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Carcinogenesis vol.34 no.2 pp.287–291, 2013
Advance Access publication October 26, 2012
Fine-mapping of the 6q25 locus identifies a novel SNP associated with breast cancer
risk in African–American women
Edward A.Ruiz-Narváez1,2,*, Lynn Rosenberg1,2,
Song Yao3, Charles N.Rotimi4, Adrienne L.Cupples5, Elisa
V.Bandera6, Christine B.Ambrosone3, Lucile L.Adams-
Campbell7 and Julie R.Palmer1,2
1Slone Epidemiology Center, Boston University, Boston, MA 02215,
USA, 2Department of Epidemiology, Boston University School of Public
Health, Boston, MA 02118, USA, 3Department of Cancer Prevention and
Control, Roswell Park Cancer Institute, Buffalo, NY 14263, USA, 4Center
for Research on Genomics and Global Health, National Human Genome
Research Institute, National Institutes of Health, Bethesda, MD 20892, USA,
5Department of Biostatistics, Boston University School of Public Health,
Boston, MA 02118, USA, 6The Cancer Institute of New Jersey/Robert Wood
Johnson Medical School, New Brunswick, NJ 08903, USA and 7Georgetown
University Medical Center, Washington, DC 20057, WA, USA
*To whom correspondence should be addressed. Slone Epidemiology Center,
Boston University, 1010 Commonwealth Avenue, Boston, MA 02215, USA.
Tel: +617-734-6006; Fax: +617-738-5119;
The rs2046210 single nucleotide polymorphism (SNP) in the
6q25.1 region was identified in a breast cancer genome-wide asso-
ciation study of Chinese women. The SNP has been replicated in
European ancestry populations, but replication efforts have failed
in African ancestry populations. We evaluated a total of 13 tag-
ging SNPs in the linkage disequilibrium block around rs2046210
in a case-control study of breast cancer nested within the Black
Women’s Health Study, which included 1191 cases and 1941
controls. Replication of initial significant findings was carried
out in 665 cases and 821 controls of African ancestry from the
Women’s Circle of Health Study (WCHS). No significant associa-
tion was found for rs2046210 in univariate analysis. A new SNP,
rs2046211, was significantly associated with reduced risk of breast
cancer and was replicated in data from WCHS. In joint analyses
that included both SNPs, the rs2046210-A allele was associated
with increased risk of breast cancer [odds ratio (OR) = 1.14; 95%
confidence interval (CI) = 1.02–1.28], and the rs2046211-G allele
was associated with reduced risk (OR = 0.80; 95% CI = 0.67–
0.95). Haplotype analysis confirmed these results and showed
that the rs2046210-A allele is present in high-risk (rs2046211-C/
rs2046210-A) and low-risk (rs2046211-G/rs2046210-A) haplo-
types. Our results confirm the importance of 6q25.1 as a breast
cancer susceptibility region. We replicated the rs2046210 associa-
tion, after accounting for the haplotype background that included
rs2046211 in African–American women, and we report the pres-
ence of a novel signal that is tagged by rs2046211.
A genome-wide association study (GWAS) of breast cancer con-
ducted among Chinese women living in Shanghai identified a genetic
susceptibility locus at 6q25.1 (1). The A-allele in rs2046210, a sin-
gle nucleotide polymorphism (SNP) located upstream of the estrogen
receptor α (ESR1) gene, was associated with a 29% increase in risk
of breast cancer. The association was significantly stronger for estro-
gen receptor negative (ER−) breast cancer than for estrogen recep-
tor positive (ER+) breast cancer (1,2). The SNP has been associated
with breast cancer overall in several European ancestry populations
(1–4), although with a weaker association and no apparent difference
by molecular subtype (2). To date, studies of African ancestry popula-
tions have failed to replicate the association with rs2046210 (2,3,5–7).
The greater genetic variation [lower levels of linkage disequi-
librium (LD), more haplotypes, more divergent patterns of LD and
more complex patterns of population substructure] present in African
ancestry populations relative to European or Asian ancestry popula-
tions make African ancestry populations especially valuable for gen-
etic research. For example, the weaker LD seen in African ancestry
populations has been successfully used to fine-map and better localize
loci initially identified from European and east Asian populations for
multiple complex traits including type 2 diabetes (8), fasting blood
sugar (9), serum uric acid (10) and bilirubin levels (11). The weaker
LD in the genome of African ancestry populations makes it more
probably that variants found to be associated with disease risk will
occupy smaller regions, thus facilitating a more efficient search for the
underlying causal variant(s). Thus, fine-mapping in African ancestry
populations can be a productive approach to identify causal variants
(12). In addition, the long evolutionary history of African populations
and the resulting complex genetic architecture may lead to a causal
variant being on a different haplotype background compared with
those of European and east Asian populations.
We carried out fine-mapping of the 6q25.1 region in the Black
Women’s Health Study (BWHS), a prospective cohort study of 59 000
African–American women, to narrow the position of the potential
causal variant for breast cancer as well as to identify any novel genetic
signal associated with the disease. Replication was carried out among
African–American cases of breast cancer and controls who partici-
pated in the Women’s Circle of Health Study (WCHS).
Materials and methods
The black women’s health study. At baseline in 1995, approximately 59 000
African–American women from all regions of the USA enrolled in the
BWHS by completing mailed questionnaires that included comprehen-
sive questions on medical history, use of medications, demographic fac-
tors, body size, reproductive history, family history of breast cancer and
behavioral factors. Follow-up is by biennial mailed questionnaires and
annual searches of state cancer registries and the National Death Index.
Participants are asked about new diagnoses of cancer on each questionnaire,
and pathology reports and/or state cancer registry data are obtained to con-
firm self-reports of breast cancer and to obtain data on tumor characteristics.
DNA samples were obtained from BWHS participants by the mouthwash-
swish method (13) with all samples stored in freezers at −80°C. Saliva sam-
ples were provided by approximately 50% of BWHS participants (26 800
women). Women who provided a sample were slightly older than women
who did not, but the two groups were similar with regard to geographic
region of residence, educational level, body mass index and family history
of breast cancer.
Cases for this study were all participants who had been diagnosed with
breast cancer as of 2010 and had provided a DNA sample. Data on ER status
were available from medical records for 54% of cases; 63% were classified as
ER+, and 37% as ER−.
Controls were selected from among BWHS participants with DNA sam-
ples who were free of breast cancer through 2010. Approximately, two con-
trols were selected for each case, matched on year of birth (±1 year) and
geographic region of residence (northeast, south, midwest and west). The
study protocol was approved by the institutional review board of Boston
The WCHS. This study was designed to examine the role of genetic and
non-genetic factors in relation to risk of breast cancer in African–American
and European American women. The study design, enrollment criteria and
collection of bio-specimens and questionnaire data of the WCHS have
been described in detail (14). Briefly, women diagnosed with incident
breast cancer were identified from targeted hospitals with large refer-
ral patterns for African–Americans in four boroughs of the metropolitan
New York City area and from population-based rapid case ascertainment
Abbreviations: AIMs, ancestral informative markers; BWHS, Black
Women’s Health Study; CI, confidence interval; LD, linkage disequilibrium;
OR, odds ratio; SNP, single nucleotide polymorphism; WCHS, Women’s
Circle of Health Study.
by guest on November 7, 2015
in seven counties in New Jersey through the New Jersey State Cancer
Registry. Cases were 20–75 years of age at diagnosis, with no history of
cancer other than non-melanoma skin cancer, and recently diagnosed with
primary, histologically confirmed breast cancer. Controls without a his-
tory of any cancer diagnosis other than non-melanoma skin cancer living
in the same area as cases were identified through random digit dialing of
residential telephone and cell phone numbers and community recruitment,
and were matched to cases by self-reported race and 5-year age categor-
ies. Saliva samples were collected using Oragene™ kits (DNA Genotek,
Kanata, Ontario, Canada). The study protocol was approved by the institu-
tional review boards of Roswell Park Cancer Institute, the Cancer Institute
of New Jersey, Mount Sinai School of Medicine and the participating hos-
pitals in New York City.
Selection of tag SNPs and ancestral informative markers
To select SNPs for fine-mapping, we first identified a LD block of 38 kb around
the rs2046210 SNP in the HapMap release 27 of the merged phases 2 and
3 (http://hapmap.ncbi.nlm.nih.gov/) of Han Chinese in Beijing (CHB) pop-
ulation. The LD block was identified using the confidence interval (CI) D′
algorithm developed by Gabriel et al. (15) as implemented in the Haploview
software version 4.2 (http://www.broadinstitute.org/scientific-community/sci-
then downloaded SNPs covering the entire 38 kb LD block from the HapMap
Yoruba (YRI) database from the HapMap release 27 of the merged phases 2
and 3. We used the Tagger software implemented in Haploview version 4.2 to
select all tagging SNPs with a minor allele frequency ≥ 5% and r2 ≥ 0.9. The
index rs2046210 SNP was forced into the set. A total of 14 SNPs were selected
We selected 30 ancestral informative markers (AIMs) to estimate and
control for population stratification due to European admixture in the
BWHS. The 30 AIMs were selected from a list of validated SNPs in which
the top 30 AIMs had allele frequency differences between Africans and
Europeans of at least 0.75. We used a Bayesian approach, as implemented
in the Admixmap software (16,17) to estimate individual admixture propor-
tions. We have shown previously that estimation of percentage European
versus African ancestry with 30 AIMs correlates well with the ancestry
proportion estimate obtained with a full admixture panel of approximately
1500 AIMs (18).
Genotyping and quality control
DNA from BWHS samples was isolated from the mouthwash samples at the
Boston University Molecular Core Genetics Laboratory using the QIAAMP
DNA Mini Kit (Qiagen). Whole genome amplification was done with the
Qiagen RePLI-g Kits using the method of multiple displacement amplifica-
tion with input of 50 ng of genomic DNA per reaction. Amplified samples
underwent purification and PicoGreen quantification at the Broad Institute
Center for Genotyping and Analysis (Cambridge, MA) before being plated
for genotyping. Genotyping was also carried out at the Broad Institute
Center for Genotyping and Analysis, using the Sequenom MassArray iPLEX
technology. Two percent of samples were blinded duplicates included to
assess reproducibility of genotypes. An average reproducibility of 99% was
obtained. All SNPs with a call rate of <90% or a deviation from Hardy-
Weinberg equilibrium of P < 0.001 in the control sample were excluded. We
also excluded samples with call rates of <80%. The final analysis included 13
tagging SNPs in 3132 samples (1191 breast cancer cases and 1941 controls).
The analysis included 409 cases classified as ER+, and 243 cases classified
as ER−. Mean call rate in the final data set was 98% for SNPs and 98% for
Genotyping in the WCHS was carried out at the Genomics Core Facility
at Roswell Park Cancer Institute using Sequenom MassArray iPLEX tech-
nology. A panel of 98 ancestry informative markers was genotyped to ascer-
tain genetic ancestry and control for population stratification due to genetic
admixture (19). For rs2046211, genotype data were available from 665
African–American breast cancer cases and 821 African–American controls,
and were analyzed in WCHS for this replication effort. About 70% of the
cases had data on ER status; 69% were classified as ER+ (320 cases) and 31%
as ER− (146 cases).
We used PLINK (20) version 1.06 to calculate summary statistics for the geno-
type data. We tested for association with breast cancer using the Cochran–
Armitage trend test of an additive genetic model with 10 000 permutations to
calculate empirical P values. We used PROC LOGISTIC of the SAS statistical
software version 9.1.3 (SAS Institute, Cary, NC) to estimate odds ratios (OR)
and 95% CI for the SNPs significant at the nominal values (P = 0.05). We
adjusted the ORs for year of birth, geographic region of residence (northeast,
south, midwest, west), place of birth (USA, foreign country) and European
ORs of haplotypes of significant SNPs were estimated using an expectation
substitution approach (21,22) that estimates the probabilities of all possible
haplotype configurations of each individual in the sample, conditional on her
genotype and case-control status. Haplotypes with an estimated frequency of
<1% were pooled in one single group.
The A-allele of the index SNP, rs204610, showed a breast cancer
OR in the same direction in the BWHS as observed in the original
genome-wide association study (OR = 1.10 in BWHS and OR = 1.29
in Zheng et al.(1)), but the BWHS association was not statistically
significant (Table I; P = 0.10). However, we found that the minor
allele G rs2046211, located just 82 base pairs away from the index
SNP, was significantly associated with a reduced risk of breast cancer
(OR = 0.83; 95% CI = 0.70–0.99; P for trend = 0.03). The association
was most evident for ER− breast cancer (OR = 0.60; 95% CI = 0.42–
0.88, P for trend = 0.008).
We then asked WCHS investigators to genotype rs2046211 in
their African–American case and controls samples. Results from the
WCHS were in the same direction as in BWHS (Table I). In combined
analyses of BWHS and WCHS results, the G-allele of rs2046211 was
significantly associated with an overall reduced risk of breast cancer
(OR = 0.84; 95% CI = 0.73–0.97; P for trend = 0.02). The associa-
tion was somewhat stronger in ER− breast cancer (OR = 0.71; 95%
CI = 0.50–1.02) as compared with ER+ breast cancer (OR = 0.88;
95% CI = 0.72–1.09).
We then conducted a joint analysis (i.e. a logistic regression
model with both SNPs included) of the index rs2046210 SNP and
the newly found rs2046211 SNP in the BWHS. The rs2046210-A
allele was associated with increased risk of breast cancer (OR = 1.14;
95% CI = 1.02–1.28; P for trend = 0.02), and the rs2046211-G allele
was associated with reduced risk (OR = 0.80; 95% CI = 0.67–0.95;
P for trend= 0.01) (Table II). Haplotype analysis of both SNPs con-
firmed these results (Table II). Haplotype frequency distributions
were significantly different between breast cancer cases and controls
(P = 0.008). The rs2046211-C/rs2046210-A haplotype (CA haplo-
type) was more frequent in cases than controls (54.2% versus 50.3%,
respectively; P = 0.003) and was associated with a 14% increase of
Table I. ORa and 95% CIs for the previously reported rs2046210 SNP and
the newly identified rs2046211 SNP in the 6q25.1 region
SNP_alleleAllele frequency (%)Per-allele, OR
Cases (N)Controls (N)
Replication in WCHS
61.0 (1841)1.10 (0.98–1.22) 0.10
1.09 (0.93–1.28) 0.26
1.04 (0.85–1.27) 0.73
10.8 (1842)0.83 (0.70–0.99) 0.03
0.95 (0.75–1.21) 0.70
0.60 (0.42–0.88) 0.008
9.3 (821)0.86 (0.67–1.12) 0.26
0.76 (0.54–1.08) 0.13
0.88 (0.57–1.38) 0.58
10.3 (2663)0.84 (0.73–0.97) 0.02
0.88 (0.72–1.09) 0.25
0.71 (0.50–1.02) 0.07
aAdjusted for year of birth, geographic region of residence, place of birth and
bMeta-analysis under a random effects model.
E.A.Ruiz-Narváez et al.
by guest on November 7, 2015
breast cancer risk. On the other hand, the rs2046211-G/rs2046210-A
haplotype (GA haplotype) was less frequent in cases than controls
(9.1% versus 10.7%, respectively; P = 0.04) and was associated with
a 10% reduction of breast cancer risk.
We also assessed other SNPs in the 6q25.1 region that have been
reported to be associated with breast cancer risk in African ancestry pop-
ulations (2,3). None of those SNPs was associated with breast cancer
risk in the BWHS (Table III). However, it is noteworthy that all the pre-
viously reported high-risk alleles were in complete or high LD with the
high-risk CA haplotype that we are reporting in this study. For example,
the high-risk G-allele of rs9397435 reported by Stacey et al. (3) appeared
only in the presence of the high-risk CA haplotype in the BWHS (Table
III). In addition, the G-allele of rs3757322 (i.e. a perfect proxy of the
rs6913578 and rs7763637 reported by Cai et al. (2)) was in high LD
with the high-risk CA haplotype (i.e. 97% of the rs3757322-G alleles
appear in the presence of the CA haplotype). The G-allele of rs3757322
was only associated with a higher risk of breast cancer in presence of
the high-risk CA haplotype (Table III). The high LD between rs9397435
and rs3757322 with the high-risk CA haplotype suggests that these two
SNPs do not have independent effects on the risk of breast cancer. In
conditional haplotype analysis, the association between the high-risk CA
haplotype and breast cancer risk was not modified by either rs9397435
(P = 0.65) or rs3757322 (P = 0.50) (Table III).
In this study, we report a novel SNP, rs2046211, that is associated with
breast cancer risk in African–American women. The signal tagged
Table II. Combined and haplotype analysis of the rs2046210 and rs2046211 SNPs in the Black Women’s Health Study
Combined modelsPer-allele, ORa (95% CI)
P for trend
Haplotype Haplotype frequency (%) OR (95% CI)
rs2046211 rs2046210Cases Controls
aAdjusted for year of birth, geographic region of residence, place of birth and European admixture.
bP for difference of haplotype frequency between cases and controls.
Table III. ORa and 95% CIs of previously reported SNPs in fine-mapping of the 6q25.1 region and their relationships with rs2046211/rs2046210 haplotypes in
the Black Women’s Health Study
Haplotype Haplotype frequency (%)OR (95% CI)
rs9397435 rs2046211rs2046210Cases Controls
G (by itself)
P for independent effect of the rs9397435 SNP = 0.65
G (by itself)
P for independent effect of the rs3757322 SNP = 0.50
aAdjusted for year of birth, age, geographic region of residence, place of birth and European admixture.
bP for difference of haplotype frequency between cases and controls.
6q25 locus and breast cancer in black women
by guest on November 7, 2015
by rs2046211 seems to be a different one from the signal tagged by
rs2046210, which was initially identified in Chinese women (1). In our
analyses, the association with rs2046210 was statistically significant
only after adjusting for rs2046211, which may explain the previously
failed efforts to replicate rs2046210 association with breast cancer in
African ancestry populations (2,3,5–7). The present results also help
to narrow the position of the causal variants tagged by rs2046210 and
rs2046211 because both SNPs are located in a smaller LD block of
about 15 kb in HapMap YRI samples.
Interestingly, in genome-wide association study, data from the
Women’s Health Initiative African American SHARe Study, the
OR for the G-allele of rs2046211 was 0.91 (95% CI = 0.71–1.18)
(supplementary data in (6)). Meta-analysis of our estimates (BWHS +
WCHS) with the Women’s Health Initiative estimates resulted in an
overall breast cancer risk of 0.86 (95% CI = 0.75–0.97), P = 0.02 for
the G-allele of rs2046211.
The high-risk rs2046210 A-allele is more frequent in African ances-
try populations (e.g. 69% in HapMap YRI, 61% in the BWHS) as com-
pared with east Asian ancestry populations (e.g. 38% in HapMap CHB)
or European ancestry populations (e.g. 29% in HapMap CEU). This dif-
ference in allele frequencies suggests that in African ancestry popula-
tions, the rs2046210-A allele may consist of different haplotypes, with
different risk associations. Our results show that in African Americans,
the rs2046210-A allele was present in both a high-risk haplotype (i.e.
the CA haplotype) and a low-risk haplotype (i.e. the GA haplotype)
composed of a second SNP rs2046211 newly found in our analyses.
Previous replication efforts may have failed because they were only
measuring the marginal effect of the rs2046210-A allele, which would
be attenuated in an African ancestry population without considering
the neighboring rs2046211. It is noteworthy that the frequency of the
G-allele of rs2046211 is as low as 2% in HapMap CHB population
as compared with 15% in HapMap YRI population and 10% in this
study, suggesting that in east Asian populations the low-risk haplotype
is either absent or in low frequency. The rs2046210-A allele in east
Asian populations would consist, mostly, of the high-risk haplotype.
Our present results shed light on the findings of previous genotyp-
ing efforts in the 6q25.1 region. Stacey et al. (3). conducted exten-
sive genotyping in the 6q25.1 region and identified several SNPs
associated with breast cancer in east Asian, European, Nigerian and
African–American women. In particular, they reported a significant
association between rs9397435 (minor allele frequency = 32.6% in
east Asian women, 6.3% in European women and 6.3% in Nigerian
and African–American women) and breast cancer risk in the three dif-
ferent ancestries. Rs9397435 is highly correlated (r2 = 0.72, D′ = 1.00)
with rs2046210 in the HapMap CHB population. The fact that Stacey
et al. (3). reported similar ORs for both SNPs in east Asian women
(OR = 1.23 for rs9397435 and OR = 1.24 for rs2046210) suggests that
both SNPs are tagging the same causal variant in east Asian popula-
tions. Although not significant, we found rs9397435 to have an OR in
the same direction as that reported by Stacey et al. in African ancestry
women (OR = 1.17 in the BWHS and OR = 1.35 in Stacey et al. (3)).
It is noteworthy that the G-allele of rs9397435 (i.e. the high-risk allele
reported by Stacey et al.) is in complete LD with the high-risk CA
haplotype we report in this study. The fact that the association between
the high-risk CA haplotype and breast cancer risk was not modified by
the presence of the rs9397435-G allele suggests that the association
reported by Stacey et al. in African ancestry women is probably due to
the complete LD with the high-risk CA haplotype. Insufficient power
may explain the failure to find a significant association of rs9397435
by itself in the BWHS. The G-allele of rs9397435 has a frequency of
7.6% in the BWHS, and the high-risk CA haplotype has frequency of
50% in the BWHS. This means that rs9397435 G-allele is just a sub-
haplotype of the high-risk CA haplotype. The power to detect an OR
of 1.14 (i.e. the OR of the high-risk CA haplotype) in a subhaplotype
of 7.6% frequency (i.e. the GCA subhaplotype) is only 31%.
In functional studies of the region between the C6orf97 and
ESR1 genes, Cai et al.(2) identified two candidate functional SNPs.
Rs6913578 and rs7763637 are in high LD with rs2046210 in Chinese
and European ancestry populations but not in African ancestry
populations. These two SNPs were associated with breast cancer risk
in both Chinese women and European ancestry Americans, and the
associations were stronger than with rs2046210 in European ancestry
Americans. The SNPs were not associated with breast cancer risk in
African Americans; however, the per-allele ORs approached statistical
significance after control for rs2046210. Although we did not geno-
type either of these two SNPs, which are in perfect LD (r2 = 1.00)
in HapMap YRI population, we genotyped the proxy rs3757322
(r2 = 0.96). Although rs3757322 was not significantly associated with
breast cancer risk by itself, we found that in the presence of the high-
risk CA haplotype, the G-allele of rs3757322 is indeed associated
with higher risk of breast cancer. Our results show that the associ-
ations reported by Cai et al. (2) in African–American women are most
probably due to the high-risk CA haplotype, as shown by the high LD
between rs3757322 and the high-risk CA haplotype and the absence
of independent effect of rs3757322 after conditioning for the high-
risk CA haplotype.
In summary, the results provide evidence of a second signal, tagged
by rs2046211, in the 6q25.1 region that is independent of rs2046210
previously reported in east Asian women. Haplotype analysis of
rs2046211 and rs2046210 showed that the latter is indeed associated
with breast cancer risk in African–American women after adjusting
for the haplotype background that included rs2046211.
National Institutes of Health (R01 CA058420 and R01 CA098663);
and the Susan G. Komen for the Cure Foundation. The WCHS
is supported by grants from National Institutes of Health (R01
CA100598); United States Army Medical Research and Material
Command (DAMD-17-01-1-0334). The research teams of both
BWHS and WCHS are also supported by the National Cancer
Institute (P01 CA151135). National Cancer Institute (K22
CA138563 to E.V.B.).
We thank the Black Women’s Health Study participants for their continuing
participation in this research effort. The content is solely the responsibility of
the authors and does not necessarily represent the official views of the United
States Army, the National Cancer Institute or the National Institutes of Health.
We thank the following state cancer registries for pathology data (AZ, CA,
CO, CT, DE, DC, FL, GA, IL, IN, KY, LA, MD, MA, MI, NJ, NY, NC, OK,
PA, SC, TN, TX, VA); results reported do not necessarily represent their views.
Conflict of Interest Statement: None declared.
1. Zheng,W. et al. (2009) Genome-wide association study identifies a new
breast cancer susceptibility locus at 6q25.1. Nat. Genet., 41, 324–328.
2. Cai,Q. et al. (2011) Replication and functional genomic analyses of the
breast cancer susceptibility locus at 6q25.1 generalize its importance in
women of chinese, Japanese, and European ancestry. Cancer Res., 71,
3. Stacey,S.N. et al. (2010) Ancestry-shift refinement mapping of the C6orf97-
ESR1 breast cancer susceptibility locus. PLoS Genet., 6, e1001029.
4. Turnbull,C. et al. Breast Cancer Susceptibility Collaboration (UK). (2010)
Genome-wide association study identifies five new breast cancer suscepti-
bility loci. Nat. Genet., 42, 504–507.
5. Zheng,W. et al. (2009) Evaluation of 11 breast cancer susceptibility loci
in African-American women. Cancer Epidemiol. Biomarkers Prev., 18,
6. Hutter,C.M. et al. (2011) Replication of breast cancer GWAS susceptibil-
ity loci in the Women’s Health Initiative African American SHARe Study.
Cancer Epidemiol. Biomarkers Prev., 20, 1950–1959.
7. Huo,D. et al. (2012) Evaluation of 19 susceptibility loci of breast cancer in
women of African ancestry. Carcinogenesis, 33, 835–840.
8. Helgason,A. et al. (2007) Refining the impact of TCF7L2 gene variants on
type 2 diabetes and adaptive evolution. Nat. Genet., 39, 218–225.
E.A.Ruiz-Narváez et al.
by guest on November 7, 2015
9. Ramos,E. et al. (2011) Replication of genome-wide association stud-
ies (GWAS) loci for fasting plasma glucose in African-Americans.
Diabetologia, 54, 783–788.
10. Charles,B.A. et al. (2011) A genome-wide association study of serum uric
acid in African Americans. BMC Med. Genomics, 4, 17.
11. Chen,G. et al. (2012) UGT1A1 is a major locus influencing bilirubin levels
in African Americans. Eur. J. Hum. Genet., 20, 463–468.
12. Ioannidis,J.P. et al. (2009) Validating, augmenting and refining genome-
wide association signals. Nat. Rev. Genet., 10, 318–329.
13. Cozier,Y.C. et al. (2004) Comparison of methods for collection of DNA
samples by mail in the Black Women’s Health Study. Ann. Epidemiol., 14,
14. Ambrosone,C.B. et al. (2009) Conducting Molecular Epidemiological
Research in the Age of HIPAA: A Multi-Institutional Case-Control Study
of Breast Cancer in African-American and European-American Women. J.
Oncol., 2009, 871250.
15. Gabriel,S.B. et al. (2002) The structure of haplotype blocks in the human
genome. Science, 296, 2225–2229.
16. Hoggart,C.J. et al. (2003) Control of confounding of genetic associations in
stratified populations. Am. J. Hum. Genet., 72, 1492–1504.
17. McKeigue,P.M. et al. (2000) Estimation of admixture and detection
of linkage in admixed populations by a Bayesian approach: applica-
tion to African-American populations. Ann. Hum. Genet., 64(Pt 2),
18. Ruiz-Narváez,E.A. et al. (2011) Validation of a small set of ances-
tral informative markers for control of population admixture in African
Americans. Am. J. Epidemiol., 173, 587–592.
19. Smith,M.W. et al. (2004) A high-density admixture map for disease gene
discovery in african americans. Am. J. Hum. Genet., 74, 1001–1013.
20. Purcell,S. et al. (2007) PLINK: a tool set for whole-genome associ-
ation and population-based linkage analyses. Am. J. Hum. Genet., 81,
21. Zaykin,D.V. et al. (2002) Testing association of statistically inferred hap-
lotypes with discrete and continuous traits in samples of unrelated individ-
uals. Hum. Hered., 53, 79–91.
22. Stram,D.O. et al. (2003) Modeling and E-M estimation of haplotype-spe-
cific relative risks from genotype data for a case-control study of unrelated
individuals. Hum. Hered., 55, 179–190.
Received July 19, 2012; revised October 5, 2012; accepted October 18, 2012
6q25 locus and breast cancer in black women
by guest on November 7, 2015