Y chromosome haplogroups and prostate cancer in populations of European and Ashkenazi Jewish ancestry.

Abstract

Genetic variation on the Y chromosome has not been convincingly implicated in prostate cancer risk. To comprehensively analyze the role of inherited Y chromosome variation in prostate cancer risk in individuals of European ancestry, we genotyped 34 binary Y chromosome markers in 3,995 prostate cancer cases and 3,815 control subjects drawn from four studies. In this set, we identified nominally significant association between a rare haplogroup, E1b1b1c, and prostate cancer in stage I (P = 0.012, OR = 0.51; 95% confidence interval 0.30-0.87). Population substructure of E1b1b1c carriers suggested Ashkenazi Jewish ancestry, prompting a replication phase in individuals of both European and Ashkenazi Jewish ancestry. The association was not significant for prostate cancer overall in studies of either Ashkenazi Jewish (1,686 cases and 1,597 control subjects) or European (686 cases and 734 control subjects) ancestry (P(meta) = 0.078), but a meta-analysis of stage I and II studies revealed a nominally significant association with prostate cancer risk (P(meta) = 0.010, OR = 0.77; 95% confidence interval 0.62-0.94). Comparing haplogroup frequencies between studies, we noted strong similarities between those conducted in the US and France, in which the majority of men carried R1 haplogroups, resembling Northwestern European populations. On the other hand, Finns had a remarkably different haplogroup distribution with a preponderance of N1c and I1 haplogroups. In summary, our results suggest that inherited Y chromosome variation plays a limited role in prostate cancer etiology in European populations but warrant follow-up in additional large and well characterized studies of multiple ethnic backgrounds.

Full text

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Hum Genet (2012) 131:1173–1185
DOI 10.1007/s00439-012-1139-5
123
ORIGINAL INVESTIGATION
Y chromosome haplogroups and prostate cancer in populations
of European and Ashkenazi Jewish ancestry
Zhaoming Wang · Hemang Parikh · Jinping Jia · Timothy Myers · Meredith Yeager · Kevin B. Jacobs ·
Amy Hutchinson · Laurie Burdett · Arpita Ghosh · Michael J. Thun · Susan M. Gapstur · W. Ryan Diver ·
Jarmo Virtamo · Demetrius Albanes · Geraldine Cancel-Tassin · Antoine Valeri · Olivier Cussenot · Kenneth OYt ·
Ed Giovannucci · Jing Ma · Meir J. Stampfer · J. Michael Gaziano · David J. Hunter · Ana Dutra-Clarke ·
Tomas KirchhoV · Michael Alavanja · Laura B. Freeman · Stella Koutros · Robert Hoover · Sonja I. Berndt ·
Richard B. Hayes · Ilir Agalliu · Robert D. Burk · Sholom Wacholder · Gilles Thomas · Laufey Amundadottir
Received: 22 November 2011 / Accepted: 4 January 2012 / Published online: 24 January 2012
© The Author(s) 2012. This article is published with open access at Springerlink.com
Abstract
been convincingly implicated in prostate cancer risk. To
comprehensively analyze the role of inherited Y chromo-
some variation in prostate cancer risk in individuals of Euro-
pean ancestry, we genotyped 34 binary Y chromosome
markers in 3,995 prostate cancer cases and 3,815 control
subjects drawn from four studies. In this set, we identiWed
nominally signiWcant association between a rare haplogroup,
Genetic variation on the Y chromosome has not
E1b1b1c, and prostate cancer in stage I (P = 0.012,
OR = 0.51; 95% conWdence interval 0.30–0.87). Population
substructure of E1b1b1c carriers suggested Ashkenazi Jew-
ish ancestry, prompting a replication phase in individuals of
both European and Ashkenazi Jewish ancestry. The associa-
tion was not signiWcant for prostate cancer overall in studies
of either Ashkenazi Jewish (1,686 cases and 1,597 control
subjects) or European (686 cases and 734 control subjects)
ancestry (Pmeta= 0.078), but a meta-analysis of stage I and II
studies revealed a nominally signiWcant association with
prostate cancer risk (Pmeta= 0.010, OR = 0.77; 95% conW-
dence interval 0.62–0.94). Comparing haplogroup frequen-
cies between studies, we noted strong similarities between
those conducted in the US and France, in which the majority
Z. Wang and H. Parikh are co-Wrst authors.
Electronic supplementary material
article (doi:10.1007/s00439-012-1139-5) contains supplementary
material, which is available to authorized users.
The online version of this
Z. Wang · H. Parikh · J. Jia · T. Myers · M. Yeager · K. B. Jacobs ·
A. Hutchinson · L. Burdett · A. Ghosh · D. Albanes · M. Alavanja ·
L. B. Freeman · S. Koutros · R. Hoover · S. I. Berndt ·
S. Wacholder · L. Amundadottir
Division of Cancer Epidemiology and Genetics,
National Cancer Institute, National Institutes of Health,
Bethesda, MD 20892, USA
Z. Wang · T. Myers · M. Yeager · K. B. Jacobs · A. Hutchinson ·
L. Burdett
Core Genotyping Facility, SAIC-Frederick, Inc.,
NCI-Frederick, Frederick, MD 21702, USA
H. Parikh · J. Jia · T. Myers · L. Amundadottir
Laboratory of Translational Genomics, Division of Cancer
Epidemiology and Genetics, National Cancer Institute,
National Institutes of Health, Bethesda, MD 20877, USA
M. J. Thun · S. M. Gapstur · W. Ryan Diver
Epidemiology Research Program, American Cancer Society,
Atlanta, GA 30303, USA
J. Virtamo
Department of Chronic Disease Prevention, National Institute
for Health and Welfare, 00300 Helsinki, Finland
G. Cancel-Tassin · A. Valeri · O. Cussenot
Centre de Recherche pour les Pathologies Prostatiques (CeRePP),
Hôpital Tenon, Assistance Publique-Hôpitaux de Paris,
75020 Paris, France
K. OYt · A. Dutra-Clarke · T. KirchhoV
Clinical Genetics Service, Department of Medicine,
Memorial Sloan-Kettering Cancer Center, Box 192,
1275 York Avenue, New York, NY 10065, USA
E. Giovannucci · J. Ma · M. J. Stampfer · J. Michael Gaziano
Channing Laboratory, Division of Preventive Medicine,
Department of Medicine, Brigham and Women’s Hospital,
Harvard Medical School, Boston, MA 02115, USA
D. J. Hunter
Program in Molecular and Genetic Epidemiology,
Department of Epidemiology, Harvard School of Public Health,
Boston, MA 02115, USA
T. KirchhoV · R. B. Hayes
Division of Epidemiology, Department of Environmental
Medicine, New York University School of Medicine,
New York, NY 10016, USA

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1174 Hum Genet (2012) 131:1173–1185
123
of men carried R1 haplogroups, resembling Northwestern
European populations. On the other hand, Finns had a
remarkably diVerent haplogroup distribution with a prepon-
derance of N1c and I1 haplogroups. In summary, our results
suggest that inherited Y chromosome variation plays a lim-
ited role in prostate cancer etiology in European populations
but warrant follow-up in additional large and well character-
ized studies of multiple ethnic backgrounds.
Introduction
Family and twin studies have shown that prostate cancer
has a clear heritable component which may be among the
highest of all cancer types (Amundadottir et al. 2004; Lich-
tenstein et al. 2000), Over the last few years, genome wide
association studies (GWAS) have successfully identiWed
germline variants conferring risks of prostate cancer at over
45 loci (Amundadottir et al. 2006; Chung and Chanock
2011; Eeles et al. 2008, 2009; Gudmundsson et al. 2007a,
b, 2008, 2009; Haiman et al. 2007; Kote-Jarai et al. 2011;
Schumacher et al. 2011; Takata et al. 2010; Thomas et al.
2008; Yeager et al. 2007, 2009). These studies have not
implicated variants on the Y chromosome in the risk of
prostate cancer, possibly due to the fact that very few Y
chromosome SNPs have been included on most genotyping
chips used to date. Several groups have speciWcally investi-
gated the role of Y chromosome haplogroups in prostate
cancer risk. Many of these studies are inconclusive due to
the small number of samples and/or markers used. One of
the larger studies was conducted within the multi-ethnic
cohort (MEC) using samples from prostate cancer cases
and control subjects drawn from four ethnic groups. Of the
41 haplogroups observed, one was signiWcantly associated
with prostate cancer in Japanese men (Paracchini et al.
2003) but this association was not replicated in a separate
study from Korea (Kim et al. 2007). No association was
seen between Y haplogroups and prostate cancer in a large
Swedish study (Lindstrom et al. 2008).
The Y chromosome contains the largest non-recombining
region in the human genome, spanning almost the entire
length of the chromosome. This region is called the non-
recombining Y (NRY) or the male-speciWc Y (MSY)
(Rozen et al. 2003). In the absence of recombination, the
NRY passes mostly unchanged from father to son and
observed mutations reXect the evolutionary history of the Y
chromosome. Binary markers can be used to classify Y
chromosomes into haplogroups organized by a phylogenetic
tree. A Wrst generation phylogeny of the tree was published
in 2002 by the Y Chromosome Consortium (2002) and fur-
ther revised in 2008 (Karafet et al. 2008). The Y chromo-
some tree now consists of over 300 haplogroups organized
into 20 major groups or clades (Karafet et al. 2008).
Multiple lines of evidence support a possible role for
genes on the Y chromosome in prostate cancer etiology.
Loss of the Y chromosome is one of the most frequent cyto-
genetic change seen in prostate tumors and may be an early
event in tumorigenesis (Brothman et al. 1999; Jordan et al.
2001). In support of the previous assertion, chromosome
transfer studies indicate that the human Y chromosome sup-
presses tumorigenicity of human prostate cell lines in vivo
implying that it may harbor gene(s) with tumor suppressor
function (Vijayakumar et al. 2005). Based on the essential
role of the Y chromosome in secondary sexual diVerentia-
tion and its potential role in disease pathogenesis, particu-
larly related to the secondary sex organs, we explored this
genomic region to investigate whether germline variation on
this chromosome plays a role in prostate cancer risk.
Results
We analyzed 7,810 men from the Cancer Genetic Markers
of Susceptibility (CGEMS) scan in stage I of this study. Of
the 34 chromosome Y markers genotyped, 26 were
observed in our sample (8 markers were monomorphic).
With such a sample size, we were able to accurately charac-
terize and estimate the Y chromosome frequency distribu-
tion in populations of European ancestry for 28
haplogroups including three combined groups (R1b1b +
R1b*, R1a + R1* and I2b + I2c) as the leaf nodes of the
NRY tree (Fig. 1a). Stage I had 41, 76 and 95% power to
detect an association with an odds ratio of 1.3 and a MAF
I. Agalliu · R. D. Burk
Department of Epidemiology and Population Health, Albert
Einstein College of Medicine, Bronx, NewYork, NY 10461, USA
R. D. Burk
Department of Pediatrics, Albert Einstein College of Medicine,
Bronx, NewYork, NY 10461, USA
R. D. Burk
Department of Microbiology & Immunology, Albert Einstein
College of Medicine, Bronx, NewYork, NY 10461, USA
R. D. Burk
Department of Obstetrics, Gynecology and Women’s Health,
Albert Einstein College of Medicine, Bronx, NewYork,
NY 10461, USA
G. Thomas
Synergie-Lyon-Cancer, Universite Lyon 1, Centre Leon Berard,
69373 Lyon Cedex 08, France
L. Amundadottir (&)
Laboratory of Translational Genomics, Division of Cancer
Epidemiology and Genetics, National Cancer Institute,
National Institutes of Health, Gaithersburg, MD 20877, USA
e-mail: amundadottirl@mail.nih.gov

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Hum Genet (2012) 131:1173–11851175
123
Fig. 1 Chromosome Y haplogroup tree and frequency distribution in
control subjects of European ancestry in Stage I. a Chromosome Y tree
showing genotyped markers in black and those not genotyped in light
grey. Haplogroup names are according to the International Society of
Genetic Genealogy (ISOGG) 2011 update. The arrow points to the
mutational event which gave rise to the E1b1b1c haplogroup. Stage I
studies are the following: CPS-II American Cancer Society Cancer
Prevention Study II, ATBC Alpha-Tocopherol, Beta-Carotene Cancer
Prevention Study, CeRePP Centre de Recherche pour les Pathologies
Prostatiques, and PLCO Prostate, Lung Colorectal and Ovarian Cancer
Screening Trial. b The circle plots show frequencies for haplogroups
with a derived frequency of 5% or higher in diVerent colors for each
Stage I cohort (remaining haplogroups are combined in one group
shown in black)
M42
M60
P97
M168
P143
M203
M174
M96
M132
M180
M78
M81
M123
M130
M377
M285
M201P15
M522
M26
L416/L596
M307
M172
M267
M170
M304
M9
M70
M20
M526
M242
M74
M214
M46
M207
M173 M18
M269
M335
Haplogroup CPS-II ATBC CeRePP PLCO
Q 0.005 0.001 0.004 0.003
R1b1a2
R1b1b+R1b* 0.083 0 0.297 0.025

R1b1c1 0 0 0 0
0.462 0.048 0.345 0.488
R1a+R1* 0.090 0.060 0.024 0.127
R2 0 0 0.002 0.002
O 0 0.032 0 0.001
N*+N1a+N1b 0.001 0.005 0 0
N1c 0.008 0.556 0.004 0.017
L 0 0 0.002 0
T1 0.003 0 0.010 0
J2
J1


0.038 0.001 0.059 0.038
0.029 0 0.002 0.010
I1/O1a1 0.112 0.276 0.081 0.139
I2b+I2c 0.061 0.012 0.049 0.065
I2a1a 0.004 0.001 0.010 0
G2c 0.003 0 0 0.001
G1 0.001 0.001 0 0.001
G2a 0.030 0.005 0.041 0.032
E1b1b1b1 0 0 0.008 0.005
E1b1b1a1 0.028 0.002 0.042 0.024
E1b1b1c 0.020 0 0.010 0.007
C 0.003 0 0 0.001
B 0 0 0 0
D 0 0 0 0
E1a 0.001 0 0 0
E1b1a1a1 0.001 0 0 0
CPS-II
A TBC
PLCOCeRePP
E1b1b1a1G2a IOthers
A 0 0 0 0.001
A
B
M343
R1N1cJ2
M231
M215
M89
P177
M128+P43
M175
M513
M479
M429

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1176Hum Genet (2012) 131:1173–1185
123
of 0.02, 0.05 and 0.10, respectively (assuming prostate can-
cer prevalence of 1.5067% and alpha of 0.05) (http://
seer.cancer.gov/csr/1975_2007/).
Stage I association analysis
After genotyping quality control based on completion rates
and concordance analysis, a total of 3,995 prostate cancer
cases and 3,815 control subjects from four studies were
used in the analysis (1994; Calle et al. 2002; Gohagan et al.
2000; Valeri et al. 2003). This included 1,531 men diag-
nosed with non-aggressive prostate cancer (Gleason score
<7 and disease stage <III) and 2,142 men diagnosed with
aggressive prostate cancer (Gleason score ¸7 or stage
¸III).
Of the 26 haplogroup markers analyzed, one was signiW-
cantly associated with overall prostate cancer at a nominal
P value threshold of P · 0.05 (Table 1). This was haplo-
group E1b1b1c (locus M123, formerly named haplogroup
E3b1c) (P = 0.012, allelic odds ratio (OR) 0.51; 95% conW-
dence interval 0.30–0.87), a rare haplogroup with a 1.1%
frequency in control subjects in our sample set. When the
analysis was performed according to degree of diVerentia-
tion and severity of prostate cancer, this haplogroup was
signiWcantly associated with non-aggressive prostate cancer
(P = 0.017, allelic OR 0.33; 95% conWdence interval 0.13–
0.86) but not with aggressive prostate cancer (P = 0.091,
allelic OR 0.59; 95% conWdence interval 0.32–1.09). How-
ever, the diVerence between the two case groups was not
signiWcant (P = 0.48).
Based on the Y chromosome haplogroup tree structure
(see “Methods” section and Fig. 1a), we were able to test
three additional haplgroups (J1, IJ, IJK) for which markers
were not directly genotyped. These three haplogroups did
not signiWcantly associate with overall risk of prostate can-
cer (data not shown) (Table 1).
Population substructure of E1b1b1c carriers
We assessed the population substructure for E1b1b1c
haplogroup carriers using principal components analysis
(PCA) from the initial CGEMS GWAS dataset (Thomas
et al. 2008; Yeager et al. 2007, 2009). In addition we
evaluated one common haplogroup, R1b1a2 (43.7% frequency
in control subjects from stage I) as it had the second lowest
P value in stage I (P = 0.054). Carriers of the E1b1b1c
haplogroup showed a distinct distribution of the Wrst and
second eigenvectors (EV1 and EV2) in this analysis that
separates them from the majority of the European ancestry
subjects, i.e. negative values for EV1 and positive values
for EV2 (Fig. 2a). Conversely, the population substructure
of R1b1a2 haplogroup carriers was similar to that of the
majority of subjects in our study, implying Northwestern
European ancestry. We compared the population substruc-
ture pattern of E1b1b1c haplogroup carriers to the large
number of individuals in the initial CGEMS prostate can-
cer scan (Thomas et al. 2008; Yeager et al. 2007, 2009)
and a GWAS of breast cancer in families of Ashkenazi
Jewish descent (Gold et al. 2008) and noted strong cluster-
ing with a group of individuals of self-reported Ashkenazi
Jewish descent with similar values for EV1 and EV2
(Fig. 2b). The majority of E1b1b1c haplogroup carriers in
our study (37 out of 62) were Ashkenazi Jewish alike by
this comparison. Therefore, the frequency of E1b1b1c in
inferred Ashkenazi Jewish individuals in our study was
estimated to be approximately 15% (37/240). A similar
number has been reported in men of Jewish ancestry
(Hammer et al. 2009). These Wndings prompted a replica-
tion phase in sample sets of both European and Ashkenazi
Jewish ancestry.
Limited evidence for association to prostate cancer
in Stage II analysis
We attempted replication of the E1b1b1c and R1b1a2
haplogroups in three prostate cancer cohort studies of Euro-
pean ancestry from the continental USA, the Physicians’
Health Study (PHS) (Ma et al. 2008), the Health Profes-
sionals Follow-up Study (HPFS) (Chen et al. 2005), the
Agricultural Health Study (AHS) (Alavanja et al. 1996);
and in two case–control studies of Ashkenazi Jewish ances-
try collected in the USA, from the Albert Einstein College
of Medicine (Einstein) (Agalliu et al. 2009) and the Memo-
rial Sloan Kettering Cancer Center (MSKCC) (Gallagher
et al. 2010). The three European ancestry studies included a
total of 1,272 prostate cancer cases and 1,932 control sub-
jects; the two Ashkenazi Jewish ancestry studies included a
total of 1,686 prostate cancer cases and 1,597 control sub-
jects. Neither haplogroup was signiWcantly associated with
overall prostate cancer risk at a nominal P value in any
study (Table 2) nor was a meta-analysis of the combined
studies signiWcant (Pmeta= 0.078 for E1b1b1c and
Pmeta= 0.36 for R1b1a2). For non-aggressive prostate can-
cer, the E1b1b1c haplogroup was signiWcantly associated at
a nominal P value in the Einstein study only (P = 0.024,
allelic OR 0.66; 95% conWdence interval 0.45–0.95). How-
ever, a meta-analysis of non-aggressive cases in all stage II
studies was nominally signiWcant (Pmeta= 0.025, allelic OR
0.68; 95% conWdence interval 0.49–0.95). No other signiW-
cant associations were noted.
A meta-analysis of stage I and II results for the E1b1b1c
haplogroup revealed a nominally signiWcant association
with risk of prostate cancer overall (Pmeta= 0.010; allelic
OR = 0.77; 95% conWdence interval 0.62–0.94) and with
risk of non-aggressive prostate cancer (Pmeta= 0.0077; alle-
lic OR = 0.67; 95% conWdence interval 0.50–0.90) but not

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Hum Genet (2012) 131:1173–11851177
123
Table 1 Association of chromosome Y variants with risk of prostate cancer (Stage I)
Results from the unconditional logistic regression of the genotypes generated in a total of 3,995 individuals with prostate cancer and 3815 control subjects are shown. The analysis was adjusted for age in 10-year cate-
gories, study and one principal component of population stratiWcation
na* no rs number, OR odds ratio, CI 95% conWdence interval
aHaplogroup being tested based on the Y Chromosome Consortium and ISOGG 2011 nomenclature
bChrY locus/marker name
cNCBI dbSNP identiWer
dNCBI human genome build 36 location
eAncestral allele, derived allele
fControls, cases
gMinor allele frequency in control and case participants
hScore test (1df)
iFor the nonaggressive model, subjects in two categories (“FPCC” and “age <50”) could not be used because we there are no case subjects in either category. Therefore, the total number of controls is smaller than in
the overall and aggressive models
Haplogroupa
Locusb
rs numberc
Locationd
AlleleseAll cases
Nonaggressive cases
Aggressive cases
Subjectsf
MAFg
Ph
OR
Subjectsf,i
MAFg
Ph
OR
Subjectsf
MAFg
Ph
OR
E
M96
rs9306841
20238386 C|G
3739|3903 0.042|0.043 0.638 1.06 (0.84–1.32) 3233|1476 0.039|0.029 0.188 0.78 (0.54–1.13)
3739|2111 0.042|0.056 0.242 1.16 (0.90–1.50)
E1b1b
M215
rs2032654
13977218 T|C
3807|3983 0.042|0.042 0.746 1.04 (0.83–1.30) 3298|1527 0.039|0.029 0.196 0.79 (0.55–1.13)
3807|2134 0.042|0.055 0.303 1.14 (0.89–1.48)
E1b1b1a1
M78
na*
20352691 G|A
3753|3948 0.023|0.029 0.112 1.26 (0.95–1.67) 3247|1512 0.021|0.022 0.725 1.08 (0.70–1.67)
3753|2116 0.023|0.036 0.082 1.33 (0.96–1.83)
E1b1b1b1
M81
rs2032640
20351960 G|A
3243|3372 0.002|0.001 0.079 0.27 (0.06–1.29) 2738|1223 0.001|0.000 NA
NA
3243|1945 0.002|0.001 0.192 0.36 (0.07–1.77)
E1b1b1c
M123
na*
20223974 C|T
3814|3992 0.011|0.005 0.012 0.51 (0.30–0.87) 3306|1531 0.011|0.003 0.017 0.33 (0.13–0.86)
3814|2140 0.011|0.007 0.091 0.59 (0.32–1.09)
F
M89
rs2032652
20376701 A|G
3813|3994 0.043|0.044 0.641 1.05 (0.85–1.31) 3304|1531 0.040|0.031 0.267 0.82 (0.58–1.16)
3813|2141 0.043|0.057 0.255 1.16 (0.90–1.49)
G
M201
rs2032636
13536923 G|T
3804|3987 0.029|0.026 0.528 0.92 (0.70–1.20) 3296|1529 0.027|0.026 0.995 1.00 (0.68–1.48)
3804|2136 0.029|0.029 0.388 0.87 (0.62–1.20)
G1
M285
rs13447378 21151128 G|C
3807|3990 0.001|0.001 0.973 1.02 (0.26–4.11) 3300|1528 0.001|0.002 0.440 1.86 (0.38–9.12)
3807|2140 0.001|0.000 NA
NA
G2a
P15
na*
21653414 G|A
3791|3948 0.026|0.023 0.328 0.87 (0.65–1.16) 3302|1529 0.024|0.022 0.714 0.92 (0.61–1.41)
3791|2098 0.026|0.025 0.310 0.84 (0.59–1.18)
G2c
M377
na*
13536827 A|G
3750|3950 0.002|0.002 0.410 1.54 (0.55–4.35) 3241|1508 0.002|0.002 0.843 1.16 (0.28–4.85)
3750|2120 0.002|0.002 0.474 1.56 (0.46–5.29)
I
M170
rs2032597
13357186 A|C
3811|3990 0.203|0.221 0.059 1.11 (1.00–1.24) 3302|1529 0.213|0.247 0.042 1.17 (1.01–1.35)
3811|2139 0.203|0.204 0.058 1.14 (1.00–1.31)
I1/O1a1
M307
rs13447354 21160339 G|A
3804|3988 0.150|0.154 0.648 1.03 (0.91–1.17) 3298|1525 0.161|0.176 0.737 1.03 (0.87–1.22)
3804|2141 0.150|0.136 0.249 1.10 (0.94–1.29)
I2a1a
M26
rs2032629
20325209 C|T
3719|3875 0.003|0.002 0.298 0.62 (0.25–1.53) 3215|1453 0.002|0.003 0.537 1.51 (0.41–5.58)
3719|2107 0.003|0.002 0.117 0.41 (0.13–1.30)
J
M304
rs13447352 21159241 A|C
3742|3922 0.048|0.048 0.635 1.05 (0.85–1.31) 3234|1492 0.046|0.035 0.302 0.84 (0.60–1.17)
3742|2116 0.048|0.059 0.379 1.12 (0.87–1.43)
J2
M172
rs2032604
13479028 T|G
3780|3958 0.033|0.033 0.657 1.06 (0.82–1.37) 3272|1516 0.028|0.022 0.697 0.92 (0.61–1.39)
3780|2124 0.033|0.043 0.493 1.11 (0.83–1.47)
K
M9
rs3900
20189645 C|G
3799|3975 0.322|0.340 0.055 1.10 (1.00–1.21) 3294|1525 0.324|0.338 0.299 1.07 (0.94–1.22)
3799|2129 0.322|0.348 0.021 1.15 (1.02–1.29)
T1
M70
rs2032672
20353269 T|G
3708|3904 0.003|0.003 0.922 1.04 (0.44–2.47) 3202|1492 0.002|0.001 0.315 2.92 (0.33–25.65) 3708|2101 0.003|0.004 0.882 0.93 (0.37–2.32)
N
M231
rs9341278
13979118 C|T
3769|3946 0.139|0.136 0.664 0.96 (0.80–1.15) 3262|1505 0.160|0.189 0.565 0.94 (0.76–1.17)
3769|2122 0.139|0.062 0.076 0.78 (0.60–1.03)
N1c
M46/Tat rs34442126 13431977 T|C
3809|3992 0.137|0.134 0.604 0.95 (0.80–1.14) 3302|1530 0.157|0.185 0.514 0.93 (0.75–1.16)
3809|2140 0.137|0.062 0.058 0.77 (0.59–1.01)
NO
M214
rs2032674
13981319 A|G
3805|3977 0.139|0.135 0.676 0.96 (0.80–1.15) 3297|1523 0.159|0.186 0.578 0.94 (0.76–1.17)
3805|2135 0.139|0.062 0.058 0.77 (0.59–1.01)
P
M74
rs2032635
20349155 C|T
3547|3766 0.484|0.494 0.272 1.06 (0.96–1.18) 3047|1418 0.491|0.455 0.959 1.00 (0.86–1.16)
3547|2041 0.484|0.427 0.282 1.07 (0.95–1.21)
Q
M242
rs8179021
13527976 C|T
3719|3856 0.004|0.004 0.886 1.05 (0.51–2.19) 3229|1487 0.004|0.003 0.842 0.89 (0.27–2.88)
3719|2058 0.004|0.005 0.353 1.47 (0.65–3.35)
R
M207
rs2032658
14091377 T|C
3745|3908 0.486|0.499 0.088 1.09 (0.99–1.21) 3238|1497 0.490|0.453 0.663 0.97 (0.84–1.12)
3745|2098 0.486|0.436 0.094 1.11 (0.98–1.25)
R1
M173
rs2032624
13535818 A|C
3691|3876 0.477|0.487 0.144 1.08 (0.97–1.19) 3189|1481 0.500|0.467 0.783 0.98 (0.85–1.13)
3691|2076 0.477|0.423 0.160 1.09 (0.97–1.23)
R1b
M343
rs9786184
2947824
C|A
3805|3976 0.441|0.428 0.114 0.92 (0.84–1.02) 3297|1525 0.410|0.371 0.673 0.97 (0.84–1.12)
3805|2131 0.441|0.495 0.193 0.92 (0.82–1.04)
R1b1a2
M269
rs9786153
21148755 T|C
3489|3634 0.437|0.421 0.054 0.90 (0.81–1.00) 3029|1386 0.405|0.365 0.719 0.97 (0.84–1.13)
3489|1959 0.437|0.491 0.093 0.90 (0.79–1.02)

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1178Hum Genet (2012) 131:1173–1185
123
with risk of aggressive prostate cancer (Pmeta= 0.28). In
Stage II, we had 60% power to detect a variant with 13%
MAF and an OR of 0.8 in the Ashkenazi Jewish sample set,
but only 25% power to detect a variant with 3% MAF and
an OR of 0.7 in the European American sample set.
Haplogroup frequency and population distribution
Y chromosome haplogroup frequency distribution in con-
trols from each of the four study populations from phase I
was summarized and compared in Fig. 1b. Two of the stud-
ies, namely CPS-II and PLCO, include subjects from conti-
nental USA. Their haplogroup frequencies are very similar
with an average diVerence of 0.8% and a maximum diVer-
ence of 5.8% for the combined category of haplogroups
R1b1b + R1b*. The CeRePP study, conducted in France, is
relatively similar to the US studies with an average haplo-
group frequency diVerence of 2.2%, and a maximum diVer-
ence of 24.3% for the combined group of R1b1b + R1b*.
The greatest diVerence in frequency was seen for ATBC, a
Finnish study, with an average haplogroup frequency diVer-
ence of 5.2% and a maximum diVerence of 54.4%. This
stems from a very high frequency of haplogroup N1c in this
study (55.6%), while it is infrequent in the other three stud-
ies from the US and France (0.8% in CPS-II, 1.7% in
PLCO and 0.4% in CeRePP). Second, R1b, the most fre-
quent haplogroup overall, is seen in over 50% of subjects in
PLCO, CPS-II and CeRePP but only in 4.8% of Finnish
subjects. The third largest diVerence was noted for haplo-
group I1 which was more common in Finns at 27.6%, as
compared to 13.9% in PLCO, 11.2% in CPS-II and only
8.1% in CeRePP.
Haplogroup E1b was observed at low frequencies in all
studies and its sub lineage E1b1b1c was seen in approxi-
mately 1–2% of subjects from the two US studies (PLCO
and CPS-II) and the French study (CeRePP), whereas it
was absent from the Finnish study (ATBC). Other haplo-
groups were absent or rare in the four studies.
Discussion
In this study, we explored the role of germline Y chromo-
some variation in prostate cancer risk. Previous studies
have not analyzed such a large sample size with as many
markers in individuals of European ancestry. Because of
the threshold for MAF chosen for this study (¸1%), we had
limited capacity to detect risk variants with low to medium
frequency and eVect sizes. Prostate cancer GWAS to date
have used arrays with limited coverage on the Y chromo-
some. As an example, in CGEMS, of the approximately
500,000 SNPs genotyped in stage I, only ten Y chromo-
some markers passed quality control assessment and were
included in the primary analysis; this limited set of variants
on the Y chromosome included only four that mark chro-
mosome Y haplogroups (Thomas et al. 2008; Yeager et al.
2007, 2009). Other published prostate cancer GWAS stud-
ies have reported on a similar fraction of Y variants (Amun-
dadottir et al. 2006; Chung and Chanock 2011; Eeles et al.
Fig. 2 Population substructure analysis by principal component anal-
ysis and comparison to CGEMS prostate cancer GWAS. a shows the
distribution of the Wrst two principal components, EV1 and EV2, for
carriers of E1b1b1c (Wlled squares) and R1b1a2 (open circles) haplo-
groups in Stage I. Circles and squares denote eigenvalues from PCA
analysis for each individual. The distribution of EV1 and EV2 for all
Stage I subjects is shown in b. Studies are designed by diVerent colors.
CPS-II Blood blood derived DNA samples were used for genotyping,
CPS-II Buccal buccal derived DNA samples were used for genotyping.
DNA samples from ATBC, CeRePP and PLCO were all derived from
blood. Individuals of inferred Ashkenazi Jewish ancestry are circled.
PCA results were performed by EIGENSTRAT in CGEMS prostate
cancer GWAS (Thomas et al. 2008; Yeager et al. 2007, 2009)
E1b1b1c
R1b1a2
-0.01
0
0.01
0.02
0.03
0.04
0.05
0.03
EV1
EV2
-0.02-0.010 0.010.02
-0.01
0
0.01
0.02
0.03
0.04
0.05
0.03
EV1
EV2
ATBC
CPS-II:Blood
CPS-II:Buccal
CeRePP
PLCO
AJ alike cluster
-0.02-0.01 00.01 0.02
A
B

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Hum Genet (2012) 131:1173–11851179
123
Table 2 Replication analysis of notable chromosome Y signals in prostate cancer studies of Ashkenazi and European descent (Stage II)
Results from the unconditional logistic regression of the genotypes generated in Stage II are shown. The analysis was adjusted for age in 10-year categories
OR odds ratio, CI 95% conWdence interval
aHaplogroup being tested based on the Y Chromosome Consortium and ISOGG 2011 nomenclature
bChrY locus/marker name
cControls, cases
dMinor allele frequency in control and case participants
eScore test (1df) for all scenarios except for aggressive cases from HPFS which is based on a Fisher exact test (1df)
Study
All cases
Nonaggressive cases
Aggressive cases
Subjectsc
MAFd
Pe
OR
Subjectsc
MAFd
Pe
OR
Subjectsc
MAFd
Pe
OR
E1b1b1ca (M123b)
Einstein
1214|928
0.138|0.117
0.146
0.82 (0.63–1.07)
1214|413
0.138|0.097
0.024
0.66 (0.45–0.95)
1214|456
0.138|0.134
0.693
0.94 (0.68–1.29)
MSKCC
375|750
0.128|0.123
0.608
0.87 (0.52–1.46)
375|212
0.128|0.090
0.956
0.96 (0.47–1.94)
375|362
0.128|0.146
0.954
0.98 (0.53–1.83)
PHS
489|471
0.029|0.021
0.455
0.73 (0.32–1.67)
489|194
0.029|0.015
0.379
0.57 (0.16–2.02)
489|167
0.029|0.024
0.780
0.85 (0.28–2.63)
HPFS
244|215
0.033|0.023
0.540
0.70 (0.23–2.18)
244|138
0.033|0.036
0.848
1.12 (0.36–3.49)
244|44
0.033|0.000
0.210
0.00 (0.00–1.77)
R1b1a2 (M269b)
Einstein
1210|912
0.095|0.115
0.121
1.25 (0.94–1.67)
1210|408
0.095|0.120
0.147
1.30 (0.91–1.87)
1210|446
0.095|0.108
0.390
1.17 (0.82–1.69)
MSKCC
373|739
0.110|0.118
0.936
1.02 (0.61–1.71
373|206
0.110|0.121
0.981
0.99 (0.51–1.93)
373|358
0.110|0.126
0.841
1.06(0.59–1.92)
PHS
482|463
0.500|0.531
0.321
1.14 (0.88–1.47)
482|190
0.500|0.553
0.238
1.23 (0.87–1.72)
482|164
0.500|0.537
0.430
1.15 (0.81–1.65)
AHS
1159|571
0.589|0.578
0.662
0.96 (0.78–117)
1159|326
0.589|0.558
0.320
0.88(0.66–1.09)
1159|80
0.589|0.612
0.703
1.09 (0.69–1.74)

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1180 Hum Genet (2012) 131:1173–1185
123
2008, 2009; Gudmundsson et al. 2007a, b, 2008, 2009;
Haiman et al. 2007; Kote-Jarai et al. 2011; Schumacher
et al. 2011; Takata et al. 2010; Thomas et al. 2008; Yeager
et al. 2007, 2009).
One haplogroup of interest was noted in phase I of our
study; the E1b1b1c haplogroup was nominally signiWcant
in the overall prostate cancer and non-aggressive prostate
cancer groups. The marker that denotes this haplogroup is
located in the last intron of the taxilin gamma 2 pseudogene
(TXLNG2P) on chromosome Yq11.222. This haplogroup
was analyzed in a second phase using replication studies of
European and Ashkenazi Jewish ancestry along with a
more common haplogroup, R1b1a2. Neither haplogroup
was signiWcantly associated with overall prostate cancer
risk in stage II. A meta-analysis of stage I and stage II
results yielded a P value of 0.010 for the E1b1b1c haplo-
group. Although nominally signiWcant, this P value is unre-
markable in comparison with the rigorous threshold
required for signiWcance in GWAS studies (Wellcome
Trust Case Control Consortium 2007), suggesting that fur-
ther studies are required to establish this association.
Although our analysis does not provide strong evidence for
a relationship between variation in the Y chromosome and
prostate cancer, it can be argued that the appropriate statis-
tical threshold to be applied to a study of approximately 30
markers should not be as stringent as a GWAS threshold.
However, the probability of false-positive Wndings is high,
even in a study of our size and power (Wacholder et al.
2004) especially in the Wrst stage where E1b1b1c haplo-
group frequency was very low. In addition, we cannot
exclude a chance Wnding due to population stratiWcation.
Our study represents the largest analysis to date of a pos-
sible association between Y chromosome variants and pros-
tate cancer. The role of germline variation on the Y
chromosome had been assessed previously, but with limited
sample and/or marker sets. One of the most complete stud-
ies published was conducted within the MEC (Paracchini
et al. 2003). Four ethnic groups with a total of 930 cases
and 1,208 control subjects were included. One of the 41
haplogroups observed in the study was signiWcantly associ-
ated with prostate cancer risk in Japanese men with a
P value of 0.02 (Paracchini et al. 2003). Despite the large
overall sample set in this study, each ethnic group only con-
sisted of approximately 100–150 case–control pairs, limit-
ing power considerably. No haplogroups were signiWcantly
associated with prostate cancer risk in a small Korean study
that assessed 14 markers in approximately 106 cases and
110 control subjects, including the haplogroup reported in
the MEC study (Kim et al. 2007). Lack of an association
between Y haplogroups and prostate cancer was also
reported in a Swedish study assessing Wve ChrY markers in
1,452 cases and 779 control subjects of N-European back-
ground (Lindstrom et al. 2008). Our results appear to con-
Wrm an overall lack of importance for germline variants on
the Y chromosome and prostate cancer risk.
Frequencies of Y chromosome haplogroups vary consid-
erably between diVerent geographical regions and ethnic
groups, and have turned out to be informative in studies of
human evolution and migration. In Europe, marked diVer-
ences in haplogroup frequencies are observed between
countries in Northeastern, Northwestern, Southwestern,
Southeast and Central Europe (Wiik 2008). In addition, the
Ashkenazi Jewish community has a speciWc pattern that is
reminiscent of non-Ashkenazi Jewish communities in the
Near East (Behar et al. 2004). We observed a diVerent distri-
bution of major haplogroups in subjects of Northwestern
European ancestry (represented by the majority of subjects
from the US in PLCO and CPS-II), Northeastern European
ancestry (represented by Finnish subjects in ATBC) and
Western/Central European ancestry (represented by French
subjects in CeRePP). Haplogroups in the US and French
studies can mostly be accounted for by the R and I haplo-
group clans with a combined frequency of 81–85%; R1b1a2
and I1 were the most common sub branches. The R1 haplo-
group clan originated in Eurasia and migrated into Europe
where it divided into two subgroups, R1a (common in East-
ern Europe) and R1b (common in Western Europe) (Wiik
2008). R1b1a2 shows an East to West gradient in Europe
and is very common in Spain, France, UK and Ireland (Bal-
aresque et al. 2010). Haplogroup clan I1 appears to have
originated in the Balkans and migrated north throughout
Europe (Wiik 2008). It is most common in Scandinavia and
Northwestern Europe and gradually decreases in Central and
Southern Europe (Wiik 2008). Finnish subjects were strik-
ingly diVerent from the other three studies with a preponder-
ance of N1c (56%) and I1 (28%) haplogroups and few R1b
carriers. The N1c haplogroup is thought to have an Eastern
or Central Asian origin and probably reached Eastern
Europe via expansion through Siberia (Rootsi et al. 2007).
The frequency of this haplogroup in Finland has been
reported to be 58% (Wiik 2008).
Genotypes in stage II conWrmed the scarcity of E1b1b1c
in subjects of European ancestry (1–2%) and revealed a
higher frequency in the two Ashkenazi Jewish studies
(13–14%), in line with previous reports (Hammer et al.
2009) indicating similar Y chromosome haplogroup fre-
quencies in men of Ashkenazi Jewish descent living in the
US and those from Jewish communities in the Middle East.
E1b1b1c may have arisen in Northeastern Africa, and
migrated through the Levantine corridor to the Near East
and Europe (Semino et al. 2004). In a similar manner,
haplogroup R1b1a2 was seen in 50–59% of the subjects in
diVerent European American studies but only 10–11% in
the two Ashkenazi Jewish studies.
In conclusion, we found limited evidence for an associa-
tion between Y chromosome haplogroups and risk of

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Hum Genet (2012) 131:1173–11851181
123
prostate cancer in populations of European and Ashkenazi
Jewish ancestry using a large sample set close to 4,000
case–control pairs in Stage I and 2,300 case–control pairs
in Stage II. Weak but consistent evidence for a protective
eVect for haplogroup E1b1b1c was seen in all studies with a
nominally signiWcant meta-analysis, thus, calling for addi-
tional replication eVorts for this haplogroup in populations
of Ashkenazi Jewish and European ancestry. The diVerent
frequencies seen in subjects from the four stage I studies
may limit power to detect true associations for some
branches of the Y haplogroup tree. Furthermore, correcting
for population substructure based on autosomal SNPs may
not be optimal, as Y chromosome inheritance only reXects
male lineages that may have somewhat diVerent character-
istics throughout human history and population migration
as compared to that of females. Although we cannot
exclude a role for all chromosome Y haplogroups in pros-
tate cancer etiology, our study has good power to detect
common alleles with relatively large eVects. Smaller or
population speciWc eVects for the haplgroups tested here, or
for other haplogroups, could exist and should be studied by
testing comprehensive sets of chromosome Y haplogroup
markers in additional studies.
Materials and methods
Study population
Stage I of this study included 3,995 men diagnosed with
adenocarcinoma of the prostate and 3,815 control subjects
from three case–control studies nested within cohorts and
one hospital based case–control study, previously analyzed
in stages I and II of the Cancer Genetics Markers of Sus-
ceptibility study (CGEMS). Study details have been pub-
lished previously (Thomas et al. 2008; Yeager et al. 2007,
2009).The cohort studies were: the Prostate, Lung Colorec-
tal and Ovarian Cancer Screening Trial (PLCO, subjects
from continental USA) (Gohagan et al. 2000); the Ameri-
can Cancer Society Cancer Prevention Study II (CPS-II,
from continental USA) (Calle et al. 2002) and the Alpha-
Tocopherol, Beta-Carotene Cancer Prevention Study
(ATBC, from Finland) (1994). The case–control study was
the French Prostate Case–Control Study (CeRePP, Centre
de Recherche pour les Pathologies Prostatiques, from
France) (Valeri et al. 2003). The number of subjects
included from each study is shown in Supplemental
Table 1a. We incorporated prostate cancer stage and grade
at diagnosis to distinguish between non-aggressive (Glea-
son score <7 and disease stage <III, n = 1,531) and aggres-
sive prostate cancer (Gleason score ¸7 and/or disease stage
¸III, n = 2,141) as deWned in CGEMS (Thomas et al.
2008).
Stage II included 471 prostate cancer cases and 490 con-
trol subjects of European descent from the Physicians’
Health Study (PHS, from continental USA) (Ma et al.
2008); 215 prostate cancer cases and 244 control subjects
of European descent from the Health Professionals Follow-
up Study (HPFS, from continental USA) (Chen et al.
2005); 586 prostate cancer cases and 1198 control subjects
of European descent from the Agricultural Health Study
(AHS, from NC and IA) (Alavanja et al. 1996); 933 pros-
tate cancer cases and 1,221 control subjects of Ashkenazic
descent collected by the Albert Einstein College of Medi-
cine (Einstein, majority recruited from NY, FL, CA or NJ,
USA) (Agalliu et al. 2009); and 753 prostate cancer cases
and 376 male control subjects of Ashkenazic descent col-
lected at the Memorial Sloan Kettering Cancer Center
(MSKCC, from Northeast USA) (Gallagher et al. 2010).
Prostate cancer stage and grade at diagnosis were included
to distinguish between non-aggressive (Gleason score <7
AND disease stage <III, n = 194 for PHS; n = 172 for
HPFS, n = 338 for AHS; n = 416 for Einstein and n = 212
for MSKCC) and aggressive prostate cancer (Gleason score
¸7 OR disease stage ¸III, n = 167 for PHS; n = 80 for
HPFS, n = 85 for AHS; n = 457 for Einstein and n = 364
for MSKCC).
The study protocols for each study were approved by the
Institutional Review Board of each corresponding institu-
tion, and written informed consent was obtained from all
study participants.
Marker selection and genotyping
Markers were selected to detect chromosome Y haplogroups
with minor allele frequencies (MAF) ¸1% in populations of
European descent, using data from the International Society
of Genetic Genealogy (ISOGG) (http://www.isogg.org/tree/
ISOGG_YDNA_SNP_Index.html) 2011 update, the Y Chro-
mosome Consortium (http://ycc.biosci.arizona.edu/) (Karafet
et al. 2008; Underhill et al. 2001) and from HapMap (http://
hapmap.ncbi.nlm.nih.gov/). TaqMan custom genotyping
assays (ABI, Foster City, CA, USA) were designed and opti-
mized for 34 biallelic chromosome Y markers (32 SNPs and
2 insertion/deletion polymorphisms) based on the Y Chro-
mosome Consortium, ISOGG and HapMap databases.
For stage I, DNA was extracted from blood samples for
all studies except a subset of CPS-II where buccal cells
were used for a subset of subjects (n = 939). After pre-
genotyping quality control at the Core Genotyping Facility
(CGF) of the National Cancer Institute of the National
Institutes of Health, Gaithersburg, MD, USA (http://
cgf.nci.nih.gov/operations/pregenotyping-qaqc.html), 34
SNPs were genotyped on 9,501 samples in stage I using
TaqMan genotyping assays (ABI, Foster City, CA, USA).
The average concordance for 146 duplicate samples was

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1182Hum Genet (2012) 131:1173–1185
123
99.75%. Samples were excluded based on a completion rate
<80% or ¸2 heterozygous genotypes. After genotype qual-
ity control (Supplemental Table 1a), 8,157 samples
remained (including 8,011 subjects of which 7,810 men
(3,995 cases and 3,815 controls) had all covariates used in
the association analysis). Eight markers were monomorphic
in our data set (Supplemental Table 2), thus leaving 26
polymorphic markers for analysis.
For stage II, DNA was isolated from blood for all studies
except for the samples from Einstein where DNA was
obtained from mouthwash. A subset of DNA samples from
the AHS study (n = 1,858) were whole genome ampliWed
prior to genotyping using the GenomiPhi™ version 2 kit
(GE Healthcare) at the Core Genotyping Facility (CGF) of
the National Cancer Institute of the National Institutes of
Health, Gaithersburg, MD, USA (http://cgf.nci.nih.gov/
operations/wga.html). Two SNPs (M123 for haplogroup
E1b1b1c and M269 for haplogroup R1b1a2) were geno-
typed in stage II on 6,695 samples using TaqMan genotyp-
ing assays (ABI, Foster City, CA, USA) at CGF and on
1,213 samples at MSKCC (for MSKCC samples). This
included 6,487 subjects (2,958 case and 3,529 control sub-
jects). The E1b1b1c haplogroup was genotyped in samples
from Einstein, MSKCC, PHS and HPFS; the R1b1a2
haplogroup was genotyped in samples from Einstein,
MSKCC, PHS and AHS. Genotype quality control was per-
formed in a similar manner as for stage I studies (detailed in
Supplemental Table 1b). Concordance rates for duplicate
samples (n = 91) were 99.9%.
Statistical analysis
The association between haplogroups of the Y chromosome
and prostate cancer risk was examined using a logistic
regression model adjusted for age, study center and Wrst
principle component previously constructed based on
CGEMS genotype data (Thomas et al. 2008; Yeager et al.
2007, 2009) as it was signiWcant in the base model, to cor-
rect for population stratiWcation if available. All subjects
were of self-described European ancestry.
The variance weighted Wxed-eVect meta-analysis was
performed to assess the overall statistical signiWcance of
stage II studies as well as combination of stage I together
with II studies. Results were not corrected for multiple test-
ing because of the strong dependence among the markers
on this chromosome. Because all the Y haplogroups map to
a haplogroup evolutionary tree, each branch in the tree can
be cut and thus creating a bipartition of all individuals.
Individuals under each cut will have inherited the mutation
incurred on that branch. The case/control imbalance could
therefore be tested by comparing two groupings of subjects.
This is exactly the same as testing the genotypes of individ-
ual markers. To make full use of the data, genotypes from
untyped branches were imputed if possible, based on its
ancestor and sibling nodes in the tree. As an example, we
could infer genotypes for J1 because both J and J2 were
genotyped (Fig. 1a). We searched across all the branches in
the tree and tested three additional untyped haplogroups,
namely J1 (M267), IJ (M429) and IJK (M522). A branch
was not analyzed if there was a directly genotyped derived/
ancestor branch with a diVerence in frequency of <0.001.
For example, M96 and M203 are almost the same because
frequencies of haplogroup D in all study populations were
close to 0. Thus, testing of the imputed marker M203
became redundant when the directly genotyped marker
M96 was already analyzed.
Validation by sequencing
Genotypes for the two markers selected for replication
(M123 for haplogroup E1b1b1c and M269 for haplogroup
R1b1a2) were conWrmed by sequencing in 94 subjects from
the current study. They were chosen from the PLCO,
CeRePP and CPS-II studies in stage I such that approxi-
mately one-third (E1b1b1c) or half (R1b1a2) carried each
haplogroup. Primers were designed with the program
Primer3 (http://frodo.wi.mit.edu/primer3/) and used for
PCR ampliWcation of the genomic regions containing the 2
markers (Supplemental Table 3). PCR ampliWcations were
performed with 10 ng genomic DNA using the AmpliTaq
Gold 360 master mix (ABI). The samples were cleaned
using AMPure beads (Agencourt) on a Biomek FX (Beck-
man Coulter). After resuspending the beads in 50 ?l of
water, PCR products were sequenced using primers for the
two markers and an ABI PRISM Big Dye Terminator ver-
sion 3.1 cycle sequencing kit (Applied BioSystems, Foster
City, CA, USA). Sequencing was performed on an ABI
3730 capillary sequencer (Applied Biosystems). A 100%
concordance was noted for E1b1b1c and 98.9% concor-
dance for R1b1a2.
URLs
http://cgf.nci.nih.gov/operations/pregenotyping-qaqc.html
http://code.google.com/p/glu-genetics/
http://ycc.biosci.arizona.edu/
http://www.isogg.org/tree/
ISOGG_YDNA_SNP_Index.html
http://hapmap.ncbi.nlm.nih.gov/
Acknowledgments
Research Program of the Division of Cancer Epidemiology and Genet-
ics, National Cancer Institute, National Institutes of Health (NIH). The
authors acknowledge and thank both staV and participants in all studies
for donating their time and making this study possible. The authors
acknowledge support and constructive comments from Dr. Stephen J.
This study was supported by the Intramural

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Hum Genet (2012) 131:1173–1185 1183
123
Chanock, LTG, DCEG, National Cancer Institute. The content of this
publication does not necessarily reXect the views or policies of the
Department of Health and Human Services, nor does mention of trade
names, commercial products or organizations imply endorsement by
the US Government.
ConXict of interest
potential conXicts of interests.
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