Admixture mapping identifies a locus on 6q25
associated with breast cancer risk in US Latinas
Laura Fejerman1, Gary K. Chen3, Celeste Eng2, Scott Huntsman1, Donglei Hu1, Amy Williams4,
Bogdan Pasaniuc5, Esther M. John6,7, Marc Via2,10, Christopher Gignoux2, Sue Ingles3,
Kristine R. Monroe3, Laurence N. Kolonel8, Gabriela Torres-Mejı ´a9, Eliseo J. Pe ´rez-Stable1,
Esteban Gonza ´lez Burchard2, Brian E. Henderson3, Christopher A. Haiman3,∗and Elad Ziv1,∗
1Department of Medicine, Division of General Internal Medicine, Institute for Human Genetics and Helen Diller Family
Comprehensive Cancer Center and2Department of Medicine, Pulmonary and Critical Care Division, Institute for
Human Genetics, University of California San Francisco, San Francisco, CA 94158, USA,3Department of Preventive
Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los
Angeles, CA 90033, USA,4Department of Genetics, Harvard Medical School, Boston, MA 02115, USA,5Dept of
Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA and6Cancer Prevention Institute of
California, Fremont, CA 94538, USA,7Department of Health Research and Policy, Stanford University School of
Medicine, Stanford, CA 94305, USA,8University of Hawaii Cancer Center, Honolulu, HI 96813, USA,9Instituto
Nacional de Salud Publica, Cuernavaca, Morelos 62100, Mexico, and10Unit of Anthropology, Department of Animal
Biology, Universitat de Barcelona, Barcelona, Spain
Received August 10, 2011; Revised October 23, 2011; Accepted December 28, 2011
Among US Latinas and Mexican women, those with higher European ancestry have increased risk of breast
cancer. We combined an admixture mapping and genome-wide association mapping approach to search for
genomic regions that may explain this observation. Latina women with breast cancer (n 5 1497) and Latina
controls (n 5 1272) were genotyped using Affymetrix and Illumina arrays. We inferred locus-specific genetic
ancestry and compared the ancestry between cases and controls. We also performed single nucleotide poly-
morphism (SNP) association analyses in regions of interest. Correction for multiple-hypothesis testing was
conducted using permutations (Pcorrected). We identified one region where genetic ancestry was significantly
associated with breast cancer risk: 6q25 [odds ratio (OR) per Indigenous American chromosome 0.75, 95%
confidence interval (CI): 0.65–0.85, P 5 1.1 3 1025, Pcorrected5 0.02]. A second region on 11p15 showed a
trend towards association (OR per Indigenous American chromosome 0.77, 95% CI: 0.68–0.87, P 5 4.3 3
1025, Pcorrected5 0.08). In both regions, breast cancer risk decreased with higher Indigenous American ances-
try in concordance with observations made on global ancestry. The peak of the 6q25 signal includes the es-
trogen receptor 1 (ESR1) gene and 5′region, a locus previously implicated in breast cancer. Genome-wide
association analysis found that a multi-SNP model explained the admixture signal in both regions. Our
results confirm that the association between genetic ancestry and breast cancer risk in US Latinas is
partly due to genetic differences between populations of European and Indigenous Americans origin. Fine-
mapping within the 6q25 and possibly the 11p15 loci will lead to the discovery of the biologically functional
variant/s behind this association.
∗To whom correspondence should be addressed. Tel: +1 4155144930; Fax: +1 4155144982; Email: firstname.lastname@example.org (E.Z.); Tel: +1 3234427755;
Fax: +1 3234427749; Email: email@example.com (C.A.H.)
# The Author 2012. Published by Oxford University Press. All rights reserved.
For Permissions, please email: firstname.lastname@example.org
Human Molecular Genetics, 2012, Vol. 21, No. 8
Advance Access published on January 6, 2012
Breast cancer incidence varies substantially across different
racial and ethnic groups in the USA. The age-adjusted inci-
dence of breast cancer from 2002 to 2006 in US non-Latino
Whites and African Americans is 123.5 and 113.0 per
100 000 respectively, whereas US women of Latin American
origin have an incidence of 90.2 (1). We have previously
demonstrated that genetic ancestry is associated with breast
cancer risk in US Latinas (2) and replicated these results in
a sample of Mexican women (2,3). In both studies, higher
European ancestry was associated with increased risk and
higher Indigenous American ancestry was associated with
decreased risk of breast cancer. We found that multiple non-
genetic risk factors were associated with genetic ancestry
and could confound the association between ancestry and
breast cancer risk in both US Latinas and Mexican women.
However, in both studies, genetic ancestry remained statistic-
ally significant after adjustment for known non-genetic risk
factors, which suggests that genetic ancestry is a proxy for un-
measured risk factors and/or there is a genetic component to
the difference in risk. Here, we explored the latter hypothesis
using an admixture-based approach.
Admixture mapping leverages the demographic history of
admixed populations to map susceptibility loci (4–12). A
population is considered admixed if it results from the combin-
ation of two or more ancestral population groups (5). The prin-
ciple of admixture mapping is to identify genomic regions in
which cases share more of the same genetic ancestry compared
with either population-based controls (case–control analysis)
or compared with the average ancestry of the rest of the
genome among cases (case-only analysis) (7). This approach
has been used successfully to identify risk variants or risk
regions for prostate cancer (9,11), obesity (10), white cell
count (4,12), hypertension (8), interleukin 6 soluble receptor
and interleukin 6 levels (6,9).
Genome-wide association studies (GWAS) in women of
European and Asian origin have reported multiple risk variants
for breast cancer (13–23). To date, there is no published breast
cancer GWAS in Latinas. We have initiated a multi-stage
GWAS of breast cancer in Latinas and in the present study
we report results of an admixture mapping analysis in the
stage 1 sample, which was motivated by our earlier findings
of an ancestry association with breast cancer in Latinas. In
this study, we have identified regions of the genome
showing breast cancer associations with increased European
ancestry that may be putative risk loci for breast cancer.
This study included a total of 1497 US Latina cases and 1160
controls from three studies [San Francisco Bay Area Breast
Cancer Study (SFBCS), the Northern California Site of the
Breast Cancer Family Registry (NC-BCFR) and the Multi-
ethnic Cohort (MEC)] that are part of stage 1 in a GWAS of
breast cancer (Table 1), as well as an additional 112 popula-
tion controls from study of asthma in Latinos. Subjects from
the NC-BCFR were younger and a higher proportion of
cases had a family history of breast cancer, which reflects
the oversampling of cases with indicators of increased
genetic susceptibility. In contrast, women from the MEC
were 50 years and older and were significantly older on
average than women in either of the other studies. Results of
univariate analyses comparing breast cancer cases and controls
for the different characteristics are concordant with previously
reported associations. Cases in all studies reported fewer
full-term pregnancies and higher family history of breast
cancer. In the SFBCS and MEC studies, the cases were slight-
ly older than the controls. In each of the studies, the cases also
had higher European ancestry (and lower Indigenous Ameri-
can ancestry) (Table 1).
Association between locus-specific ancestry and breast
cancer risk in US Latinas
We found one region that showed a strong admixture mapping
signal at 148–155 Mb at 6q25 [odds ratio (OR) per Indigenous
American chromosome 0.75, 95% confidence interval (CI):
0.65–0.85, P ¼ 1.1 × 1025]. A second region at 12–23 Mb
at 11p15 showed a slightly weaker association (OR per Indi-
genous American chromosome 0.77, 95% CI: 0.68–0.87,
P ¼ 4.3 × 1025). There were also regions on 5p15 (11–
24 Mb), 4q28 (127–142 Mb) and 2p13 (68–76 Mb) showing
suggestive associations (5p15 OR 1.31, 95% CI: 1.14–1.49,
P ¼ 8.3 × 1025; 4q28 OR 1.29, 95% CI: 1.13–1.47, P ¼
2.0 × 1024; 2p13 0.77, 95% CI: 0.68–0.89, P ¼ 2.5 × 1024)
(Fig. 1). Previous GWAS have not reported risk variants
within these last three regions (for a list of genes within
each oftheseregions, see
Table S1). For the two strongest signals at 6q25 and 11p15,
increased Indigenous American ancestry was associated with
reduced breast cancer risk. As expected, the results for the
European component of ancestry were inversely correlated
with the results of the Indigenous American component. We
compared the results of the HAPMIX (24) -based admixture
mapping analysis to results obtained using the LAMP 2.5 soft-
ware for locus-specific ancestry estimation (25) and the signals
were consistent between the two analyses.
Genome-wide significance for admixture mapping has been
empirically evaluated for African Americans (26), but has not
yet been empirically evaluated for Latin American popula-
tions. Therefore, we evaluated the significance of the
admixture mapping peaks by means of a permutation test
(Supplementary Material, Table S3). Case/control status was
permuted within five individual Indigenous American ancestry
categories to reproduce the asymmetry of the global ancestry
distribution between cases and controls at each permutation.
A signal equal or stronger to the one at 6q25 occurred in 21
of 1000 permutations (Pcorrected¼ 0.022) and in 78 of 1000
(Pcorrected¼ 0.079) at 11p15. The signals at 5p15, 4q28
and 2p13 had a corrected P-value . 0.1 and are no longer
The 7 Mb region at 6q25 contains 74 genes, with the peak
of the signal spanning the estrogen receptor 1 (ESR1) gene
[MIM: 133430], which has been previously identified as a sus-
ceptibly locus for breast cancer reported in GWAS in Asian
and European ancestry populations (18,27,28). The 11 Mb
region at 11p15 contains 110 genes, with the peak of the
1908Human Molecular Genetics, 2012, Vol. 21, No. 8
signal spanning the neuron navigator 2 (NAV2) gene [MIM:
607026] (Supplementary Material, Table S1).
There is increasing evidence of etiologic heterogeneity due
to both genetic and non-genetic risk factors for breast cancer
subtypes (19,20,29–31). Therefore, we performed hypothesis-
generating analyses by subgroups defined by ER status (Fig. 2,
Supplementary Material, Fig. S2) for the two regions with sig-
nificant admixture mapping signals. The signal at 6q25 was
stronger for ER-positive breast cancer (n ¼ 827 cases) as
opposed to the association with ER-negative breast cancer
(n ¼ 297 cases). There was no apparent difference at 11p15
by ER status. In examining the signals for ER-positive
breast cancer, we observed no other significant or near-
significant peaks besides the 6q25 locus. The difference in
the strength of the ER-positive signal could be due to the
smaller sample size for the ER-negative tumors. We further
tested for heterogeneity by evaluating the effect of locus-
specific ancestry at these two regions by ER-positive versus
ER-negative disease. We did not find statistically significant
associations. For the 6q25 region, the OR for the association
of Indigenous American locus-specific ancestry and risk of
ER-positive disease (versus ER-negative disease) was 0.76
(95%CI: 0.47–1.23, P ¼ 0.27) and, for the 11p15 region, it
was 1.25 (95%CI: 0.78–2.01, P ¼ 0.36).
Body mass index is a strong predictor of post-menopausal
breast cancer risk (32–35) and also varies with genetic ances-
try (36). Therefore, we re-tested the models for locus-specific
ancestry after adjustment for age and body mass index. We
found that the results were unchanged for both 6q25 (OR
per Indigenous ¼ 0.74, P ¼ 1.4 × 1025) and 11p15 (OR per
Indigenous chromosome ¼ 0.76, P ¼ 5.6 × 1025).
Attempt to fine map the admixture signals at 6q25 and
6q25: multiple single nucleotide polymorphisms (SNPs) at
6q25 in the 5′of ESR1 have been associated with breast
cancer in previous studies (18,22,27,28). In Latinas, we
Table 1. Sample characteristics by study
n ¼ 345
n ¼ 625
n ¼ 546
n ¼ 551
n ¼ 59
n ¼ 558
Mean age at diagnosis or
Mean European ancestry (SD)b
Mean Ind. American ancestry
Mean African ancestry (SD)b
Family history BC
Age at first FTP
,20 years (%)
20–30 years (%)
.30 years (%)
Age at menarche
≤12 years (%)
13–14 years (%)
≥15 years (%)
Number of FTP
HT use if postmenop.
56.0 (11.2) 54.0 (11.0)0.006 47.7 (10.0)48.9 (11.4)0.366 65.9 (7.9) 64.6 (7.7)0.005
0.08 (0.04)0.08 (0.07)0.582 0.08 (0.09)0.08 (0.05) 0.7530.06 (0.03)0.06 (0.03)0.199
SD: standard deviation; Ind. American, Indigenous American; HT, hormone therapy; BC, breast cancer; BMI, body mass index; FTP, full-term pregnancies.
aP-values for two-way tables Fisher exact test of association for binary variables and two sample t test for continuous variables.
bThe difference in average global individual ancestry is not statistically significant between individuals with ER positive and negative tumors.
Human Molecular Genetics, 2012, Vol. 21, No. 81909
found no statistically significant associations between these
[rs3757318 (22) (G/A) OR ¼ 1.18, P ¼ 0.15, risk allele
frequency (RAF): 0.07 (A allele); rs2046210 (18) (G/A)
OR ¼ 1.07, P ¼ 0.23, RAF: 0.28 (A allele); rs9397435 (28)
(A/G)OR ¼ 1.15,
P ¼ 0.22,RAF:0.06 (Gallele);
Figure 1. Results of breast cancer admixture mapping. On the X-axis are genomic positions by chromosome. On the Y-axis are the negative log10P-values for
the association between locus-specific ancestry and breast cancer risk. (A) Admixture mapping for Indigenous American component. (B) Admixture mapping for
European component. (C) Admixture mapping for Africa component.
Figure 2. Results of ER subtype-specific breast cancer admixture mapping for the Indigenous American component. On the X-axis are genomic positions within
each chromosome. On the Y-axis are the negative log10P-values for the association between locus-specific ancestry and ER-specific breast cancer subtype.
Results for ER-positive analyses are in blue and for ER-negative analyses are in red.
1910 Human Molecular Genetics, 2012, Vol. 21, No. 8
rs6913578 (27) (A/C) OR ¼ 1.09, P ¼ 0.17, RAF: 0.25 (C
allele)], nor evidence that these variants account for the ad-
mixture signal in the region (OR per Indigenous American
chromosome 0.75, 95%CI: 0.69–0.81, P ¼ 3.0 × 1025adjust-
ing for known risk SNPs). We then investigated the possibility
that a single variant not previously reported may explain the
association between locus-specific ancestry and breast cancer
risk. We tested genotyped and imputed SNPs (imputed from
the 1000 genome project, http://www.1000genomes.org) that
were nominally significant for association with breast cancer
risk in analyses adjusted for global and locus-specific ancestry;
within the 7 Mb admixture signal at 6q25, there were 206
SNPs (out of 16 690 with minor allele frequency (MAF) .
5%) with a P , 0.001 (Supplementary Material, Table S2).
We found that no individual SNP could completely attenuate
the locus-specific ancestry signal (Fig. 3). The strongest
single association was with rs79692348 which attenuated the
association with locus-specific ancestry but did not completely
eliminate it (OR ¼ 0.82 per Indigenous chromosome, P ¼
Based on this observation, we investigated models with
more than one SNP. We used a step-forward approach and
successively included the SNPs with the lowest P-values
within the region that were weakly correlated with each
Figure 3. Admixture mapping and SNP association results. The solid line represents the admixture mapping signal. The blue dots represent the negative log10
P-values of association between single SNPs and breast cancer risk (all SNPs that showed an association with breast cancer risk at a P-value ≤ 0.05 were
included). The red dots represent the locus-specific ancestry association after adjustment for selected individual SNPs (SNPs that showed an association with
breast cancer at a P-value ≤ 0.001). The blue dots with black hollow squares are the SNPs that modified the locus-specific ancestry association signal represented
by the red dots. (A) 6q25 region. (B) 11p15 region.
Human Molecular Genetics, 2012, Vol. 21, No. 81911
other (r2≤ 0.2). We stopped adding SNPs at the point in which
the locus-specific ancestry association had a P-value . 0.05.
At 6q25, a multi-SNP model could explain the locus-specific
ancestry signal with four SNPs (rs79692348, rs4304175,
rs9383928, rs7747474). Three of these SNPs are within the
5′region of the ESR1 locus (within the C6orf97 gene). In add-
ition, none of these SNPs is correlated with those previously
reported to be associated with breast cancer at the ESR1
locus (r2≤ 0.1). The rs79692348 marker, which shows the
strongest association with risk in the SNP association analysis,
has an allele frequency of ,1% in African and European
populations (Supplementary Material, Table S4).
11p15: there were 128 SNPs (out of 26 051 with MAF .
5%) that were nominally significant (P , 0.001) in the
GWAS case–control analysis in the 11 Mb region (Supple-
mentary Material, Table S2). In conditional analyses with
locus-specific ancestry, no individual SNP could fully
account for the local ancestry signal (Fig. 3). However, a
two-SNP model attenuated the locus-specific ancestry com-
pletely (rs10444227, rs4757841) (Table 2). These two SNPs
are within the NAV2 gene. Allele frequencies for these
markers differ slightly between Asians/Indigenous American
and European populations and are less common in Africans
(Supplementary Material, Table S4).
The 11p15 signal is 18 Mb from the LSP1 gene [MIM:
153432] found to be associated with breast cancer risk in pre-
vious GWAS (17,22), and therefore does not overlap with the
LSP1 region association previously reported. The published
associated SNPs within the LSP1 region did not show a statis-
tically significant association in the Latinas GWAS analysis
[rs909116 (C/T), P ¼ 0.14 and rs3817198 (C/T), P ¼ 0.45].
The allele frequencies for the two published SNPs are
similar between Europeans and the US Latinas (0.53/0.57
and 0.30/0.22). Therefore, it is unlikely that an association
with the SNPs within the LSP1 gene is driving the admixture
mapping results on 11p15.
In the first breast cancer admixture mapping scan in US
Latinas, we found a genome-wide statistically significant
signal of increased European ancestry among cases compared
with controls at 6q25. A second region at 11p15 also demon-
strated a trend towards increased European ancestry among
cases. At both regions, higher Indigenous American ancestry
was associated with reduced breast cancer risk, whereas
higher European ancestry was associated with increased risk.
The direction of the locus-specific ancestry associations is
consistent with our previous result showing that global indi-
vidual ancestry in US Latina and Mexican women is asso-
ciated with breast cancer risk, with higher Indigenous
American ancestry being associated with reduced risk (2,3).
The associations with locus-specific ancestry could not be
explained by any single common SNP from the GWAS data.
Thus, these signals are likely to be reflecting associations
with variants in these regions that are biologically functional
and that are not well captured by the SNPs we tested.
The peak of the signal at 6q25 is located at the ESR1 locus,
which has been associated with breast cancer in previous
GWAS in Asians and Europeans (18,22). Even though differ-
ent studies have reported associations near the ESR1 gene,
results are not consistent as different SNPs seem to be respon-
sible for the association in different populations (22,28). The
original GWAS study that reported an association between
variant rs2046210 and breast cancer was conducted in a
sample of Chinese women from Shanghai (18). Turnbull
et al. (22) evaluated the 6q25.1 region in breast cancer cases
and controls of European ancestry and reported that another
SNP (rs3757318) showed the strongest association (r2with
rs2046210 of 0.48 and 0.09 in Asian and European populations
from HapMap, respectively). A multiethnic fine-mapping study
in samples of European, Asian and African origin reported a
third marker (rs9397435) to be consistently associated with
risk across populations (r2. 0.65 with rs2046210 and
rs3757318 in Asians) (28). A later study involving Chinese,
Japanese, European and African American samples reported
that the effect of the rs2046210 variant might be due to its as-
sociation (r2¼ 0.91 inChinese and 0.83 inindividuals of Euro-
pean ancestry) with another putatively functional variant
identified in the region, rs6913578 (27).
None of these SNPs was significantly associated with breast
cancer risk in our analyses, although statistical power to detect
the reported OR’s was limited (we had 25–80% power to
detect the reported effect sizes for these risk variants). The
Table 2. Locus-specific ancestry (LSA) association adjusting for multiple SNPs
aOR shows effect of LSA per chromosome.
bThese are the P-values for the effect of LSA in the model with no adjustment and the models adjusting for multiple SNPs.
cTested allele/reference allele.
dAllele frequency for the tested allele in US Latinas (in parenthesis is the frequency in Europeans, Supplementary Material, Table S4).
eOR per allele for each SNP (per allele) and breast cancer risk.
1912 Human Molecular Genetics, 2012, Vol. 21, No. 8
ORs for these previously published SNPs in our study were in
the same direction as those reported.
Our results showed that there were no individual SNPs
within the admixture mapping signal that accounted for the
locus-specific ancestry association. Instead, we found that a
multi-SNP model, comprised of SNPs that were associated
with risk (P , 0.001) and that were weakly correlated, could
attenuate the admixture mapping signal. Our results suggest
that the locus-specific ancestry signal as well as the multi-SNP
model may be capturing the presence of a separate single or
multiple risk variants for breast cancer at this locus. Three
of the SNPs in the multi-SNP model are located within the
C6orf97 gene. A recent study showed three open reading
frames located upstream 50–250 Kb of ESR1 (C6orf97,
C6orf96 and C6orf211) that are co-expressed with ESR1
(37). Therefore, the biologically functional variant(s) at this
region may either directly affect ESR1 expression and activity
or affect the expression and activity of one or more of these
In the 11p15 region, several SNPs were independently
associated with breast cancer risk (the lowest P-value was
6.4 × 1026) (Supplementary Material, Table S2); however,
none of these SNPs alone could account for the strong associ-
ation with local ancestry. All of the variants are located within
the NAV2 gene also known as helicase, APC down-regulated 1
(HELAD1) and retinoic acid inducible in neuroblastoma cells
(RAINB1). NAV2 spans 400 Kb and has been reported to be
up-regulated in colorectal carcinomas (38) and to be involved
in neuronal development (39). Like at 6q25, multiple SNPs
define the admixture signal; however, their independent asso-
ciations were not strong which suggests that local ancestry is
the best proxy of any biologically functional variant(s) in
We were not able to find any individual SNP that could
explain the association between breast cancer risk and local
ancestry in these regions. Prior studies utilizing admixture
mapping have revealed a single common variant that underlies
the association between IL6 soluble receptor level (6) and
white blood cell count (12). However, admixture mapping
for prostate cancer in African Americans revealed several dif-
ferent independent SNPs that were responsible for the associ-
ation with African ancestry at 8q24 (40). In addition, the
association of end-stage renal disease and ancestry at the
22q12 locus, initially identified by admixture mapping, was
thought to be in MYH9 [MIM: 160775] (41,42). However,
fine-mapping and sequencing at these region revealed that
the association was actually best explained, and more likely
due to two variants in the APOL1 [MIM: 603743] gene
which is nearby (43,44). Therefore, care should be taken
with interpreting SNP associations in an admixture mapping
locus until detailed fine-mapping data are available.
iants may underlie some of the associations with common
variants detected by GWAS (45). Since no single common
iants attenuate the signal, one plausible explanation may be that
multiple rare variants at the 6q25 locus may be accounting for
the admixture mapping result that we observed. This would
explain why unlinked common variants are explaining the
admixture mapping signal. The ideal way to resolve this
question would be through sequencing studies at both loci, fol-
lowed by functional work.
Our results demonstrate that there are genomic regions that
may harbor risk variants that vary in frequency between ances-
tral populations and influence differences in breast cancer in-
cidence among US racial/ethnic groups. In previous studies,
we demonstrated that at least part of the association between
breast cancer and genetic ancestry among US Latinas and
Mexican women was due to confounding between genetic an-
cestry and non-genetic risk factors (2,3,36). In addition, there
is evidence showing that breast cancer risk increases for
second and third generation US Latinas compared with
recent immigrants (46) which supports the hypothesis that re-
productive, lifestyle and demographic factors strongly contrib-
ute to breast cancer risk. Therefore, differences in both genetic
and non-genetic factors are likely to contribute to differences
in breast cancer risk between racial/ethnic groups.
In summary, we used an admixture mapping approach to
identify two regions where genetic ancestry is associated
with breast cancer susceptibility among Latina women. One
of them, 6q25, is genome-wide statistically significant and
has been previously associated with breast cancer risk, but
the specific variants reported to affect risk do not explain
the association in our data. The other signal, 11p15, is novel
but is marginally significant at the genome-wide level and
will require further replication to be confirmed. We were not
able to find any one variant that explained the ancestry asso-
ciations at either locus. Fine-mapping within these regions
will lead to the discovery of the variant or variants that
contribute to the admixture mapping associations and will
improve our understanding of the architecture of breast
cancer risk predisposition in the Latina population.
MATERIALS AND METHODS
All participants provided written informed consent as
approved by local Human Subjects Committees.
The SFBCS is a population-based case–control study of breast
cancer, which includes 821 Latina breast cancer cases and 916
Latina controls (47,48). Cases aged 35–79 years and diag-
nosed with invasive breast cancer from 1995 to 2002 were
identified through the Greater Bay Area Cancer Registry. Con-
trols were identified by random-digit dialing in the same geo-
graphic region and were frequency matched by 5-year age
intervals. Blood specimen collection was initiated in 1999.
The present analysis includes 351 cases and 579 controls
from this study who self-identified their ethnic background
as Latina or Hispanic.
The BCFR is an international, NCI-funded resource that has
recruited and followed over 13 000 breast cancer families (49).
The present study includes BCFR samples from the
population-based Northern California site of the BCFR
(NC-BCFR). Cases aged 18–64 years and diagnosed from
1995 to 2007 were ascertained through the Greater Bay Area
Cancer Registry. Cases with indicators of increased genetic
susceptibility (diagnosis at age ,35 years, bilateral breast
Human Molecular Genetics, 2012, Vol. 21, No. 81913
cancer with the first diagnosis at age ,50 years, a personal
history of ovarian or childhood cancer, a family history of
breast or ovarian cancer in first-degree relatives) were over--
sampled. Cases not meeting these criteria were randomly
sampled (50). Population controls were identified through
random-digit dialing and frequency matched on 5-year age
group to cases diagnosed from 1995 to 1998. The present
study includes 641 cases and 61 controls from the NC-BCFR.
The MEC is a large prospective cohort study in California
(mainly Los Angeles County) and Hawaii (51). The breast
cancer study is a nested case–control study, including
women with invasive breast cancer age .50 and controls
matched by age and self-identified ethnicity (51). For the
current study, we used data and DNA samples from 546
Latina women with breast cancer and 558 matched controls.
Genetics of Asthma in Latino Americans (GALA1): the
GALA1 study is a family-based study (including children
with asthma and their parents) of pediatric asthma in Latino
Americans (52). The sample includes 294 individuals of
Mexican origin and 365 individuals from Puerto Rico. We
included 112 females of Mexican origin from the GALA1
study to our set of population controls. The individuals are
between 11 and 42 years of age (85% are older than 20).
Genotyping and quality-control procedures
The SFBCS, NC-BCFR and GALA samples were genotyped
with the Affymetrix 6.0 array according to the manufacturer’s
instructions (https://www.affymetrix.com) in the laboratory of
Esteban Gonzalez Burchard at UCSF. The MEC samples were
genotyped with the Illumina Infinitum 660W array (http://
www.illumina.com) in the Epigenome Data Production
Center at USC.
We excluded 15 cases and 30 controls from the SFBCS/
NC-BCFR/GALA set that had a genotyping call rate ,95%
or showed either known or cryptic relatedness. We excluded
48 samples from the MEC that had a genotyping call rate of
,95% and 34 that showed either known or cryptic relatedness.
The final sample included 1699 individuals from the SFBCS/
NC-BCFR/GALA set (977 cases and 722 controls) and 1070
from the MEC (520 cases and 550 controls).
We excluded all SNPs with minor allele frequency of ,1%
and call rate of ,99%. In order to reduce the noise of our
locus-specific ancestry estimates as a result of stranding
issues and genotyping error, we filtered G/C and A/T SNPs
(since for those changes it is more difficult to detect stranding
issues) and SNPs that had large differences between expected
and observed frequencies in the admixed individuals based on
the allele frequencies of the ancestral populations [Europeans
from the Human Genome Diversity Project (HGDP) and
Behar et al. (53), HapMap Yorubans (http://hapmap.ncbi.
nlm.nih.gov) and Indigenous Americans from Reich et al., in
submission]. The final number of SNPs included in the admix-
ture mapping meta-analysis after filtering and matching with
ancestral genotypes was 59 211.
Locus-specific ancestry estimation
There are various available methods for locus-specific ances-
try estimation using genomewide data (24,25,54) that have
relatively low error rates when the admixed populations
are composed of well-differentiated ancestral groups (e.g.
African Americans, Latinos) (24,55). In our analysis, we
used the HAPMIX software to estimate locus-specific ances-
try, which is a model-based method that uses detailed haplo-
type information (24). We developed an add-on extension to
the HAPMIX method that supports local ancestry inference
from three source populations. By default, HAPMIX supports
ancestry inference from two source populations, but Latinos
are three-way mixed. Briefly, this method works by first
running HAPMIX three different ways, assigning reference
panel 1 with haplotypes from one of Indigenous American,
European or African samples and reference panel 2 with the
combined haplotypes from the other two ancestries. The
output from each of these three runs provides probabilistic
estimates for the number of copies (0, 1 or 2) of ancestry
from panel 1. To determine the ancestral state at each locus,
the method uses ordinary least squares to solve a system of
nine equations equivalent to these output probabilities, deter-
mining ancestry probabilities for the six unknown possible
diploid ancestral types (Indigenous American/Indigenous
African/African). In simulations, this method has between
93.2 and 97.8% accuracy. We also used the program LAMP
(version 2.5) (25) to obtain locus-specific ancestry and com-
pared the results with those obtained using HAPMIX. We esti-
mated global individual ancestry as the average locus-specific
ancestry across all loci for each individual.
The significance of the difference in mean values for age at
diagnosis and overall genetic ancestry between cases and con-
trols was assessed using t-tests. We used Fisher’s exact test for
evaluating the difference in the distribution of categorical vari-
ables between cases and controls (number of full-term preg-
nancies, family history of breast cancer, age at menarche,
age at first full-term pregnancy, menopausal status and
hormone therapy and body mass index). The program Stata
11 was used for these analyses (56).
We applied logistic regression models to test the association
between locus-specific ancestry and breast cancer risk, includ-
ing Indigenous American and African individual ancestry as
covariates for the SFBCS/NC-BCFR/GALA samples and the
MEC samples separately. We combined the results of the
two analyses using the inverse variance method. These ana-
lyses were conducted using R (57).
To test if a particular SNP would account for the locus-
specific ancestry association in any of the two regions with
strong admixture mapping signals, we conducted a logistic re-
gression for each of the SNPs within the signal that was asso-
ciated with breast cancer risk at a 5% level of significance
(Supplementary Material, Table S2). The SNP association ana-
lysis included genotyped as well as imputed SNPs for better
coverage. Sample data were phased and missing markers
were imputed using the software Beagle 3.3 (58). Phased
data of 1094 samples from the 1000 Genomes Project (www.
1000genomes.org) were used as the reference data set. These
samples are from African, African American, Asian, Caucasian
1914Human Molecular Genetics, 2012, Vol. 21, No. 8
and Native American populations. The correlation between the
allele dosage with highest posterior probability and the true
allele dosage for the marker was evaluated by Beagle 3.3.
Markers with the square of correlation coefficient .0.8 were
used in further analyses. The logistic regression included the
locus-specific ancestry at the peak of the signal, the individual
Indigenous American and African ancestries and the genotypes
for the particular SNP being tested. The data from the different
studies were combined and a study variable was included in the
analysis as a covariate.
We evaluated the effect of multiple SNPs on the admixture
mapping signal by means of a logistic regression model that
included the locus-specific ancestry at the peak of the signal,
individual Indigenous American and African ancestries, and
we added one SNP at a time, starting with the SNP that
showed the strongest association with breast cancer risk.
The final model included the minimum number of SNPs that
contributed to the attenuation of the locus-specific ancestry
signal. We stopped adding SNPs to the model once the locus-
specific ancestry signal had an associated P-value of more
than 0.05. We ran one model in which the successively
added SNPs could not be highly correlated (r2≤ 0.2) and
another model in which we allowed for correlation up to an
r2of 0.4. Results were similar. Samples were pooled for
A permutation procedure was conducted to obtain an empirical
distribution of Z statistics that would allow us to evaluate the
significance of the admixture mapping signals. Case/control
status was permuted for the SFBCS/NC-BCFR/GALA and
MEC samples separately within five individual Indigenous
American ancestry categories (0–20, 20–40, 40–60, 60–80
and 80–100) and at each permutation we calculated the asso-
ciation between locus-specific ancestry and breast cancer risk
controlling for global Indigenous American and African an-
cestry. By permuting within the five ancestry categories, we
were able to reproduce the asymmetry of the global ancestry
distribution between cases and controls at each permutation.
We then combined the results of each permutation for the
two sets of samples using the inverse variance method. The
significance of the admixture mapping signals was evaluated
by comparing the value of the Z statistics of the original
results with the maximum Z statistic for a thousand permuta-
tions (Supplementary Material, Table S3).
Adding to the ancestry-based permutation procedure, we
evaluated how well controlling for global Indigenous Ameri-
can and African ancestry in the admixture mapping analysis
addressed the issue of the asymmetry in the distribution of
global ancestry between cases and controls. We compared
the distribution of the (Z)2statistics from our analysis to the
expected x2distribution under the null and we observed that
the inflation of high Z statistics in our study was due to the sta-
tistics obtained within the regions that show a strong locus-
specific ancestry association. Once those regions were
removed, the QQ plot showed that there was no inflation in
our statistics compared with the expectation (Supplementary
Materials, Fig. S3).
Supplementary Material is available at HMG online.
We want to thank the study participants.
Conflict of Interest statement. None declared.
This work was supported by the National Cancer Institute
CA132839 (C.A.H.)]. L.F. was partially supported by a
BIRCWH K12 training grant sponsored by NIH/NICHHD
(CA160607). Additional support came from the National Insti-
tutes of Health [R01 HG006399 (B.P.)], the NIH Ruth Kirsch-
stein F32 award (A.W.) and the Beatriu de Pinos Program
[2006 BP-A 10144 and 2009 BP-B 00274 (MV)]. Each of
the participating studies was supported by the following
R01-63446 and R01-CA77305, California Breast Cancer Re-
search Program grant 7PB-0068); Cancer Prevention Institute
of California (U01 CA69417); University of California, Irvine
Informatics Support Center (U01 CA078296); MEC (National
Institutes of Health grants R01 CA63464 and R37 CA54281);
GALA1 (The National Institutes of Health (HL078885,
AI077439, HL088133), the Flight Attendant Medical Research
Institute (FAMRI), American Asthma Foundation and the
Sandler Foundation). The Breast Cancer Family Registry
(BCFR) was supported by the National Cancer Institute, Na-
tional Institutes of Health under RFA CA-06-503 and
through cooperative agreements with members of the BCFR
and Principal Investigators. The content of this manuscript
does not necessarily reflect the views or policies of the Nation-
al Cancer Institute or any of the collaborating centers in the
BCFR, nor does mention of trade names, commercial products
or organizations imply endorsement by the US Government or
the BCFR. The funders of this research had no role in study
design, data collection and analysis, decision to publish or
preparation of the manuscript.
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