: by National Insti-
tutes of Health (U01-CA69417); CBCS: by National Institutes
of Health Specialized Program of Research Excellence in
Breast Cancer (P50-CA58223) and Center for Environmental
Health and Susceptibility, National Institute of Environmental
Health Sciences, National Institutes of Health (P30-ES10126);
PLCO: by Intramural Research Program, National Cancer
Institute, National Institutes of Health; NBHS: by National
Institutes of Health (R01-CA100374); WFBC: by National
Institutes of Health (R01-CA73629). The Breast Cancer
Family Registry (BCFR) was supported by the National
Cancer Institute, National Institutes of Health under (RFA
CA-95-011)and throughcooperative
members of the Breast Cancer Family Registry and Principal
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A. et al. (2007) Common variants on chromosomes 2q35 and 16q12
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12 December 2013
25/07/2006 Good stopover camping. Located nearby the soccer stadium. Not a problem in the summer. There was a danger for flooding at serious rainfall. Friendly personnel! Camping shop was very limited, yet the centre and supermarkets were nearby.
27/05/2006 The camping was location at the soccer stadium. Quite quiet location. Good sanitary facilities. A true camping for people on a stopover.
27/05/2006 Definitely no entertainment camping, but a very good operating base for exploring the Bourgogne. Nice to cycle along the canal of Nivernais. The camping had a quiet location, unless there was a soccer match at the stadium. I recommend this place to cyclists and strolelrs. Auxerre was lovely and the centre was a 10 minutes walk. The camping wasn't far away from the supermarkets (Aldi and Leclerc).
In 2014 I'll most probably go on (select the option you think fits best):

subset: commoncrawl


text:
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COMMERCIAL DESCRIPTION An aggressive and old-school American Double IPA here, and a well named one, as this beer rips out your palate and the flies off to regurgitate it into the mouths of its frenzied young. Its combo of five malts and six hops creates a unique experience too. Anyone who touts themselves as a true hophead should seek out this beer now. Malts: Specialty 2 Row, Wheat, Munich, Vienna, CaraMunich 40. Hops: Warrior, Cascade, Amarillo, Summit, Pilgrim, Centennial. Dry Hop: Amarillo, Summit, Simcoe.
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By Caroline Russock
09/23/2013 | 0 Comments Posted
We've been loving Scott Schroeder's series of pop ups at American Sardine Bar (1800 Federal St.) and the latest installment is looking pretty sweet. On Thursday, September 26th Meal Ticket founding father Drew Lazor and City Paper staff photographer extraordinaire Neal Santos are taking over the ASB kitchen for an evening of Filipino eats. Here's Drew with a little intel about the event:
"Named after our moms — my mom's Generosa and Neal's mom is Rosalinda — Tita Rosy's (tita = Tagalog for aunt) will be super casual. The menu is all Filipino classics with little tweaks and twists. We've got lumpia, or Filipino spring rolls; Filipino BBQ skewers; adobo, the world-famous vinegar stew that white people really like (hi Mark Bittman!); and more. We're even doing halo-halo, the popular dessert of shaved ice and condensed milk, in ice cream form for dessert!"
As per usual with the pop ups, the menu is affordable and a la carte, the food starts at 6 p.m. and the beer selection is predictably awesome. And yeah, Team Meal Ticket will be there.
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Company Overview of ContraFect Corporation
Executive Profile
Vincent A. Fischetti Ph.D.Chairman of Scientific Advisory Board, ContraFect Corporation |
Age | Total Calculated Compensation | This person is connected to 2 Board Members in 2 different organizations across 2 different industries. See Board Relationships |
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Corporate Headquarters28 Wells Avenue Phone: 914-207-2300Yonkers, New York 10701 United States Fax: 914-207-2399 Board Members MembershipsMember of Board of Trustees and Member of Scientific Advisory Board
EducationMS 1967 Long Island University BS 1962 Wagner College PhD 1970 NYU Elaine A. and Kenneth G. Langone Medical Center
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May 23 - Homily: Your Mission To Preach
Uploaded by AirMaria on May 23, 2013
To bring about a new evangelization, Father reminds us that at confirmation we received the power of the Holy Spirit to be soldiers of Christ, to carry out His mission of preaching to the whole world. Ave Maria! Mass: Thursday in Pentecost Week - Ferial - Form:�EF, Spiritus Domini Readings:� 1st: act 8:5-8 Gsp: luk 9:1-6 To Download Audio go to http://airmaria.com?p=35976
New Evangelization
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The May 21 Judgement Day lunatics are quitting their jobs, spending their life savings and screwing over their children's future (npr.org)
submitted 2 years ago by niton
view the rest of the comments →
[–]bigbleem 7 points8 points9 points 2 years ago
Yep, so if there are any earthquakes in that five month period then get ready for the gloating. Bizarre.
DAE spot this gem? ; "their second child is due in June"
So funny.
[–]nanr93 1 point2 points3 points 2 years ago
But they're not planning for the future, of course. Interesting birth, that one's going to have.
[–]danger_one 1 point2 points3 points 2 years ago
And they budgeted to make it only to May 21. So on the 22 there will be two losers with a kid (and one on the way) sucking on the government teet. This is the harm that religion causes.
[–]FTWingman 0 points1 point2 points 2 years ago
[–]mannyotr 0 points1 point2 points 2 years ago
Yes! I came here to make sure someone else had pointed it out because that is damn funny.
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The Falcons will warm up vs. the Chiefs, vs. the Patriots (nationally televised), at the Dolphins and at the Jaguars.
You may think that you are a fantasy football guru, but can you prove it? At the same time, can you help rep this blog in a Fantasy Football contest? The Falcoholic is asking you to play in this exclusive 1-week fantasy football contest for both money and bragging rights. Enter SB Nation contest here
While we're rapping about potential free agents that the Falcons could pick up, let's go with an extremely unlikely choice: current Miami Dolphins SS Yeremiah Bell. Chalk this one up as something...
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Chart 6: NIC shipments by interface type, 2Q09-4Q10 (k units)
Chart 7: NIC shipment proporti on by interface type, 2Q09-4Q10
Chart 8: Wireless router production value, 2Q09-2Q10 (US$ million)
Chart 10: Wireless router shipments by standard, 2Q09-4Q10 (k units)
Chart 11: Wireless router shipment proportion by standard, 2Q09-4Q10
Chart 14: Wireless router shipments by maker, 1Q09-2Q10 (k units)
Chart 15: Wireless router shipment proportion by maker tier, 1Q09-2Q10
Chart 16: Shipments of WLAN chip makers, 2Q09-2Q10 (k units)
Global 3Q13 semiconductor equipment billings drop 16% on year, says SEMI
Bits + chips | 7h 34min ago
MediaTek to post shipment drop in 1Q14
Bits + chips | 9h 18min ago
TSMC moves 16nm FinFET to risk production
Bits + chips | 9h 57min ago
Below 50-inch models to take up 60% of Ultra HD TV panel output in 2014, say Taiwan makers
Before Going to Press | 8h 42min ago
G-Tech to offer green building glass
Before Going to Press | 8h 57min ago
Digitimes Research: Taiwan makers to ship 36 million LCD TVs in 2014
Before Going to Press | 8h 57min ago
MLCC suppliers Holy Stone, 3H post mixed November results
Before Going to Press | 8h 58min ago
ASE reportedly losing bumping
Before Going to Press | 8h 58min ago
Foxconn reportedly to start production of small-size OLED panels in 2015
Before Going to Press | 8h 59min ago
Film-based touch panel makers expected to benefit from fast growing demand for inexpensive smartphones in 2014
Before Going to Press | 9h 31min ago
Pegatron chairman may head Taipei Computer Association
Before Going to Press | 9h 32min ago
Compeq to report record revenues for 4Q13
Before Going to Press | 10h 18min ago
Digitimes Research: MediaTek to become AP market leader in 2014
Before Going to Press | 10h 50min ago
TAIWAN FPD | Nov 14, 15:38
Taiwan's monitor makers are bracing for a weak second-half 2013 as end-market demand remains sluggish. Their shipments for the second half of the year are expected to be lower than those for the first half.
TAIWAN FPD | Nov 7, 15:12
Orders from North America and Europe drove up Taiwan makers' LCD TV shipments sequentially in the third quarter. However, with the overall LCD TV market remaining weak, the Taiwan makers' shipments continued to drop on an annual basis.
Taiwan small- to mid-size LCD panels – 3Q 2013
TAIWAN FPD | Nov 5, 15:40
Taiwan-based makers face growing competition from Japan- and Korea-based firms who are using more advanced panel lines to produce small- to medium-size applications. Some international handset vendors have shifted orders from Taiwan to Japan and Korea.
2014 global notebook demand forecast
RESEARCH EXTRAS | Dec 5, 16:35
Digitimes Research estimates that global notebook shipments in 2014 will reach around 160 million units, down from a peak of over 200 million in 2011, but the drop in 2014 will be lower than the on-year drop in 2013, with new market developments, new product...
TD-LTE market developments and forecast, 2014-2016
CHINA MOBILE | Nov 28, 17:14
TD-LTE has become the mainstream global choice for the construction of 4G asymmetric frequency spectrum networks, with the GSA calculating that commercial TD-LTE services were already in operation by 21 carriers in 17 countries worldwide as of the third quarter...
Taiwan makers to see 2014 touch panel shipments up for smartphones, notebooks, down for tablets
TAIWAN FPD | Dec 10, 10:08
Melfas emerging as leading touchscreen controller IC player in Korea
RESEARCH EXTRAS | Dec 6, 11:45
Notebook vendors and ODMs post shipment gains in November
TAIWAN ICT | Dec 4, 16:05
Global LCD TV shipments to reach 213 million units in 2014
CHINA FPD | Dec 4, 15:13
Global AIO PC shipments to grow 4.9% in 2014
TAIWAN ICT | Dec 3, 13:55
Taiwan top foundries to see combined revenues decrease in 4Q13
RESEARCH EXTRAS | Nov 29, 10:32
Large-size panel shipments expected to decrease 1.4% in 2014
RESEARCH EXTRAS | Nov 28, 20:12
iPhone shipments up over 25% on year in 3Q13
GLOBAL SMARTPHONE | Nov 28, 13:55
Global smartphone shipments to reach 1.24 billion in 2014
GLOBAL SMARTPHONE | Nov 25, 21:15
China smartphone sales dip 8.8% sequentially in 3Q13
CHINA SMARTPHONE | Nov 25, 14:50
Monitor vendors look to new sizes and dual interface technology to push sales
RESEARCH EXTRAS | Nov 21, 14:12
Non-Apple brand vendors to ship 105 million tablets in 2014
GLOBAL TABLET | Nov 19, 15:11
40.1% of handset panels to have better than 300ppi resolution
CHINA FPD | Nov 18, 22:14
Global application processor market to grow more slowly in 2014
GLOBAL SMARTPHONE | Nov 18, 16:06
China panel makers to increase global proportion of small-size panel production
CHINA FPD | Nov 14, 21:26
- Blogs
- Press releases
- Trends in the upstream LED equipment and materials industries, 2H13
This report examines the outlook for upstream, which includes MOCVD equipment, rare earth materials and sapphire substrates, is also particularly significant as an indicator of trends in the LED industry as a whole over the next year.
- Global AMOLED market analysis and forecast, 2011-2015
This report analyzes the current state of development and strategies of the two largest AMOLED panel makers, Samsung and LG Display, examines the potential of the AMOLED handset panel and OLED TV markets, and takes an in-depth look at the competitiveness of S. Korea in the AMOLED sector.
- ASPs of TD-LTE chips to remain stable initially as suppliers are limited
While a number of IC vendors have begun shipping chips supporting TD-LTE, including base band chips, radio frequency chips, APs, SoC solutions and soft modems, shipments of base band chips account for a majority share of total TD-LTE chip shipments currently, according to Digitimes Research.


text:
Chinese Pay Raises Will Make Your Electronics More Expensive [China]
This year forget buying your tech in the post-Christmas sales. Because a 20 per cent increase in Chinese minimum wage is gonna hike up electronics prices come January. More »
Twilio Raises A $70M Series D As They Consider An IPO
Twilio, the company whose APIs help developers easily add SMS, voice, and VoIP functionality to their applications, has closed a Series D round of $70M dollars.The round was led by Redpoint Ventures and existing investors Bessemer Venture Partners, and backed by Draper Fisher Jurvetson. As part of the deal, Redpoint's Scott Raney will be joining the company's board of directors.
Here's The 'Specific Evidence' Of The US Hacking China That Snowden Might Spill
Motorized La-Z-Boy Chair Is the Best Invention Ever
How to Take Flawless Phone Pics of Your Naked Body
This post originally appeared on Gizmodo last March, but in light of Anthony Weiner's recent troubles, we thought it might be time for a reminder. If it's a nudie pic worth taking, it's worth taking right. Read more...
Minilogs Raises €200K Because Social Bookmarking Isn't Done Yet - Apparently
You'd think that social bookmarking as a startup opportunity has had its day. But in actual fact, linking to, and therefore sharing content, is built into the Web's plumbing, while the success of Pinterest has no doubt inspired other startups to try their hand. One of those -- at least on the surface -- is Paris-based Minilogs.
BrightEdge Raises $42.8M For Content Marketing And SEO
BrightEdge, a company that offers tools for search engine optimization and content marketing, is announcing that it has raised a big $42.8 million Series D.The round was led by Insight Venture Partners, with participation from existing investors Intel Capital, Battery Ventures, Altos Ventures and Illuminate Ventures. The company has now raised more than $63 million total.


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Evercore Partners Set to Join the S&P SmallCap 600
NEW YORK, June 26, 2013 /PRNewswire/ -- Evercore Partners Inc. (NYSE: EVR) will replace Lufkin Industries Inc. (NASD: LUFK) in the S&P SmallCap 600 after the close of trading on Monday, July 1. A subsidiary of S&P 100 & 500 constituent General Electric Co. (NYSE: GE) is acquiring Lufkin Industries in a deal expected to be completed soon pending final approvals.
Evercore Partners operates as an independent investment banking advisory firm. Headquartered in New York, NY, the company will be added to the S&P SmallCap 600 GICS (Global Industry Classification Standard) Investment Banking & Brokerage Sub-Industry index.
Following is a summary of the change:
S&P SMALLCAP 600 INDEX – July 1, 2013 | |||
Evercore Partners |
Financials |
Investment Banking & Brokerage |
Lufkin Industries |
Energy |
Oil & Gas Equipment & Services |
Additions to and deletions from S&P Dow Jones Indices do not in any way reflect an opinion on the investment merits of the companies involved.
About S&P Dow Jones Indices
S&P Dow Jones Indices LLC, a subsidiary of The McGraw-Hill Companies is the world's largest, global resource for index-based concepts, data and research. Home to iconic financial market indicators, such as the S&P 500® and the Dow Jones Industrial AverageSM, S&P Dow Jones Indices LLC has over 115 years of experience constructing innovative and transparent solutions that fulfill the needs of institutional and retail investors. More assets are invested in products based upon our indices than any other provider in the world. With over 830,000 indices covering a wide range of assets classes across the globe, S&P Dow Jones Indices LLC defines the way investors measure and trade the markets. To learn more about our company, please visit www.spdji.com.
It is not possible to invest directly in an index. S&P Dow Jones Indices LLC, Dow Jones, and their respective affiliates, parents, subsidiaries, directors, officers, shareholders, employees and agents (collectively "S&P Dow Jones Indices") does not sponsor, endorse, sell, or promote any investment fund or other vehicle that is offered by third parties and that seeks to provide an investment return based on the returns of any S&P Dow Jones Indices index. This document does not constitute an offer of services in jurisdictions where S&P Dow Jones
Indices or its affiliates do not have the necessary licenses. S&P Dow Jones Indices receives compensation in connection with licensing its indices to third parties
STANDARD & POOR'S and S&P are registered trademarks of Standard & Poor's Financial Services LLC. "Dow Jones" is a registered trademark of Dow Jones Trademark Holdings LLC ("Dow Jones")
For more information:
Dave Guarino
S&P Dow Jones Indices
(212) 438-1471
David Blitzer
Managing Director and Chairman of the Index Committee
S&P Dow Jones Indices
david.blitzer@ spdji.com
(212) 438-3907
SOURCE S&P Dow Jones Indices
More by this Source
Facebook Set to Join the S&P 100 & 500; Alliance Data Systems and Mohawk to Join the S&P 500; Changes to the S&P MidCap 400 and the S&P SmallCap 600
Dec 11, 2013, 18:11 ET
S&P 500 Dynamic VEQTOR Index Named Innovation of the Year
Dec 11, 2013, 09:30 ET
General Growth Properties Set to Join the S&P 500
Dec 04, 2013, 17:46 ET
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