Hum Genet (2012) 131:1173–1185

DOI 10.1007/s00439-012-1139-5

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 Genetic variation on the Y chromosome has notbeen convincingly implicated in prostate cancer risk. Tocomprehensively analyze the role of inherited Y chromo-some variation in prostate cancer risk in individuals of Euro-pean ancestry, we genotyped 34 binary Y chromosomemarkers in 3,995 prostate cancer cases and 3,815 controlsubjects drawn from four studies. In this set, we identiWednominally signiWcant association between a rare haplogroup,

E1b1b1c, and prostate cancer in stage I (P = 0.012,OR = 0.51; 95% conWdence interval 0.30–0.87). Populationsubstructure of E1b1b1c carriers suggested Ashkenazi Jew-ish ancestry, prompting a replication phase in individuals ofboth European and Ashkenazi Jewish ancestry. The associa-tion was not signiWcant for prostate cancer overall in studiesof either Ashkenazi Jewish (1,686 cases and 1,597 controlsubjects) or European (686 cases and 734 control subjects)ancestry (Pmeta = 0.078), but a meta-analysis of stage I and IIstudies revealed a nominally signiWcant association withprostate 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 betweenthose conducted in the US and France, in which the majority

Z. Wang and H. Parikh are co-Wrst authors.

Electronic supplementary material The online version of this article (doi:10.1007/s00439-012-1139-5) contains supplementary material, which is available to authorized users.

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. AmundadottirDivision 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. BurdettCore Genotyping Facility, SAIC-Frederick, Inc., NCI-Frederick, Frederick, MD 21702, USA

H. Parikh · J. Jia · T. Myers · L. AmundadottirLaboratory 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 DiverEpidemiology Research Program, American Cancer Society, Atlanta, GA 30303, USA

J. VirtamoDepartment of Chronic Disease Prevention, National Institute for Health and Welfare, 00300 Helsinki, Finland

G. Cancel-Tassin · A. Valeri · O. CussenotCentre de Recherche pour les Pathologies Prostatiques (CeRePP), Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, 75020 Paris, France

K. OYt · A. Dutra-Clarke · T. KirchhoVClinical 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 GazianoChanning Laboratory, Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA

D. J. HunterProgram in Molecular and Genetic Epidemiology, Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA

T. KirchhoV · R. B. HayesDivision of Epidemiology, Department of Environmental Medicine, New York University School of Medicine, New York, NY 10016, USA

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http://dx.doi.org/10.1007/s00439-012-1139-5

1174 Hum Genet (2012) 131:1173–1185

of men carried R1 haplogroups, resembling NorthwesternEuropean populations. On the other hand, Finns had aremarkably diVerent haplogroup distribution with a prepon-derance of N1c and I1 haplogroups. In summary, our resultssuggest that inherited Y chromosome variation plays a lim-ited role in prostate cancer etiology in European populationsbut warrant follow-up in additional large and well character-ized studies of multiple ethnic backgrounds.

Introduction

Family and twin studies have shown that prostate cancerhas a clear heritable component which may be among thehighest of all cancer types (Amundadottir et al. 2004; Lich-tenstein et al. 2000), Over the last few years, genome wideassociation studies (GWAS) have successfully identiWedgermline variants conferring risks of prostate cancer at over45 loci (Amundadottir et al. 2006; Chung and Chanock2011; 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 notimplicated variants on the Y chromosome in the risk ofprostate cancer, possibly due to the fact that very few Ychromosome SNPs have been included on most genotypingchips used to date. Several groups have speciWcally investi-gated the role of Y chromosome haplogroups in prostatecancer risk. Many of these studies are inconclusive due tothe small number of samples and/or markers used. One of

the larger studies was conducted within the multi-ethniccohort (MEC) using samples from prostate cancer casesand control subjects drawn from four ethnic groups. Of the41 haplogroups observed, one was signiWcantly associatedwith prostate cancer in Japanese men (Paracchini et al.2003) but this association was not replicated in a separatestudy from Korea (Kim et al. 2007). No association wasseen between Y haplogroups and prostate cancer in a largeSwedish study (Lindstrom et al. 2008).

The Y chromosome contains the largest non-recombiningregion in the human genome, spanning almost the entirelength 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, theNRY passes mostly unchanged from father to son andobserved mutations reXect the evolutionary history of the Ychromosome. Binary markers can be used to classify Ychromosomes into haplogroups organized by a phylogenetictree. A Wrst generation phylogeny of the tree was publishedin 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 organizedinto 20 major groups or clades (Karafet et al. 2008).

Multiple lines of evidence support a possible role forgenes 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 earlyevent in tumorigenesis (Brothman et al. 1999; Jordan et al.2001). In support of the previous assertion, chromosometransfer studies indicate that the human Y chromosome sup-presses tumorigenicity of human prostate cell lines in vivoimplying that it may harbor gene(s) with tumor suppressorfunction (Vijayakumar et al. 2005). Based on the essentialrole 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 thisgenomic region to investigate whether germline variation onthis chromosome plays a role in prostate cancer risk.

Results

We analyzed 7,810 men from the Cancer Genetic Markersof Susceptibility (CGEMS) scan in stage I of this study. Ofthe 34 chromosome Y markers genotyped, 26 wereobserved 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 28haplogroups including three combined groups (R1b1b +R1b*, R1a + R1* and I2b + I2c) as the leaf nodes of theNRY tree (Fig. 1a). Stage I had 41, 76 and 95% power todetect an association with an odds ratio of 1.3 and a MAF

I. Agalliu · R. D. BurkDepartment of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NewYork, NY 10461, USA

R. D. BurkDepartment of Pediatrics, Albert Einstein College of Medicine, Bronx, NewYork, NY 10461, USA

R. D. BurkDepartment of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NewYork, NY 10461, USA

R. D. BurkDepartment of Obstetrics, Gynecology and Women’s Health, Albert Einstein College of Medicine, Bronx, NewYork, NY 10461, USA

G. ThomasSynergie-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, USAe-mail: amundadottirl@mail.nih.gov

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Hum Genet (2012) 131:1173–1185 1175

Fig. 1 Chromosome Y haplogroup tree and frequency distribution incontrol subjects of European ancestry in Stage I. a Chromosome Y treeshowing genotyped markers in black and those not genotyped in lightgrey. Haplogroup names are according to the International Society ofGenetic Genealogy (ISOGG) 2011 update. The arrow points to themutational event which gave rise to the E1b1b1c haplogroup. Stage Istudies are the following: CPS-II American Cancer Society Cancer

Prevention Study II, ATBC Alpha-Tocopherol, Beta-Carotene CancerPrevention Study, CeRePP Centre de Recherche pour les PathologiesProstatiques, and PLCO Prostate, Lung Colorectal and Ovarian CancerScreening Trial. b The circle plots show frequencies for haplogroupswith a derived frequency of 5% or higher in diVerent colors for eachStage I cohort (remaining haplogroups are combined in one groupshown in black)

M42

M60

P97

M168

P143

M203

M174

M96

M132

M180

M78

M81

M123

M130

M377

M285

M201 P15

M522

M26

M307

M172

M170

M304

M9

M70

M20

M526M242

M74

M214

M46

M207

M173 M18

M269

Haplogroup CPS-II ATBC CeRePP PLCO

Q 0.005 0.001 0.004 0.003

R1b1a2 0.462 0.048 0.345 0.488 R1b1b+R1b* 0.083 0 0.297 0.025

R1b1c1 0 0 0 0

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 0.038 0.001 0.059 0.038

J1 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 ATBC PLCOCeRePP

E1b1b1a1 G2a I Others

A 0 0 0 0.001

A

B

M267

M343

R1N1cJ2

M231

M215

M89

P177

M128+P43

M175

M513

M479

M429

M335

L416/L596

123

1176 Hum Genet (2012) 131:1173–1185

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 ratesand concordance analysis, a total of 3,995 prostate cancercases and 3,815 control subjects from four studies wereused 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

Hum Genet (2012) 131:1173–1185 1177

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(0.

95–1

.21)

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242

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5279

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856

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004

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05 (

0.51

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9)32

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003

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0.27

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8)37

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0.00

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005

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47 (

0.65

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5)

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(0.

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|195

90.

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10.

093

0.90

(0.

79–1

.02)

123

1178 Hum Genet (2012) 131:1173–1185

with risk of aggressive prostate cancer (Pmeta = 0.28). InStage 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 andan 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 Iwas 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 similarwith an average diVerence of 0.8% and a maximum diVer-ence of 5.8% for the combined category of haplogroupsR1b1b + R1b*. The CeRePP study, conducted in France, isrelatively 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, aFinnish study, with an average haplogroup frequency diVer-ence of 5.2% and a maximum diVerence of 54.4%. Thisstems from a very high frequency of haplogroup N1c in thisstudy (55.6%), while it is infrequent in the other three stud-ies from the US and France (0.8% in CPS-II, 1.7% inPLCO and 0.4% in CeRePP). Second, R1b, the most fre-quent haplogroup overall, is seen in over 50% of subjects inPLCO, CPS-II and CeRePP but only in 4.8% of Finnishsubjects. The third largest diVerence was noted for haplo-group I1 which was more common in Finns at 27.6%, ascompared to 13.9% in PLCO, 11.2% in CPS-II and only8.1% in CeRePP.

Haplogroup E1b was observed at low frequencies in allstudies and its sub lineage E1b1b1c was seen in approxi-mately 1–2% of subjects from the two US studies (PLCOand CPS-II) and the French study (CeRePP), whereas itwas 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 studieshave not analyzed such a large sample size with as manymarkers in individuals of European ancestry. Because ofthe threshold for MAF chosen for this study (¸1%), we hadlimited capacity to detect risk variants with low to mediumfrequency and eVect sizes. Prostate cancer GWAS to datehave used arrays with limited coverage on the Y chromo-some. As an example, in CGEMS, of the approximately500,000 SNPs genotyped in stage I, only ten Y chromo-some markers passed quality control assessment and wereincluded in the primary analysis; this limited set of variantson 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 thedistribution of the Wrst two principal components, EV1 and EV2, forcarriers of E1b1b1c (Wlled squares) and R1b1a2 (open circles) haplo-groups in Stage I. Circles and squares denote eigenvalues from PCAanalysis for each individual. The distribution of EV1 and EV2 for allStage 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 fromblood. Individuals of inferred Ashkenazi Jewish ancestry are circled.PCA results were performed by EIGENSTRAT in CGEMS prostatecancer 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

EV

2

-0.02 -0.01 0 0.01 0.02

-0.01

0

0.01

0.02

0.03

0.04

0.05

0.03

EV1

EV

2

ATBCCPS-II:BloodCPS-II:Buccal

CeRePP

PLCO

AJ alike cluster

-0.02 -0.01 0 0.01 0.02

A

B

123

Hum Genet (2012) 131:1173–1185 1179

Tab

le2

Rep

licat

ion

anal

ysis

of

nota

ble

chro

mos

ome

Y s

igna

ls in

pro

stat

e ca

ncer

stu

dies

of

Ash

kena

zi a

nd E

urop

ean

desc

ent (

Stag

e II

)

Res

ults

fro

m th

e un

cond

ition

al lo

gist

ic r

egre

ssio

n of

the

geno

type

s ge

nera

ted

in S

tage

II

are

show

n. T

he a

naly

sis

was

adj

uste

d fo

r ag

e in

10-

year

cat

egor

ies

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odd

s ra

tio,

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conW

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e in

terv

ala

Hap

logr

oup

bein

g te

sted

bas

ed o

n th

e Y

Chr

omos

ome

Con

sort

ium

and

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nom

encl

atur

eb

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Y lo

cus/

mar

ker

nam

ec

Con

trol

s, c

ases

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inor

all

ele

freq

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y in

con

trol

and

cas

e pa

rtic

ipan

tse

Sco

re te

st (

1df)

for

all

scen

ario

s ex

cept

for

agg

ress

ive

case

s fr

om H

PFS

whi

ch is

bas

ed o

n a

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er e

xact

test

(1d

f)

Stud

yA

ll c

ases

Non

aggr

essi

ve c

ases

Agg

ress

ive

case

s

Sub

ject

scM

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Pe

OR

Sub

ject

scM

AFd

Pe

OR

Sub

ject

scM

AFd

Pe

OR

E1b

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a (M

123b

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Ein

stei

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0.11

70.

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(0.

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.07)

1214

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560.

138|

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693

0.94

(0.

68–1

.29)

MSK

CC

375|

750

0.12

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0.60

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87 (

0.52

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6)37

5|21

20.

128|

0.09

00.

956

0.96

(0.

47–1

.94)

375|

362

0.12

8|0.

146

0.95

40.

98 (

0.53

–1.8

3)

PHS

489|

471

0.02

9|0.

021

0.45

50.

73 (

0.32

–1.6

7)48

9|19

40.

029|

0.01

50.

379

0.57

(0.

16–2

.02)

489|

167

0.02

9|0.

024

0.78

00.

85 (

0.28

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3)

HPF

S24

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50.

033|

0.02

30.

540

0.70

(0.

23–2

.18)

244|

138

0.03

3|0.

036

0.84

81.

12 (

0.36

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9)24

4|44

0.03

3|0.

000

0.21

00.

00 (

0.00

–1.7

7)

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(M26

9b)

Ein

stei

n12

10|9

120.

095|

0.11

50.

121

1.25

(0.

94–1

.67)

1210

|408

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5|0.

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0.91

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10|4

460.

095|

0.10

80.

390

1.17

(0.

82–1

.69)

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CC

373|

739

0.11

0|0.

118

0.93

61.

02 (

0.61

–1.7

137

3|20

60.

110|

0.12

10.

981

0.99

(0.

51–1

.93)

373|

358

0.11

0|0.

126

0.84

11.

06(0

.59–

1.92

)

PHS

482|

463

0.50

0|0.

531

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14 (

0.88

–1.4

7)48

2|19

00.

500|

0.55

30.

238

1.23

(0.

87–1

.72)

482|

164

0.50

0|0.

537

0.43

01.

15 (

0.81

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5)

AH

S11

59|5

710.

589|

0.57

80.

662

0.96

(0.

78–1

17)

1159

|326

0.58

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558

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00.

88(0

.66–

1.09

)11

59|8

00.

589|

0.61

20.

703

1.09

(0.

69–1

.74)

123

1180 Hum Genet (2012) 131:1173–1185

2008, 2009; Gudmundsson et al. 2007a, b, 2008, 2009;Haiman et al. 2007; Kote-Jarai et al. 2011; Schumacheret al. 2011; Takata et al. 2010; Thomas et al. 2008; Yeageret al. 2007, 2009).

One haplogroup of interest was noted in phase I of ourstudy; the E1b1b1c haplogroup was nominally signiWcantin the overall prostate cancer and non-aggressive prostatecancer groups. The marker that denotes this haplogroup islocated in the last intron of the taxilin gamma 2 pseudogene(TXLNG2P) on chromosome Yq11.222. This haplogroupwas analyzed in a second phase using replication studies ofEuropean and Ashkenazi Jewish ancestry along with amore common haplogroup, R1b1a2. Neither haplogroupwas signiWcantly associated with overall prostate cancerrisk in stage II. A meta-analysis of stage I and stage IIresults 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 thresholdrequired for signiWcance in GWAS studies (WellcomeTrust Case Control Consortium 2007), suggesting that fur-ther studies are required to establish this association.Although our analysis does not provide strong evidence fora relationship between variation in the Y chromosome andprostate cancer, it can be argued that the appropriate statis-tical threshold to be applied to a study of approximately 30markers 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 cannotexclude 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 Ychromosome had been assessed previously, but with limitedsample and/or marker sets. One of the most complete stud-ies published was conducted within the MEC (Paracchiniet al. 2003). Four ethnic groups with a total of 930 casesand 1,208 control subjects were included. One of the 41haplogroups observed in the study was signiWcantly associ-ated with prostate cancer risk in Japanese men with aP value of 0.02 (Paracchini et al. 2003). Despite the largeoverall 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 signiWcantlyassociated with prostate cancer risk in a small Korean studythat assessed 14 markers in approximately 106 cases and110 control subjects, including the haplogroup reported inthe MEC study (Kim et al. 2007). Lack of an associationbetween Y haplogroups and prostate cancer was alsoreported in a Swedish study assessing Wve ChrY markers in1,452 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 onthe Y chromosome and prostate cancer risk.

Frequencies of Y chromosome haplogroups vary consid-erably between diVerent geographical regions and ethnicgroups, and have turned out to be informative in studies ofhuman evolution and migration. In Europe, marked diVer-ences in haplogroup frequencies are observed betweencountries in Northeastern, Northwestern, Southwestern,Southeast and Central Europe (Wiik 2008). In addition, theAshkenazi Jewish community has a speciWc pattern that isreminiscent of non-Ashkenazi Jewish communities in theNear East (Behar et al. 2004). We observed a diVerent distri-bution of major haplogroups in subjects of NorthwesternEuropean ancestry (represented by the majority of subjectsfrom the US in PLCO and CPS-II), Northeastern Europeanancestry (represented by Finnish subjects in ATBC) andWestern/Central European ancestry (represented by Frenchsubjects in CeRePP). Haplogroups in the US and Frenchstudies can mostly be accounted for by the R and I haplo-group clans with a combined frequency of 81–85%; R1b1a2and I1 were the most common sub branches. The R1 haplo-group clan originated in Eurasia and migrated into Europewhere it divided into two subgroups, R1a (common in East-ern Europe) and R1b (common in Western Europe) (Wiik2008). R1b1a2 shows an East to West gradient in Europeand is very common in Spain, France, UK and Ireland (Bal-aresque et al. 2010). Haplogroup clan I1 appears to haveoriginated in the Balkans and migrated north throughoutEurope (Wiik 2008). It is most common in Scandinavia andNorthwestern Europe and gradually decreases in Central andSouthern 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 R1bcarriers. The N1c haplogroup is thought to have an Easternor Central Asian origin and probably reached EasternEurope via expansion through Siberia (Rootsi et al. 2007).The frequency of this haplogroup in Finland has beenreported to be 58% (Wiik 2008).

Genotypes in stage II conWrmed the scarcity of E1b1b1cin subjects of European ancestry (1–2%) and revealed ahigher 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 theUS and those from Jewish communities in the Middle East.E1b1b1c may have arisen in Northeastern Africa, andmigrated through the Levantine corridor to the Near Eastand Europe (Semino et al. 2004). In a similar manner,haplogroup R1b1a2 was seen in 50–59% of the subjects indiVerent European American studies but only 10–11% inthe two Ashkenazi Jewish studies.

In conclusion, we found limited evidence for an associa-tion between Y chromosome haplogroups and risk of

123

Hum Genet (2012) 131:1173–1185 1181

prostate cancer in populations of European and AshkenaziJewish ancestry using a large sample set close to 4,000case–control pairs in Stage I and 2,300 case–control pairsin Stage II. Weak but consistent evidence for a protectiveeVect for haplogroup E1b1b1c was seen in all studies with anominally signiWcant meta-analysis, thus, calling for addi-tional replication eVorts for this haplogroup in populationsof Ashkenazi Jewish and European ancestry. The diVerentfrequencies seen in subjects from the four stage I studiesmay limit power to detect true associations for somebranches of the Y haplogroup tree. Furthermore, correctingfor population substructure based on autosomal SNPs maynot be optimal, as Y chromosome inheritance only reXectsmale lineages that may have somewhat diVerent character-istics throughout human history and population migrationas compared to that of females. Although we cannotexclude a role for all chromosome Y haplogroups in pros-tate cancer etiology, our study has good power to detectcommon alleles with relatively large eVects. Smaller orpopulation speciWc eVects for the haplgroups tested here, orfor other haplogroups, could exist and should be studied bytesting comprehensive sets of chromosome Y haplogroupmarkers in additional studies.

Materials and methods

Study population

Stage I of this study included 3,995 men diagnosed withadenocarcinoma of the prostate and 3,815 control subjectsfrom three case–control studies nested within cohorts andone hospital based case–control study, previously analyzedin 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, subjectsfrom 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 wasthe French Prostate Case–Control Study (CeRePP, Centrede Recherche pour les Pathologies Prostatiques, fromFrance) (Valeri et al. 2003). The number of subjectsincluded from each study is shown in SupplementalTable 1a. We incorporated prostate cancer stage and gradeat diagnosis to distinguish between non-aggressive (Glea-son score

1182 Hum Genet (2012) 131:1173–1185

99.75%. Samples were excluded based on a completion rate

Hum Genet (2012) 131:1173–1185 1183

Chanock, LTG, DCEG, National Cancer Institute. The content of thispublication does not necessarily reXect the views or policies of theDepartment of Health and Human Services, nor does mention of tradenames, commercial products or organizations imply endorsement bythe US Government.

ConXict of interest All authors report no Wnancial interests orpotential conXicts of interests.

Open Access This article is distributed under the terms of the Crea-tive Commons Attribution License which permits any use, distribution,and reproduction in any medium, provided the original author(s) andsource are credited.

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Y chromosome haplogroups and prostate cancer in populations of European and Ashkenazi Jewish ancestryAbstractIntroductionResultsStage I association analysisPopulation substructure of E1b1b1c carriersLimited evidence for association to prostate cancer in Stage II analysisHaplogroup frequency and population distribution

DiscussionMaterials and methodsStudy populationMarker selection and genotypingStatistical analysisValidation by sequencing

URLsAcknowledgmentsReferences