ARTICLE
Ge mline a ia ion a 8q24 and p os a e cance
isk in men o Eu opean ances y
Ma co Ma ejcic1, Edwa d J. Saunde s e al.
#
Ch omosome 8q24 is a suscep ibili y locus o mul iple cance s, including p os a e cance .
He e we combine gene ic da a ac oss he 8q24 suscep ibili y egion om 71,535 p os a e
cance cases and 52,935 con ols o Eu opean ances y o define he o e all con ibu ion o
ge mline a ia ion a 8q24 o p os a e cance isk. We iden i y 12 independen isk signals o
p os a e cance (p< 4.28 × 10−15), including h ee isk a ian s ha ha e ye o be epo ed.
F om a polygenic isk sco e (PRS) model, de i ed o assess he cumula i e e ec o isk
a ian s a 8q24, men in he op 1% o he PRS ha e a 4- old (95%CI =3.62–4.40) g ea e
isk compa ed o he popula ion a e age. These 12 a ian s accoun o ~25% o wha can be
cu en ly explained o he amilial isk o p os a e cance by known gene ic isk ac o s. These
findings highligh he o e whelming con ibu ion o ge mline a ia ion a 8q24 on p os a e
cance isk which has implica ions o popula ion isk s a ifica ion.
Ma co Ma ejcic, Edwa d J. Saunde s e al.
#
DOI: 10.1038/s41467-018-06863-1 OPEN
Co espondence and eques s o ma e ials should be add essed o C.A.H. (email: Ch is op[email p o ec ed]).
#
A ull lis o au ho s and hei
a filia ions appea s a he end o he pape .
NATURE COMMUNICATIONS | (2018) 9:4616 | DOI: 10.1038/s41467-018-06863-1 | www.na u e.com/na u ecommunica ions 1
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P os a e cance (PCa) is he mos common cance among
men in he US, wi h 161,360 new cases and 26,730 ela ed
dea hs es ima ed in 20171. Familial and epidemiological
s udies ha e p o ided e idence o subs an ial he i abili y o PCa2,
and ~170 common isk loci ha e been iden ified h ough
genome-wide associa ion s udies (GWAS)3. The suscep ibili y
egion on ch omosome 8q24 has been shown o be a majo
con ibu o o PCa isk, wi h mul iple a ian s clus e ed in fi e
linkage disequilib ium (LD) blocks spanning ~600 Mb ha a e
independen ly associa ed wi h isk4. Many o hese associa ion
signals epo ed a 8q24 ha e been eplica ed ac oss acial/e hnic
popula ions5,6, poin ing o common sha ed unc ional a ian s
wi hin 8q24. Howe e , a e ances y-specific a ian s ha e also
been de ec ed, which con e la ge ela i e isks o PCa (odds
a ios [ORs] >2.0) han common isk a ian s in he egion and
signi y allelic he e ogenei y in he con ibu ion o ge mline a -
ia ion a 8q24 o PCa isk ac oss popula ions7.
In he cu en s udy, we pe o m a comp ehensi e in es iga-
ion o gene ic a ia ion ac oss he 1.4 Mb cance suscep ibili y
egion a 8q24 (127.6–129.0 Mb) in ela ion o PCa isk. We
combine geno yped and impu ed da a om wo la ge GWAS
conso ia (PRACTICAL/ELLIPSE OncoA ay and iCOGS)
including >124,000 indi iduals o Eu opean ances y o sea ch o
no el isk a ian s, as well as o de e mine he o e all con ibu-
ion o gene ic a ia ion a 8q24 o PCa he i abili y. Ou findings
unde sco e he sizable impac o gene ic a ia ion in he 8q24
egion in explaining in e -indi idual di e ences in PCa isk, wi h
po en ial clinical u ili y o gene ic isk p edic ion.
Resul s
Ma ginal and condi ional associa ion analysis. Geno ype da a
om he Illumina OncoA ay and iCOGS a ay and impu a ion
o 1000 Genomes P ojec (1KGP) we e gene a ed among 71,535
PCa cases and 52,935 con ols o Eu opean ances y om 86 case-
con ol s udies (see Me hods). O he 5600 geno yped and
impu ed a ian s a 8q24 (127.6–129.0 Mb) wi h mino allele
equency (MAF) > 0.1% e ained o analysis (see Me hods),
1268 (23%) we e associa ed wi h PCa isk a p< 5×10−8while
2772 (49%) we e ma ginally associa ed a p< 0.05. These 5600
ma ke s cap u e, a 2> 0.8, 90% and 97% o all a ian s a 8q24
(127.6–129.0 Mb) wi h MAF ≥1% and ≥5%, espec i ely (based
on 1KGP Phase 3 EUR panel). In a o wa d and backwa d
s epwise selec ion model on a ian s ma ginally associa ed wi h
PCa isk (p< 0.05, n=2772; see Me hods), we iden ified 12
a ian s wi h condi ional p- alues om he Wald es be ween
2.93 × 10−137 and 4.28 × 10−15 (Table 1). None o he o he
a ian s we e s a is ically significan a p<5×10
−8a e adjus -
men o he 12 independen hi s (Fig. 1). The 8q24 egion is
shown in Supplemen a y Fig. 1. O hese 12 s epwise signals, h ee
had alleles wi h ex eme isk allele equencies (RAFs) ha con-
eyed la ge e ec s ( s77541621, RAF =2%, OR =1.85, 95%CI =
1.76–1.94; s183373024, RAF =1%, OR =2.67, 95%CI =
2.43–2.93; s190257175, RAF =99%, OR =1.60, 95%CI =
1.42–1.80). The emaining a ian s had RAFs be ween 0.11 and
0.92 and condi ional ORs ha we e mo e modes and anged
om 1.10 o 1.37 (Table 1). Fo 8 o he 12 a ian s, he allele
ound o be posi i ely associa ed wi h PCa isk was he p e-
dominan allele (i.e., >50% in equency). Fo wo a ian s,
s78511380 and s190257175, he ma ginal associa ions we e no
genome-wide significan and subs an ially weake han hose in
he condi ional model. Fo s78511380, he ma ginal OR was
sligh ly p o ec i e (OR =0.97; p=0.027), bu e e sed di ec ion
and was highly s a is ically significan when condi ioning on he
o he 11 a ian s (OR =1.19; p=3.5 × 10−18; Table 1).
Haplo ype analysis. The haplo ype analysis showed an addi i e
e ec o he 12 independen isk a ian s consis en wi h ha
p edic ed in he single a ian es ; co-occu ence o he 8q24 isk
alleles on he same haplo ype does no u he inc ease he isk o
PCa (Supplemen a y Table 1). The unique haplo ype ca ying he
e e ence allele o s190257175 (GCTTAT, 0.5% equency) is
also he sole haplo ype associa ed wi h a educed isk o PCa,
sugges ing ha ha ing he C allele con e s a p o ec i e e ec . The
e e ence allele o s78511380 (A, 8% equency) occu s on a
haplo ype in block 2 oge he wi h he isk alleles o
s190257175, s72725879 and s5013678 (haplo ype GTTTAA,
8%) which obscu es he posi i e associa ion wi h he T allele o
s78511380. Thus, he ma ginal p o ec i e e ec associa ed wi h
he isk allele o s78511380 eflec s an inc eased isk associa ed
wi h he occu ence on a isk haplo ype wi h o he isk alleles
(Supplemen a y Table 1).
Table 1 Ma ginal and condi ional es ima es o gene ic ma ke s a 8q24 independen ly associa ed wi h p os a e cance isk
Va ian IDaPosi ionbAllelecRAFdLD clus e eCondi ional associa ion Ma ginal associa ion
OR (95%CI)gp- alue OR (95%CI)hp- alue
s1914295 127910317 T/C 0.68 block 1 1.10 (1.08–1.12) 7.30 × 10−25 1.09 (1.07–1.11) 3.07 × 10−21
s1487240 128021752 A/G 0.74 block 1 1.20 (1.17–1.22) 2.77 × 10−66 1.16 (1.14–1.18) 2.97 × 10−54
s77541621 128077146 A/G 0.02 block 2 1.85 (1.76–1.94) 2.93 × 10−137 1.83 (1.74–1.92) 4.33 × 10−137
s190257175 128103466 T/C 0.99 block 2 1.60 (1.42–1.80) 4.28 × 10−15 1.36 (1.22–1.53) 6.90 × 10−8
s72725879 128103969 T/C 0.18 block 2 1.31 (1.28–1.35) 1.26 × 10−83 1.17 (1.14–1.19) 3.96 × 10−48
s5013678 128103979 T/C 0.78 block 2 1.10 (1.08–1.13) 1.58 × 10−19 1.20 (1.17–1.22) 4.44 × 10−68
s183373024 128104117 G/A 0.01 block 2 2.67 (2.43–2.93) 4.89 × 10−95 3.20 (2.92–3.50) 6.60 × 10−138
s78511380 128114146 T/A 0.92 block 2 1.19 (1.14–1.23) 3.48 × 10−18 0.97 (0.94–1.00) 0.027
s17464492 128342866 A/G 0.72 block 3 1.16 (1.14–1.18) 3.01 × 10−52 1.17 (1.15–1.19) 9.05 × 10−61
s6983267 128413305 G/T 0.51 block 4 1.18 (1.16–1.20) 5.68 × 10−84 1.23 (1.21–1.25) 3.15 × 10−135
s7812894 128520479 A/T 0.11 block 5 1.37 (1.33–1.40) 1.55 × 10−122 1.45 (1.41–1.49) 1.20 × 10−181
s12549761 128540776 C/G 0.87 block 5 1.21 (1.18–1.24) 1.61 × 10−45 1.28 (1.25–1.31) 1.38 × 10−78
aVa ian s ha emained genome-wide significan ly associa ed wi h PCa isk (p<10
−8) in he final s epwise model
bCh omosome posi ion based on human genome build 37
cRisk allele/ e e ence allele
dRisk allele equency
eLD clus e s we e in e ed based on ecombina ion ho spo s using Haplo iew 4.229 and defined as p e iously epo ed by Al Olama e al.4
Each a ian was inco po a ed in he s epwise model based on he s eng h o ma ginal associa ion om he me a-analysis o OncoA ay and iCOGS da a
gPe -allele odds a io and 95% confidence in e al adjus ed o coun y, 7(OncoA ay)/8(iCOGS) p incipal componen s and all o he a ian s in he able
hPe -allele odds a io and 95% confidence in e al adjus ed o coun y and 7(OncoA ay)/8(iCOGS) p incipal componen s
ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-06863-1
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Co ela ion wi h known isk loci. The 12 isk a ian s spanned
ac oss he fi e LD blocks p e iously epo ed o ha bo isk
a ian s o PCa a 8q244, wi h block 2 ha bo ing six signals,
blocks 1 and 5 wo signals each, and blocks 3 and 4 only one
(Supplemen a y Fig. 2). Excep o a weak co ela ion be ween
s72725879 and s78511380 in block 2 ( 2=0.28), he isk a -
ian s we e unco ela ed wi h each o he ( 2≤0.09; Supplemen a y
Da a 1), which co obo a es hei independen associa ion wi h
PCa isk. Eigh o he a ian s ( s1487240, s77541621,
s72725879, s5013678, s183373024, s17464492, s6983267,
s1914295
s1487240
s77541621
s190257175
s72725879
s5013678
s183373024
s78511380
s17464492
s6983267
s7812894
s12549761
0
20
40
60
80
100
120
140
160
180
200
−Log10(p)
−Log10(p)
Ma ginal
s1914295
s1487240
s77541621
s190257175
s72725879
s5013678
s183373024
s78511380
s17464492
s6983267
s7812894
s12549761
0
20
40
60
80
100
120
140
Condi ional
s1914295
s1487240
s77541621
s190257175
s72725879
s5013678
s183373024
s78511380
s17464492
s6983267
s7812894
s12549761
LD 2 Hi s
His one
128,000,000 128,200,000 128,400,000
DNaseI
Conse ed
Ch omHMM
eQTL
Bio ea u es
PCAT1
POU5F1B
CASC8
128,000,000 128,200,000 128,400,000
Genes
FAM84B POU5F1B
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s7812894) ha e been p e iously epo ed ei he di ec ly (Sup-
plemen a y Table 2) o a e co ela ed ( 2≥0.42) wi h known
ma ke s o PCa isk om s udies in popula ions o Eu opean,
A ican o Asian ances y (Supplemen a y Da a 1)4,7–10. The
ma ginal es ima es o p e iously published PCa isk a ian s
a 8q24 in he cu en s udy a e shown in Supplemen a y Table 2.
The a ian s1914295 in block 1 is only weakly co ela ed
wi h he p e iously epo ed isk a ian s s12543663 and
s10086908 ( 2=0.17 and 0.14, espec i ely), while s7851380
is modes ly co ela ed wi h he p e iously epo ed isk a ian
s1016343 ( 2=0.28). The emaining wo a ian s, s190257175
and s12549761, a e no co ela ed ( 2< 0.027) wi h any known
PCa isk ma ke .
Polygenic isk sco e and amilial ela i e isk. To es ima e he
cumula i e e ec o ge mline a ia ion a 8q24 on PCa isk, a
polygenic isk sco e (PRS) was calcula ed o he 12 independen
isk alleles om he final model based on allele dosages weigh ed
by he pe -allele condi ionally adjus ed ORs (see Me hods).
Compa ed o he men a ‘a e age isk’(i.e., he 25 h–75 h PRS
ange among con ols), men in he op 10% o he PRS
dis ibu ion had a 1.93- old ela i e isk (95%CI =1.86–2.01)
(Table 2), wi h he isk being 3.99- old highe (95%CI =
3.62–4.40) o men in he op 1%. Risk es ima es by PRS ca ego y
we e no modified by amily his o y (FamHis -yes: OR =4.24,
95%CI =2.85–6.31; FamHis -no: OR =3.38, 95%CI =
2.88–3.97). To quan i y he impac o ge mline a ia ion a 8q24,
we also es ima ed he p opo ion o amilial ela i e isk (FRR)
and he i abili y o PCa con ibu ed by 8q24 and compa ed his o
he p opo ions explained by all known PCa isk a ian s
including 8q24 (see Me hods). The 175 es ablished PCa sus-
cep ibili y loci iden ified o da e3,11 a e es ima ed o explain
37.08% (95%CI =32.89–42.49) o he FRR o PCa, while he 12
independen signals a 8q24 alone cap u e 9.42% (95%CI =
8.22–10.88), which is 25.4% o he o al FRR explained by known
gene ic isk ac o s o PCa (Table 3). This is simila o he
p opo ion o he i abili y explained by 8q24 a ian s (22.2%)
compa ed o he o al explained he i abili y by he known isk
a ian s (0.118). In compa ison, he nex highes con ibu ion o
an indi idual suscep ibili y egion o he FRR o PCa is he TERT
egion a ch omosome 5p15, whe e 5 independen signals con-
ibu ed 2.63% (95%CI =2.34–3.00). No o he indi idual GWAS
Fig. 1 LocusExplo e plo s o he 12 a ian s a 8q24 significan ly associa ed wi h PCa isk. ‘Ma ginal’and ‘Condi ional’Manha an plo panels show
ma ginal and condi ional associa ion esul s, espec i ely. Va ian posi ions (x-axis) and −log
10
p- alues om he Wald es (y-axis) a e shown, wi h he
ed line indica ing he h eshold o genome-wide significan associa ion wi h PCa isk (p≤5×10
−8) and blue peaks local es ima es o ecombina ion a es.
The posi ion o he 12 independen a ian s is labeled in each plo . Clus e s o co ela ed a ian s o each independen signal a e dis inguished using
di e en colo s and also depic ed on he ‘LD 2Hi s’ ack. S onge shading indica es g ea e co ela ion wi h he lead a ian , wi h a ian s no co ela ed
a 2≥0.2 wi h any lead a ian uncolo ed. Pai wise co ela ions a e based on he Eu opean ances y (EUR) panel om he 1000 Genomes P ojec (1KGP)
Phase 3. The ela i e posi ion o Re Seq genes and biological anno a ions a e shown in he ‘Genes’and ‘Bio ea u es’panels, espec i ely. Genes on he
posi i e s and a e deno ed in g een and hose on he nega i e s and in pu ple. Anno a ions displayed a e: his one modifica ions in ENCODE ie 1 cell lines
(His one ack), he posi ions o any a ian s ha we e eQTLs wi h p os a e umo exp ession in TCGA p os a e adenoca cinoma samples and he
espec i e genes o which exp ession is al e ed (eQTL ack), ch oma in s a e ca ego iza ions in he P EC cell-line by Ch omHMM (Ch omHMM ack),
he posi ion o conse ed elemen peaks (Conse ed ack) and he posi ion o DNaseI hype sensi i i y si e peaks in ENCODE p os a e cell-lines (DNaseI
ack). The da a displayed in his plo may be explo ed in e ac i ely h ough he LocusExplo e applica ion (h p://www.oncogene ics.ic .ac.uk/8q24/)
Table 2 Rela i e isk o PCa o polygenic isk sco e (PRS) g oups
Risk ca ego y pe cen ileaNo. o indi iduals Risk es ima es o PRS g oups
Con ols Cases OR (95% CI)bp- alue
≤1% 530 339 0.52 (0.45–0.59) 2.11 × 10−20
1%–10% 4771 3636 0.62 (0.59–0.65) 6.26 × 10−90
10%–25% 7936 7359 0.75 (0.72–0.78) 3.62 × 10−54
25%–75% 26,464 32,743 1.00 (Re )
75%–90% 7940 13,431 1.37 (1.32–1.41) 6.55 × 10−77
90%–99% 4766 11,451 1.93 (1.86–2.01) 4.13 × 10−249
>99% 528 2576 3.99 (3.62–4.40) 5.64 × 10−172
No e: PRS we e calcula ed o a ian s om he final s epwise model wi h allele dosage om OncoA ay and iCOGS weigh ed by he pe -allele condi ionally adjus ed odds a ios om he me a-analysis
aRisk ca ego y g oups we e based on he pe cen ile dis ibu ion o isk alleles in o e all con ols
bEs ima ed e ec o each PRS g oup ela i e o he in e qua ile ange (25–75%) in OncoA ay and iCOGS da ase s sepa a ely, and hen me a-analyzed ac oss he wo s udies; odds a ios we e adjus ed
o coun y and 7(OncoA ay)/8(iCOGS) p incipal componen s
Table 3 P opo ion o amilial ela i e isk (FRR) and he i abili y (h
g
2) o PCa explained by known isk a ian s
Sou ce No. o a ian s P opo ion o FRR (95%CI) % o o al FRR h
g
2(SE) % o o al h
g
2
8q24a12 9.42 (8.22–10.88) 25.4 0.027 (0.011) 22.2
HOXB13b1 1.91 (1.20–2.85) 5.2 0.004 (0.005) 3.0
All o he a ian sb,c 162 25.77 (22.94–29.36) 69.5 0.092 (0.010) 74.9
To al 175 37.08 (32.89–42.49) 100 0.118 (0.012) 100
aCondi ional es ima es we e de i ed by fi ing a single model wi h all a ian s om OncoA ay da a
bRisk es ima es and allele equencies o egions wi h a single a ian a e om a me a-analysis o OncoA ay, iCOGS and 6 addi ional GWAS3
cRisk a ian s included om fine-mapping o PCa suscep ibili y loci in Eu opean ances y popula ions11
ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-06863-1
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locus has been es ablished as explaining >2% o he FRR,
including he low equency, non-synonymous, mode a e pene-
ance HOXB13 a ian ( s138213197) a ch omosome 17q21
ha is es ima ed o explain only 1.91% (95%CI =1.20–2.85) o
he FRR11.
JAM analysis. We explo ed ou da a wi h a second fine-mapping
app oach, JAM (Join Analysis o Ma ginal summa y s a is ics)12,
which uses GWAS summa y s a is ics o iden i y c edible se s o
a ian s ha define he independen associa ion signals in sus-
cep ibili y egions (see Me hods). The 95% c edible se o he
JAM analysis confi med all o he independen signals om
s epwise analysis excep s190257175, o which e idence o an
associa ion was weak ( a ian -specific Bayes ac o (BF) =1.17).
The e we e 50 o al a ian s included in he 95% c edible se , and
174 a e including a ian s in high LD ( 2> 0.9) wi h hose in he
c edible se (Supplemen a y Da a 2).
Discussion
In his la ge s udy o ge mline gene ic a ia ion ac oss he 8q24
egion, we iden ified 12 independen associa ion signals among
men o Eu opean ances y, wi h h ee o he isk a ian s
( s1914295, s190257175, and s12549761) being weakly co e-
la ed ( 2≤0.17) wi h known PCa isk ma ke s. The combina ion
o hese 12 independen signals a 8q24 cap u e app oxima ely
one qua e o he o al PCa FRR explained by known gene ic isk
ac o s, which is subs an ially g ea e han any o he known PCa
isk locus.
The 8q24 egion is he majo suscep ibili y egion o PCa;
howe e , he unde lying biological mechanism(s) h ough which
ge mline a ia ion in his egion influences PCa isk emains
unce ain. Fo each o he 12 isk a ian s a 8q24, he 95%
c edible se defined no ewo hy (i.e., pu a i e unc ional) a ian s
based on summa y s a is ics while accoun ing o LD. To in o m
biological unc ionali y, we o e laid epigene ic unc ional anno-
a ion using publicly a ailable da ase s (see Me hods) wi h he
loca ion o he 12 independen signals (and co esponding 174
a ian s wi hin hei 95% c edible se s; Supplemen a y Da a 3).
O he 12 independen lead a ian s, 6 a e si ua ed wi hin pu a i e
ansc ip ional enhance s in p os a e cell-lines; ei he h ough
in e sec ion wi h H3K27AC ( s72725879, s5013678, s78511380,
s6983267 and s7812894) o h ough a Ch omHMM enhance
anno a ion ( s17464492, s6983267, s7812894). Eigh o he
12 s epwise hi s ( s77541621, s190257175, s5013678,
s183373024, s78511380, s17464492, s6983267, s7812894)
also in e sec ansc ip ion ac o binding si e peaks om mul i-
ple ChIP-seq da ase s ep esen ing he AR, ERG, FOXA1,
GABPA, GATA2, HOXB13, and NKX3.1 ansc ip ion ac o s,
wi h all 8 in e sec ing a FOXA1 ma k and hal an AR binding si e.
These a ian s may he e o e exe hei e ec h ough egula ion
o enhance ac i i y and long- ange exp ession o genes impo -
an o cance umo igenesis and/o p og ession13. The a ian
s6983267 has also been shown o ac in an allele-specific manne
o egula e p os a e enhance ac i i y and exp ession o he p o o-
oncogene MYC in i o and in i o14,15. Howe e , despi e he
close p oximi y o he MYC locus, no di ec associa ion has
been de ec ed be ween 8q24 isk alleles and MYC exp ession in
no mal and umo human p os a e issues16. The a e a ian
wi h he la ges e ec on isk, s183373024, shows high e idence
o unc ionali y based on o e lap wi h mul iple DNaseI and
ansc ip ion ac o binding si e peaks ( o AR, FOXA1,
HOXB13, and NKX3.1), which suppo s p e ious findings o an
allele-dependen e ec o his a ian on he dis up ion o a
FOXA1 binding mo i 17. Se en independen signals ( s1914295,
s1487240, s77541621, s72725879, s5013678, s183373024,
s78511380) and a ian s co ela ed a 2> 0.9 wi h hese signals
(Supplemen a y Da a 2) a e loca ed wi hin o nea a numbe o
p os a e cance –associa ed long noncoding RNAs (lncRNAs),
including PRNCR1,PCAT1, and CCAT2, p e iously epo ed o
be up egula ed in human PCa cells18 and issues19,20. Based on
eQTL anno a ions in p os a e adenoca cinoma cells, he inde-
penden signal s1914295 and h ee co ela ed a ian s ( 2> 0.9;
Supplemen a y Da a 2) a e associa ed wi h o e exp ession o
FAM84B, a gene p e iously associa ed wi h p og ession and poo
p ognosis o PCa in animal s udies21. Va ian s co ela ed a 2>
0.9 wi h s7812894 (n=9; Supplemen al Table 4) a e eQTLs o
POU5F1B, a gene o e exp essed in cance cell lines and cance
issues22,23, al hough i s ole in PCa de elopmen is unknown.
Whils we ha e success ully efined he 8q24 egion and iden ified
a subse o a ian s wi h pu a i e biological unc ion wi hin ou
c edible se , mul i-e hnic compa isons may help efine he asso-
cia ion signals e en u he and p ecisely iden i y he unc ional
alleles and biological mechanisms ha modi y PCa isk.
Whe eas he indi idual associa ions o he 8q24 a ian s wi h
PCa isk a e ela i ely modes (ORs < 2.0, excep o
s183373024), hei cumula i e e ec s a e subs an ial, wi h isk
being 4- old highe o men in he op 1% o he 8q24-only PRS.
The con ibu ion o he o e all FRR o PCa is subs an ially g ea e
o he 8q24 egion (9.42%) han o any o he known GWAS
locus, including he mode a e pene ance non-synonymous a -
ian in HOXB13 (1.91%). The abili y o hese ma ke s o explain
~25.4% o wha can be cu en ly explained by all known PCa isk
a ian s is a clea indica ion o he impo an con ibu ion o
ge mline a ia ion a 8q24 on PCa isk. Ou s udy was p e-
dominan ly powe ed o analyze a ian s wi h MAF > 1% as he
impu ed a ian s wi h MAF =0.1-1% we e mos likely o ail
quali y con ol (QC); howe e , he high densi y o geno yped
ma ke s and haplo ypes a 8q24 in he OncoA ay and iCOGS
s udies p o ided a obus backbone o impu a ion and inc eased
he chances o impu e lowe MAF a ian s wi h high impu a ion
quali y sco e. Unde s anding o he biology o hese a ian s and
he unde lying gene ic basis o PCa could p o ide new insigh s
in o he iden ifica ion o eliable isk-p edic ion bioma ke s o
PCa, as well as enable he de elopmen o e ec i e s a egies o
a ge ed sc eening and p e en ion.
Me hods
S udy subjec s, geno yping, and quali y con ol. We combined geno ype da a
om he PRACTICAL/ELLIPSE OncoA ay and iCOGS conso ia3,24, which
included 143,699 men o Eu opean ances y om 86 case-con ol s udies la gely
based in ei he he US o Eu ope. In each s udy, cases p ima ily included men wi h
inciden PCa while con ols we e men wi hou a p io diagnosis o he disease.
Bo h o he OncoA ay and iCOGS cus om a ays we e designed o p o ide
high co e age o common alleles (mino allele equency [MAF] > 5%) ac oss 8q24
(127.6–129.0 Mb) based on he 1000 Genomes P ojec (1KGP) Phase 3 o
OncoA ay, and he Eu opean ances y (EUR) panel om HapMap Phase 2 o
iCOGS. A o al o 57,580 PCa cases and 37,927 con ols o Eu opean ances y we e
geno yped wi h he Illumina OncoA ay, and 24,198 PCa cases and 23,994 con ols
o Eu opean ances y we e geno yped wi h he Illumina iCOGS a ay. Fo bo h
s udies, sample exclusion c i e ia included duplica e samples, fi s -deg ee ela i es,
samples wi h a call a e <95% o wi h ex eme he e ozygosi y (p<10
−6), and
samples wi h an es ima ed p opo ion o Eu opean ances y <0.83,24. In o al,
geno ype da a o 53,449 PCa cases and 36,224 con ols om OncoA ay and
18,086 PCa cases and 16,711 con ols om iCOGS we e included in he analysis.
Gene ic a ian s wi h call a es <0.95, de ia ion om Ha dy-Weinbe g equilib ium
(p<10
−7in con ols), and geno ype disc epancy in >2% o duplica e samples we e
excluded. O he final 498,417 geno yped a ian s on he OncoA ay and 201,598
on he iCOGS a ay ha passed QC, 1581 and 1737 wi hin he 8q24 egion,
espec i ely, we e e ained o impu a ion.
All s udies complied wi h all ele an e hical egula ions and we e app o ed by
he ins i u ional e iew boa ds a each o he pa icipa ing ins i u ions. In o med
consen was ob ained om all s udy pa icipan s. Addi ional de ails o each s udy
a e p o ided in he Supplemen a y No e 1.
Impu a ion analysis. Impu a ion o bo h OncoA ay and iCOGS geno ype da a
was pe o med using SHAPEIT25 and IMPUTE 226 o he Oc obe 2014 (Phase 3)
NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-06863-1 ARTICLE
NATURE COMMUNICATIONS | (2018) 9:4616 | DOI: 10.1038/s41467-018-06863-1 | www.na u e.com/na u ecommunica ions 5

elease o he 1KGP e e ence panel. A o al o 10,136 a ian s om OncoA ay
and 10,360 a ian s om iCOGS wi h MAF > 0.1% we e impu ed ac oss he isk
egion a 8q24 (127.6-129.0 Mb). Va ian s wi h an impu a ion quali y sco e >0.8
we e e ained o a o al o 5600 o e lapping a ian s be ween he wo da ase s.
S a is ical analysis. Uncondi ional logis ic eg ession was used o es ima e
pe -allele odds a ios (ORs) and 95% confidence in e als (CIs) o he associa ion
be ween gene ic a ian s (single nucleo ide polymo phisms and inse ion/
dele ion polymo phisms) and PCa isk adjus ing o coun y and p incipal
componen s (7 o OncoA ay and 8 o iCOGS). Allele dosage e ec s we e es ed
h ough a 1-deg ee o eedom wo- ailed Wald end es . The ma ginal isk
es ima es o he 5600 a ian s a 8q24 ha passed QC we e combined by a
fixed e ec me a-analysis wi h in e se a iance weigh ing using METAL27.A
modified o wa d and backwa d s epwise model selec ion wi h inclusion and
exclusion c i e ia o p≤5×10
−8was pe o med on a ian s ma ginally associa ed
wi h PCa isk om he me a esul s (p< 0.05, n=2772). A each s ep, he e ec
es ima es o he candida e a ian s om bo h s udies (OncoA ay and iCOGS)
we e me a-analyzed and each a ian was inco po a ed in o he model based on he
s eng h o associa ion. All emaining a ian s we e included one-a -a- ime in o
he logis ic eg ession model condi ioning on hose al eady inco po a ed in he
model. We applied a conse a i e h eshold o independen associa ions, wi h
a ian s kep in he model i hei me a p- alue om he Wald es was genome-
wide significan a p≤5×10
−8a e adjus men o he o he a ian s in he
model. Co ela ions be ween a ian s in he final model and p e iously published
PCa isk a ian s a 8q24 we e es ima ed using he 1KGP Phase 3 EUR panel
(Supplemen a y Da a 1).
Haplo ype analysis. Haplo ypes we e es ima ed in he Oncoa ay da a only using
a ian s om he final s epwise model selec ion (n=12) and he EM algo i hm28
wi hin LD block egions in e ed based on ecombina ion ho spo s using
Haplo iew 4.2 (B oad Ins i u e, Camb idge, MA, USA)29. Only haplo ypes wi h
an es ima ed equency ≥0.5% we e es ed.
Polygenic isk sco e and amilial ela i e isk. An 8q24-only polygenic isk sco e
(PRS) was calcula ed o a ian s om he final model (n=12) wi h allele dosage
om OncoA ay and iCOGS weigh ed by he pe -allele condi ionally adjus ed ORs
om he me a-analysis. Ca ego iza ion o he PRS was based on he pe cen ile
dis ibu ion in con ols, and he isk o each ca ego y was es ima ed ela i e o he
in e qua ile ange (25–75%) in OncoA ay and iCOGS sepa a ely, and hen me a-
analyzed ac oss he wo s udies. We es ima ed he con ibu ion o 8q24 a ian s o
he amilial (fi s -deg ee) ela i e isk (FRR) o PCa (FRR =2.5)30 unde a mul-
iplica i e model, and compa ed his o he FRR explained by all known PCa isk
a ian s including 8q24 (Supplemen a y Da a 4). We also es ima ed he i abili y o
PCa using he LMM app oach as implemen ed in GCTA31. Fo egions which ha e
been fine-mapped using he OncoA ay me a-analysis da a, we used he upda ed
ep esen a i e lead a ian s, o he wise he o iginally epo ed a ian was included
p o ided ha i had eplica ed a genome-wide significance in he me a-analysis;
his iden ified a o al o 175 independen ly associa ed PCa a ian s o he FRR and
he i abili y calcula ions3,11. Fo hese analyses, we used condi ional es ima es om
fi ing a single model wi h all a ian s in he OncoA ay da ase o egions wi h
mul iple a ian s and he o e all ma ginal me a-analysis esul s om Schumache
e al.3 o egions wi h a single a ian . To co ec o po en ial bias in e ec
es ima ion o newly disco e ed a ian s, we implemen ed a Bayesian e sion o he
weigh ed co ec ion32, which inco po a es he unce ain y in he e ec es ima e
in o he final es ima es o he bias-co ec ed ORs, 95%CIs and he co esponding
calcula ions o pe cen FRR explained.
JAM analysis. To confi m he s epwise esul s and iden i y candida e a ian s o
po en ial unc ional ollow-up, we used a second fine-mapping app oach, JAM
(Join Analysis o Ma ginal summa y s a is ics)12. JAM is a mul i a ia e Bayesian
a iable selec ion amewo k ha uses GWAS summa y s a is ics o iden i y he
mos likely numbe o independen associa ions wi hin a locus and define c edible
se s o a ian s d i ing hose associa ions. JAM was applied o summa y s a is ics
om he me a-analysis esul s using LD es ima ed om impu ed indi idual le el
da a om 20,000 cases and 20,000 con ols andomly selec ed om he OncoA ay
sub-s udy. LD p uning was pe o med using P io i y P une (h p://p io i yp une .
sou ce o ge.ne /) on he 2772 ma ginally associa ed a ian s a 2=0.9, esul ing in
825 ag a ian s analyzed in ou independen JAM uns wi h a ying s a ing
seeds. C edible se s we e de e mined as he ag a ian s ha we e selec ed in he
op models ha summed o a specific cumula i e pos e io p obabili y in all ou o
he independen JAM uns, plus hei designa ed high LD p oxy a ian s om he
p uning s ep.
Func ional anno a ion. Va ian s in he 95% c edible se (n=50) plus a ian s
co ela ed a 2> 0.9 wi h hose in he c edible se (n=174) we e anno a ed o
pu a i e e idence o biological unc ionali y using publicly a ailable da ase s as
desc ibed by Dadae e al.11. B iefly, a ian s we e anno a ed o p oximi y o gene
(GENCODE 19), miRNA ansc ip s (miRBase elease 20), e olu iona y cons ain
(acco ding o GERP++, SiPhy and Phas Cons algo i hms), likelihood o
pa hogenici y (CADD 1.3) and o e lap wi h p ospec i e egula o y elemen s in
p os a e-specific da ase s (DNaseI hype sensi i i y si es, H3K27Ac, H3K27me3
and H3K4me3 his one modifica ions, and o AR, CTCF, ERG, FOXA1, GABPA,
GATA2, HOXB13, and NKX3.1 ansc ip ion ac o binding si es) in a mix u e
o LNCaP, PC-3, P EC, RWPE1, and VCaP cell lines and human p os a e umo
issues downloaded om he Cis ome Da a B owse (h p://cis ome.o g/db/). The
ch oma in s a e in which each a ian esides was assessed using Ch omHMM
anno a ions om wo p os a e cell lines (P EC and PC3). Cis-gene egula ion
was e alua ed using 359 p os a e adenoma cases om The Cance Genome
A las (TCGA PRAD; h ps://gdc-po al.nci.nih.go ) ha passed QC11. The eQTL
analysis was pe o med using Fas QTL wi h 1000 pe mu a ions o each gene
wi hin a 1Mb window. We hen used he me hod by Nica e al.33 ha in eg a es
eQTLs and GWAS esul s in o de o e eal he subse o associa ion signals ha
a e due o cis eQTLs. Fo each significan eQTL, we added he candida e a ian o
he linea eg ession model o assess i he inclusion be e explains he change
in exp ession o he gene. We e ie ed he p- alue o he model, assigning p- alue
o 1 i he eQTL and a ian a e he same. Then we anked he p- alues in
descending o de o each eQTL, and finally calcula ed he colocaliza ion sco e
o each pai o eQTL and a ian s. In gene al, i an eQTL and candida e a ian
ep esen he same signal, his will be eflec ed by he a ian ha ing a high p- alue,
a low ank and consequen ly a high colocaliza ion sco e.
Da a a ailabili y
The au ho s decla e ha da a suppo ing he findings o his s udy a e a ailable wi hin
he pape [and in he supplemen a y in o ma ion files]. Howe e , some o he da a used
o gene a e he esul s o his s udy a e a ailable om he fi s au ho and he PRAC-
TICAL Conso ium upon eques .
Recei ed: 7 Feb ua y 2018 Accep ed: 1 Oc obe 2018
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Acknowledgemen s
Geno yping o he OncoA ay was unded by he US Na ional Ins i u es o Heal h (NIH)
[U19 CA 148537 o ELucida ing Loci In ol ed in P os a e Cance SuscEp ibili y
(ELLIPSE) p ojec and X01HG007492 o he Cen e o Inhe i ed Disease Resea ch
(CIDR) unde con ac numbe HHSN268201200008I]. Addi ional analy ic suppo was
p o ided by NIH NCI U01 CA188392 (PI: Schumache ). The PRACTICAL conso ium
(h p://p ac ical.ic .ac.uk/) was suppo ed by Cance Resea ch UK G an s C5047/A7357,
C1287/A10118, C1287/A16563, C5047/A3354, C5047/A10692, C16913/A6135, Eu -
opean Commission's Se en h F amewo k P og amme g an ag eemen n° 223175
(HEALTH-F2-2009-223175), and The Na ional Ins i u e o Heal h (NIH) Cance Pos -
Cance GWAS ini ia i e g an : No. 1 U19 CA 148537-01 ( he GAME-ON ini ia i e). We
wish o hank all GWAS s udy g oups con ibu ing o he da a se om which his s udy
was conduc ed: OncoA ay; iCOGS; The PRACTICAL (P os a e Cance Associa ion
G oup o In es iga e Cance -Associa ed Al e a ions in he Genome) Conso ium; and
The GAME-ON/ELLIPSE Conso ium. De ailed acknowledgemen s and unding in o -
ma ion o all GWAS s udy g oups and om all he indi idual s udies in ol ed in he
PRACTICAL Conso ium a e included in Supplemen a y No e 1. We would also like o
hank he ollowing o unding suppo : The Ins i u e o Cance Resea ch and The
E e yman Campaign, The P os a e Cance Resea ch Founda ion, P os a e Resea ch
Campaign UK (now P os a e Ac ion), The O chid Cance Appeal, The Na ional Cance
Resea ch Ne wo k UK, The Na ional Cance Resea ch Ins i u e (NCRI) UK. We
a e g a e ul o suppo o NIHR unding o he NIHR Biomedical Resea ch Cen e
a The Ins i u e o Cance Resea ch and The Royal Ma sden NHS Founda ion T us .
Au ho con ibu ions
M.M. and E.J.S. con ibu ed equally o his wo k. R.A.E., Z.K.-J., D.V.C., and C.A.H.
join ly supe ised his wo k. T.D. con ibu ed wi h JAM analysis. M.N.B. con ibu ed
wi h FRR analysis. K.W. con ibu ed wi h o wa d and backwa d s epwise selec ion.
X.S. con ibu ed wi h co e age analysis. A.A.A.O., F.R.S., S.A.I., K.G., S.B., S.I.B., D.A.,
S.K., K.M., V.L.S., S.M.G., C.M.T., J.B., J.C., H.G., N.P., J.S., A.W., C.W., L.Mu., P.K.,
G.C.-T., K.D.S., L.Ma., E.M.G., S.S.S., D.E.N., F.C.H., J.L.D., R.C.T., R.J.H., B.R., Y.-J.L.,
G.G.G., A.S.K., A.V., J.T.B., M.K., K.L.P., J.Y.P., J.L.S., C.C., B.G.N., H.B., C.M., J.K.,
M.R.T., S.L.N., K.D.R., A.R., L.F.N., D.L., R.K., N.U., F.C., P.A.T., M.G.D., M.J.R., F.M.,
K.-T.K., L.A.C.-A., H.P., S.N.T., D.J.S., The PRACTICAL Conso ium, F.W., S.J.C.,
and D.F.E. we e in ol ed in sample and da a collec ion.
Addi ional in o ma ion
Supplemen a y In o ma ion accompanies his pape a h ps://doi.o g/10.1038/s41467-
018-06863-1.
Compe ing in e es s: The au ho s decla e no compe ing in e es s.
Rep in s and pe mission in o ma ion is a ailable online a h p://npg.na u e.com/
ep in sandpe missions/
Publishe 's no e: Sp inge Na u e emains neu al wi h ega d o ju isdic ional claims in
published maps and ins i u ional a filia ions.
Open Access This a icle is licensed unde a C ea i e Commons
A ibu ion 4.0 In e na ional License, which pe mi s use, sha ing,
adap a ion, dis ibu ion and ep oduc ion in any medium o o ma , as long as you gi e
app op ia e c edi o he o iginal au ho (s) and he sou ce, p o ide a link o he C ea i e
Commons license, and indica e i changes we e made. The images o o he hi d pa y
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he copy igh holde . To iew a copy o his license, isi h p://c ea i ecommons.o g/
licenses/by/4.0/.
© The Au ho (s) 2018
Ma co Ma ejcic
1
, Edwa d J. Saunde s
2
, Tokhi Dadae
2
, Ma k N. B ook
2
, Kan Wang
1
, Xin Sheng
1
,
Ali Amin Al Olama
3,4
, F ed ick R. Schumache
5,6
, Sue A. Ingles
1
, Ko eela Go indasami
2
, Sa a Benlloch
2,3
,
Sonja I. Be nd
7
, Deme ius Albanes
7
, S ella Kou os
7
, Kenne h Mui
8,9
, Vic o ia L. S e ens
10
,
Susan M. Gaps u
10
, Ca he ine M. Tangen
11
, Jyo sna Ba a
12,13
, Judi h Clemen s
12,13
, Hen ik G onbe g
14
,
No a Pashayan
15,16
, Johanna Schleu ke
17,18,19
, Alicja Wolk
20
, Ca ha ine Wes
21
, Lo elei Mucci
22
,
Pe e K a
23
, Gé aldine Cancel-Tassin
24,25
, Ka ina D. So ensen
26,27
, Lo ise Maehle
28
, Eli M. G indedal
28
,
Sa a S. S om
29
, Da id E. Neal
30,31
, F eddie C. Hamdy
32
, Jenny L. Dono an
33
, Ru h C. T a is
34
,
Robe J. Hamil on
35
, Ba y Rosens ein
36,37
, Yong-Jie Lu
38
, G aham G. Giles
39,40
, Adam S. Kibel
41
, Ana Vega
42
,
Jeane e T. Bensen
43
, Manolis Koge inas
44,45,46,47
, Ka h yn L. Penney
48
, Jong Y. Pa k
49
, Jane L. S an o d
50,51
,
Ceza y Cybulski
52
, Bø ge G. No des gaa d
53,54
, He mann B enne
55,56,57
, Ch is iane Maie
58
, Je i Kim
59
,
NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-06863-1 ARTICLE
NATURE COMMUNICATIONS | (2018) 9:4616 | DOI: 10.1038/s41467-018-06863-1 | www.na u e.com/na u ecommunica ions 7
Manuel R. Teixei a
60,61
, Susan L. Neuhausen
62
, Kim De Ruyck
63
, Azad Razack
64
, Lisa F. Newcomb
50,65
,
Da o Lessel
66
, Radka Kane a
67
, Nawaid Usmani
68,69
, F ank Claessens
70
, Paul A. Townsend
71
,
Manuela G. Dominguez
72,73
, Monique J. Roobol
74
, Flo ence Menegaux
75
, Kay-Tee Khaw
76
,
Lisa A. Cannon-Alb igh
77,78
, Ha de Pandha
79
, S ephen N. Thibodeau
80
,
Daniel J. Schaid
81
, The PRACTICAL Conso ium, F ed ik Wiklund
14
, S ephen J. Chanock
7
,
Douglas F. Eas on
3,15
, Rosalind A. Eeles
2,82
, Zsofia Ko e-Ja ai
2
, Da id V. Con i
1
& Ch is ophe A. Haiman
1
1
Depa men o P e en i e Medicine, Keck School o Medicine, Uni e si y o Sou he n Cali o nia/No is Comp ehensi e Cance Cen e , Los
Angeles, CA 90033, USA.
2
The Ins i u e o Cance Resea ch, London SW7 3RP, UK.
3
Cen e o Cance Gene ic Epidemiology, Depa men o
Public Heal h and P ima y Ca e, S angeways Resea ch Labo a o y, Uni e si y o Camb idge, Camb idge CB1 8RN, UK.
4
Depa men o Clinical
Neu osciences, Uni e si y o Camb idge, Camb idge CB2 0QQ, UK.
5
Depa men o Popula ion and Quan i a i e Heal h Sciences, Case Wes e n
Rese e Uni e si y, Cle eland, OH 44106-7219, USA.
6
Seidman Cance Cen e , Uni e si y Hospi als, Cle eland, OH 44106, USA.
7
Di ision o
Cance Epidemiology and Gene ics, Na ional Cance Ins i u e, NIH, Be hesda, MD 20892, USA.
8
Ins i u e o Popula ion Heal h, Uni e si y o
Manches e , Manches e M13 9PL, UK.
9
Wa wick Medical School, Uni e si y o Wa wick, Co en y CV4 7AL, UK.
10
Epidemiology Resea ch
P og am, Ame ican Cance Socie y, 250 Williams S ee , A lan a, GA 30303, USA.
11
SWOG S a is ical Cen e , F ed Hu chinson Cance Resea ch
Cen e , Sea le, WA 98109, USA.
12
Aus alian P os a e Cance Resea ch Cen e-Qld, Ins i u e o Heal h and Biomedical Inno a ion and School o
Biomedical Science, Queensland Uni e si y o Technology, B isbane, QLD 4059, Aus alia.
13
T ansla ional Resea ch Ins i u e, B isbane, QLD 4102,
Aus alia.
14
Depa men o Medical Epidemiology and Bios a is ics, Ka olinska Ins i u e, SE-171 77 S ockholm, Sweden.
15
Cen e o Cance Gene ic
Epidemiology, Depa men o Oncology, S angeways Resea ch Labo a o y, Uni e si y o Camb idge, Camb idge CB1 8RN, UK.
16
Depa men o
Applied Heal h Resea ch, Uni e si y College London, London WC1E 7HB, UK.
17
Depa men o Medical Biochemis y and Gene ics, Ins i u e o
Biomedicine, Uni e si y o Tu ku, FI-20014 Tu ku, Finland.
18
Tyks Mic obiology and Gene ics, Depa men o Medical Gene ics, Tu ku Uni e si y
Hospi al, 20521 Tu ku, Finland.
19
BioMediTech, Uni e si y o Tampe e, 33520 Tampe e, Finland.
20
Di ision o Nu i ional Epidemiology, Ins i u e o
En i onmen al Medicine, Ka olinska Ins i u e , SE-171 77 S ockholm, Sweden.
21
Di ision o Cance Sciences, Manches e Academic Heal h Science
Cen e, Radio he apy Rela ed Resea ch, Manches e NIHR Biomedical Resea ch Cen e, The Ch is ie Hospi al NHS Founda ion T us , Uni e si y o
Manches e , Manches e M13 9PL, UK.
22
Depa men o Epidemiology, Ha a d School o Public Heal h, Bos on, MA 02115, USA.
23
P og am in
Gene ic Epidemiology and S a is ical Gene ics, Depa men o Epidemiology, Ha a d T.H. Chan School o Public Heal h, Bos on, MA 02115, USA.
24
GRC N°5 ONCOTYPE-URO, UPMC Uni Pa is 06, Tenon Hospi al, F-75020 Pa is, F ance.
25
CeRePP, Tenon Hospi al, F-75020 Pa is, F ance.
26
Depa men o Molecula Medicine, Aa hus Uni e si y Hospi al, 8200 Aa hus N, Denma k.
27
Depa men o Clinical Medicine, Aa hus Uni e si y,
8200 Aa hus N, Denma k.
28
Depa men o Medical Gene ics, Oslo Uni e si y Hospi al, 0424 Oslo, No way.
29
Depa men o Epidemiology, The
Uni e si y o Texas MD Ande son Cance Cen e , Hous on, TX 77030, USA.
30
Depa men o Oncology, Addenb ooke’s Hospi al, Uni e si y o
Camb idge, Camb idge CB2 0QQ, UK.
31
Cance Resea ch UK Camb idge Resea ch Ins i u e, Li Ka Shing Cen e, Camb idge CB2 0RE, UK.
32
Nu field
Depa men o Su gical Sciences, Uni e si y o Ox o d, Ox o d OX1 2JD, UK.
33
School o Social and Communi y Medicine, Uni e si y o B is ol,
Canynge Hall, 39 Wha ley Road, B is ol BS8 2PS, UK.
34
Cance Epidemiology, Nu field Depa men o Popula ion Heal h, Uni e si y o Ox o d,
Ox o d OX3 7LF, UK.
35
Depa men o Su gical Oncology, P incess Ma ga e Cance Cen e, To on o, ON M5G 2M9, Canada.
36
Depa men o
Radia ion Oncology, Icahn School o Medicine a Moun Sinai, New Yo k, NY 10029, USA.
37
Depa men o Gene ics and Genomic Sciences, Icahn
School o Medicine a Moun Sinai, New Yo k, NY 10029-5674, USA.
38
Cen e o Molecula Oncology, John Vane Science Cen e, Ba s Cance
Ins i u e, Queen Ma y Uni e si y o London, London EC1M 6BQ, UK.
39
Cance Epidemiology & In elligence Di ision, Cance Council Vic o ia,
Melbou ne, VIC 3004, Aus alia.
40
Cen e o Epidemiology and Bios a is ics, Melbou ne School o Popula ion and Global Heal h, The Uni e si y o
Melbou ne, Melbou ne, VIC 3010, Aus alia.
41
Di ision o U ologic Su ge y, B igham and Womens Hospi al, Bos on, MA 02115, USA.
42
Fundación
Pública Galega de Medicina Xenómica-SERGAS, G upo de Medicina Xenómica, CIBERER, IDIS, 15706 San iago de Compos ela, Spain.
43
Depa men o Epidemiology, Gillings School o Global Public Heal h, Uni e si y o No h Ca olina, Columbia, SC 29208, USA.
44
Cen e o
Resea ch in En i onmen al Epidemiology (CREAL), Ba celona Ins i u e o Global Heal h (ISGlobal), 08003 Ba celona, Spain.
45
CIBER Epidemiología
y Salud Pública (CIBERESP), 28029 Mad id, Spain.
46
IMIM (Hospi al del Ma Resea ch Ins i u e), 08003 Ba celona, Spain.
47
Uni e si a Pompeu
Fab a (UPF), 08002 Ba celona, Spain.
48
Channing Di ision o Ne wo k Medicine, Depa men o Medicine, B igham and Women’s Hospi al/
Ha a d Medical School, Bos on, MA 02184, USA.
49
Depa men o Cance Epidemiology, Mo fi Cance Cen e , Tampa, FL 33612, USA.
50
Di ision o Public Heal h Sciences, F ed Hu chinson Cance Resea ch Cen e , Sea le, WA 98109-1024, USA.
51
Depa men o Epidemiology,
School o Public Heal h, Uni e si y o Washing on, Sea le, WA 98195, USA.
52
In e na ional He edi a y Cance Cen e , Depa men o Gene ics and
Pa hology, Pome anian Medical Uni e si y, 70-115 Szczecin, Poland.
53
Facul y o Heal h and Medical Sciences, Uni e si y o Copenhagen, 2200
Copenhagen, Denma k.
54
Depa men o Clinical Biochemis y, He le and Gen o e Hospi al, Copenhagen Uni e si y Hospi al, He le , 2200
Copenhagen, Denma k.
55
Di ision o Clinical Epidemiology and Aging Resea ch, Ge man Cance Resea ch Cen e (DKFZ), D-69120 Heidelbe g,
Ge many.
56
Ge man Cance Conso ium (DKTK), Ge man Cance Resea ch Cen e (DKFZ), D-69120 Heidelbe g, Ge many.
57
Di ision o
P e en i e Oncology, Ge man Cance Resea ch Cen e (DKFZ) and Na ional Cen e o Tumo Diseases (NCT), 69120 Heidelbe g, Ge many.
58
Ins i u e o Human Gene ics, Uni e si y Hospi al Ulm, 89075 Ulm, Ge many.
59
Depa men o Geni ou ina y Medical Oncology, The Uni e si y
o Texas MD Ande son Cance Cen e , Hous on, TX 77030, USA.
60
Depa men o Gene ics, Po uguese Oncology Ins i u e o Po o, 4200-072
Po o, Po ugal.
61
Biomedical Sciences Ins i u e (ICBAS), Uni e si y o Po o, 4050-313 Po o, Po ugal.
62
Depa men o Popula ion Sciences,
Beckman Resea ch Ins i u e o he Ci y o Hope, Dua e, CA 91010, USA.
63
Ghen Uni e si y, Facul y o Medicine and Heal h Sciences, Basic
Medical Sciences, B-9000 Gen , Belgium.
64
Depa men o Su ge y, Facul y o Medicine, Uni e si y o Malaya, 50603 Kuala Lumpu , Malaysia.
65
Depa men o U ology, Uni e si y o Washing on, Sea le, WA 98195, USA.
66
Ins i u e o Human Gene ics, Uni e si y Medical Cen e Hambu g-
Eppendo , D-20246 Hambu g, Ge many.
67
Molecula Medicine Cen e , Depa men o Medical Chemis y and Biochemis y, Medical Uni e si y o
Sofia, 1431 Sofia, Bulga ia.
68
Depa men o Oncology, C oss Cance Ins i u e, Uni e si y o Albe a, Edmon on, AB T6G 1Z2, Canada.
69
Di ision o
Radia ion Oncology, C oss Cance Ins i u e, Uni e si y o Albe a, Edmon on, AB T6G 1Z2, Canada.
70
Molecula Endoc inology Labo a o y,
Depa men o Cellula and Molecula Medicine, KU Leu en, BE-3000 Leu en, Belgium.
71
Manches e Cance Resea ch Cen e, Facul y o Biology
Medicine and Heal h, Manches e Academic Heal h Science Cen e, NIHR Manches e Biomedical Resea ch Cen e, Heal h Inno a ion Manches e ,
Uni e si y o Manches e , Manches e M13 9WL, UK.
72
Genomic Medicine G oup, Galician Founda ion o Genomic Medicine, Ins i u o de
In es igacion Sani a ia de San iago de Compos ela (IDIS), Complejo Hospi ala io Uni e si a io de San iago, Se icio Galego de Saúde, SERGAS,
ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-06863-1
8NATURE COMMUNICATIONS | (2018) 9:4616 | DOI: 10.1038/s41467-018-06863-1 | www.na u e.com/na u ecommunica ions
15706 San iago de Compos ela, Spain.
73
Moo es Cance Cen e , Uni e si y o Cali o nia San Diego, La Jolla, CA 92037, USA.
74
Depa men o
U ology, E asmus Uni e si y Medical Cen e , 3015 CE Ro e dam, The Ne he lands.
75
Cance and En i onmen G oup, Cen e o Resea ch in
Epidemiology and Popula ion Heal h (CESP), INSERM, Uni e si y Pa is-Sud, Uni e si y Pa is-Saclay, 94807 Villejui Cédex, F ance.
76
Clinical
Ge on ology Uni , Uni e si y o Camb idge, Camb idge CB2 2QQ, UK.
77
Di ision o Gene ic Epidemiology, Depa men o Medicine, Uni e si y o
U ah School o Medicine, Sal Lake Ci y, UT 84112, USA.
78
Geo ge E. Wahlen Depa men o Ve e ans A ai s Medical Cen e , Sal Lake Ci y, UT
84148, USA.
79
The Uni e si y o Su ey, Guild o d, Su ey GU2 7XH, UK.
80
Depa men o Labo a o y Medicine and Pa hology, Mayo Clinic,
Roches e , MN 55905, USA.
81
Di ision o Biomedical S a is ics and In o ma ics, Mayo Clinic, Roches e , MN 55905, USA.
82
Royal Ma sden NHS
Founda ion T us , London SW3 6JJ, UK. These au ho s con ibu ed equally: Ma co Ma ejcic, Edwa d J. Saunde s. These au ho s join ly supe ised
his wo k: Rosalind A. Eeles, Zsofia Ko e‑Ja ai, Da id V. Con i, Ch is ophe A. Haiman. A ull lis o conso ium membe s appea s a he end o he
pape .
The PRACTICAL (P os a e Cance Associa ion G oup o In es iga e Cance -Associa ed Al e a ions in
he Genome) Conso ium
B ian E. Hende son
1
, Ma iana C. S e n
1
, Alison Thwai es
2
, Michelle Guy
2
, Ian Whi mo e
2
, Angela Mo gan
2
,
Cy il Fishe
2
, S e e Hazel
2
, Naomi Li ni
2
, Ma ga e Cook
3
, Lau a Fachal
3,42
, S ephanie Weins ein
7
,
Lau a E. Beane F eeman
7
, Robe N. Hoo e
7
, Mi chell J. Machiela
7
, A i aya Lopha ananon
8,9
, B ian D. Ca e
10
,
Phyllis Goodman
11
, Lei e Moya
12,13
, S ilakshmi S ini asan
12,13
, Ma y-Anne Kedda
12,13
, T ina Yeadon
12,13
,
Allison Ecke
12,13
, Ma in Eklund
14
, Ca in Ca alli-Bjoe kman
14
, Alison M. Dunning
15
, Csilla Sipeky
17
,
Niclas Hakansson
20
, Rebecca Ellio
21
, Ha deep Ranu
22
, Edwa d Gio annucci
22
, Cons ance Tu man
23
,
Da id J. Hun e
23
, Oli ie Cusseno
24,25
, To ben Falck O n o
26,27
, A hene Lane
33
, Sa ah J. Lewis
33
,
Michael Da is
33
, Tim J. Key
34
, Paul B own
35
, Gi ish S. Kulka ni
35
, Alexand e R. Zlo a
35
, Neil E. Fleshne
35
,
An onio Finelli
35
, Xueying Mao
38
, Jacek Ma zec
38
, Robe J. MacInnis
39,40
, Roge Milne
39,40
, John L. Hoppe
40
,
Miguel Aguado
42
, Ma iona Bus aman e
44
, Gemma Cas año-Vinyals
44,45,46,47
, Es he G acia-La edan
44,45,46,47
,
Lluís Cecchini
46
, Mei S amp e
48
, Jing Ma
48
, Thomas A. Selle s
49
, Milan S. Geybels
49
, Hyun Pa k
49
,
Babu Zacha iah
49
, Suzanne Kolb
50
, Dominika Wokolo czyk
52
, Jan Lubinski
52
, Wojciech Kluzniak
52
,
Sune F. Nielsen
53,54
, Ma en Weishe
54
, Ka a ina Cuk
55
, Wal he Vogel
58
, Manuel Luedeke
58
,
Ch is ophe J. Logo he is
59
, Paula Paulo
60
, Ma a Ca doso
60
,Sofia Maia
60
, Ma ia P. Sil a
60
, Linda S eele
62
,
Yuan Chun Ding
62
, Ge De Mee lee
63
,Sofie De Langhe
63
, Hube Thie ens
63
, Jasmine Lim
64
, Meng H. Tan
64
,
Aik T. Ong
64
, Daniel W. Lin
50,65
, Da ina Kachako a
67
, A anaska Mi ko a
67
, Vanio Mi e
67
,
Ma hew Pa liamen
68,69
, Guido Jens e
74
, Ch is ophe Bangma
74
, F.H. Sch ode
74
, Thé èse T uong
75
,
Y es Akoli Koudou
75
, Agnieszka Michael
79
, And zej Kie zek
79
, Ami Ka lsson
79
, Michael B oms
79
, Huihai Wu
79
,
Clai e Aukim-Has ie
79
, Lo i Tillmans
80
, Shaun Riska
80
, Shannon K. McDonnell
81
, Da id Dea naley
2,82
,
Amanda Spu dle
83
, Robe Ga dine
84,85
, Vanessa Hayes
86
, Lisa Bu le
87
, Renea Taylo
88
, Melissa Papa gi is
88
,
Pamela Saunde s
89
, Paula Kujala
90
, Ki si Talala
91
, Kimmo Taa i
92
, Sø en Ben zen
93
, Belynda Hicks
94
,
Au elie Vog
94
, Amy Hu chinson
95
, Angela Cox
96
, Anne Geo ge
97
, An s Toi
98
, And ew E ans
99
,
Theodo us H. an de Kwas
99
, Takashi Imai
100
, Shi o Sai o
101
, Shan-Chao Zhao
102
, Guoping Ren
103
,
Yangling Zhang
103
, Yongwei Yu
104
, Yudong Wu
105
,JiWu
106
, Bo Zhou
107
, John Pede sen
108
,
Ramón Loba o-Bus o
109
, José Manuel Ruiz-Dominguez
110
, Lou des Mengual
111,112
, An onio Alca az
113
,
Julio Pow-Sang
114
, Ka hleen He komme
115
, Aleksand ina Vlaho a
116
, Tihomi Diko
116
, S e lana Ch is o a
116
,
Angel Ca acedo
42,117,118
, B igi e T e a e
119
, Xa ie Rebilla d
120
, Clai e Mulo
121
, Jan Adol sson
122,123
,
Pa S a in
124,125
, Jan-E ik Johansson
126
, Richa d M. Ma in
33,127,128
, Ian M. Thompson J .
129
,
Suzanne Chambe s
130,131
, Joanne Ai ken
130,131
, Lisa Ho a h
132,133
, Anne-Ma ee Haynes
86,133
, Wayne Tilley
134
,
Gail Risb idge
135,136
, Ma kus Aly
14,137
, Tobias No ds öm
14,138
, Paul Pha oah
3,139
, Teu o L.J. Tammela
140
,
Teemu Mu ola
140,141
, Anssi Au inen
142
, Neil Bu ne
143
, Gill Ba ne
143
, Ge ald And iole
144
, Aleksand a Klim
144
,
Be ina F. D ake
144
, Michael Bo e
27,145
, Sa ah Ke ns
146
, Ha y Os e
147
, Hong-Wei Zhang
148
, Guangwen Cao
148
,
Ji Lin
148
, Jin Ling
148
, Meiling Li
148
, Ninghan Feng
149
, Jie Li
150
, Weiyang He
150
, Xin Guo
150,151
, Zan Sun
151
,
NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-06863-1 ARTICLE
NATURE COMMUNICATIONS | (2018) 9:4616 | DOI: 10.1038/s41467-018-06863-1 | www.na u e.com/na u ecommunica ions 9