ASSOCIATION STUDIES ARTICLE
Va ia ion a 2q35 (PNKD and TMBIM1) in luences
colo ec al cance isk and iden i ies a pleio opic e ec
wi h in lamma o y bowel disease
Giulia O lando
1,†
, Philip J. Law
1,†
, Kimmo Palin
2,3,†
, Sa i Tuupanen
2,3
,
Alexand a Gyl e
2,3,‡
, Ul ika A. H€
anninen
2,3
, Ta iana Cajuso
2,3
,
Tomas Tanskanen
2,3
, Johanna Kondelin
2,3
, Ee i Kaasinen
2,3
,
An i-Pekka Sa in
4
, Jaakko Kap io
4,5
, Johan G. E iksson
6,7
, Ha i Rissanen
5
,
Paul Knek
5
, Ee o Pukkala
8,9
, Pekka Jousilah i
5
, Veikko Salomaa
5
,
Samuli Ripa i
4
, Aa no Palo ie
4,10,11,12
, Heikki J€
a inen
13
,
Lau a Renkonen-Sinisalo
14
, Anna Lepis o¨
14
, Jan Bo¨hm
15
,
Jukka-Pekka Mecklin
16
, Nada A. Al-Tassan
17
, Clai e Palles
18
, Lynn Ma in
18
,
Ella Ba clay
18
, Albe Tenesa
19,20
, Susan Fa ing on
19
, Ma ia N. Timo ee a
19
,
B ian F. Meye
17
, Salma M. Wakil
17
, Ha y Campbell
21
,
Ch is ophe G. Smi h
22
, Shelley Idziaszczyk
22
, Timo hy S. Maughan
23
,
Richa d Kaplan
24
, Rachel Ke
25
, Da id Ke
26
, Daniel D. Buchanan
27,28
,
Aung Ko Win
28
, John Hoppe
28
, Ma k Jenkins
28
, No alane M. Lindo
29
,
Polly A. Newcomb
30
, S e e Gallinge
31
, Da id Con i
32
, F ed Schumache
32
,
G aham Casey
32
, Jussi Taipale
2,3,33
, Je emy P. Cheadle
22
, Malcolm G.
Dunlop
19
, Ian P. Tomlinson
18
, Lau i A. Aal onen
2,3
and Richa d S. Houls on
1,
*
1
Di ision o Gene ics and Epidemiology, The Ins i u e o Cance Resea ch, London SW7 3RP, UK,
2
Genome-Scale
Biology Resea ch P og am, Resea ch P og ams Uni ,
3
Depa men o Medical and Clinical Gene ics, Medicum
and
4
Ins i u e o Molecula Medicine Finland, Uni e si y o Helsinki, Helsinki 00014, Finland,
5
Na ional
Ins i u e o Heal h and Wel a e, Helsinki 00271, Finland,
6
Folkh€
alsan Resea ch Cen e, Helsinki 00250, Finland,
7
Uni o Gene al P ac ice and P ima y Heal h Ca e, Uni e si y o Helsinki and Helsinki Uni e si y Hospi al,
Helsinki 00014, Finland,
8
Finnish Cance Regis y, Ins i u e o S a is ical and Epidemiological Cance
Resea ch, Helsinki 00130, Finland,
9
School o Heal h Sciences, Uni e si y o Tampe e, Tampe e 33014, Finland,
†
These au ho s con ibu ed equally o his wo k.
‡
P esen add ess: Human Longe i y Inc., La Jolla, CA 92121, USA.
Recei ed: Oc obe 16, 2015. Re ised: Feb ua y 5, 2016. Accep ed: Ma ch 14, 2016
V
CThe Au ho 2016. Published by Ox o d Uni e si y P ess.
This is an Open Access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion License (h p://c ea i ecommons.o g/licenses/by/4.0/),
which pe mi s un es ic ed euse, dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed.
2349
Human Molecula Gene ics, 2016, Vol. 25, No. 11 2349–2359
doi: 10.1093/hmg/ddw087
Ad ance Access Publica ion Da e: 22 Ma ch 2016
Associa ion S udies A icle
a Tampe e Uni e si y Lib a y. Depa men o Heal h Sciences on Oc obe 31, 2016h p://hmg.ox o djou nals.o g/Downloaded om
10
Analy ic and T ansla ional Gene ics Uni , Depa men o Medicine, Massachuse s Gene al Hospi al, Bos on,
MA 02114, USA,
11
P og am in Medical and Popula ion Gene ics, The B oad Ins i u e o MIT and Ha a d,
Camb idge, MA 02142, USA,
12
Depa men o Neu ology, Massachuse s Gene al Hospi al, Bos on, MA 02114,
USA,
13
Depa men o Su ge y, Helsinki Uni e si y Cen al Hospi al, Hospi al Dis ic o Helsinki and Uusimaa,
Helsinki 00029, Finland,
14
Depa men o Su ge y, Abdominal Cen e , Helsinki Uni e si y Hospi al, Helsinki
00029, Finland,
15
Depa men o Pa hology, Cen al Finland Cen al Hospi al, Jy €
askyl€
a 40620, Finland,
16
Depa men o Su ge y, Jy €
askyl€
a Cen al Hospi al, Uni e si y o Eas e n Finland, Jy €
askyl€
a 40620, Finland,
17
Depa men o Gene ics, King Faisal Specialis Hospi al and Resea ch Cen e , Riyadh 12713, Saudi A abia,
18
Wellcome T us Cen e o Human Gene ics and NIHR Comp ehensi e Biomedical Resea ch Cen e, Ox o d
OX3 7BN, UK,
19
Colon Cance Gene ics G oup, Uni e si y o Edinbu gh and MRC Human Gene ics Uni , Wes e n
Gene al Hospi al, Edinbu gh EH4 2XU, UK,
20
The Roslin Ins i u e, Uni e si y o Edinbu gh, Eas e Bush, Roslin
EH25 9RG, UK,
21
Cen e o Popula ion Heal h Sciences, Uni e si y o Edinbu gh, Edinbu gh EH8 9AG, UK,
22
Ins i u e o Cance and Gene ics, School o Medicine, Ca di Uni e si y, Ca di CF14 4XN, UK,
23
CRUK/MRC
Ox o d Ins i u e o Radia ion Oncology, Uni e si y o Ox o d, Ox o d OX3 7DQ, UK,
24
MRC Clinical T ials Uni ,
A ia ion House, London WC2B 6NH, UK,
25
Depa men o Oncology, Ox o d Cance Cen e, Chu chill Hospi al
and
26
Nu ield Depa men o Clinical Labo a o y Sciences, John Radcli e Hospi al, Uni e si y o Ox o d,
Ox o d OX3 7LE, UK,
27
Colo ec al Oncogenomics G oup, Gene ic Epidemiology Labo a o y, Depa men o
Pa hology and
28
Cen e o Epidemiology and Bios a is ics, The Uni e si y o Melbou ne, Melbou ne, Vic. 3010,
Aus alia,
29
Depa men o Heal h Sciences Resea ch, Mayo Clinic, Sco sdale, AZ 85259, USA,
30
Cance
P e en ion P og am, F ed Hu chinson Cance Resea ch Cen e , Sea le, WA 98109, USA,
31
Lunen eld-
Tanenbaum Resea ch Ins i u e, Moun Sinai Hospi al, To on o, ON M5G 1X5, Canada,
32
Depa men o
P e en i e Medicine, Uni e si y o Sou he n Cali o nia, Los Angeles, CA 90033, USA and
33
Depa men o
Biosciences and Nu i ion, SciLi e Cen e , Ka olinska Ins i u e, S ockholm, SE 141 83, Sweden
*To whom co espondence should be add essed. Tel: þ44 (0)208722 4175; Fax: þ44 (0)7224365; Email: [email p o ec ed]
Abs ac
To iden i y new isk loci o colo ec al cance (CRC), we conduc ed a me a-analysis o se en genome-wide associa ion s udies
(GWAS) wi h independen eplica ion, o alling 13 656 CRC cases and 21 667 con ols o Eu opean ances y. The combined
analysis iden i ied a new isk associa ion o CRC a 2q35 ma ked by s992157 (P¼3.15 10
8
, odds a io ¼1.10, 95%
con idence in e al ¼1.06–1.13), which is in onic o PNKD (pa oxysmal non-kinesigenic dyskinesia) and TMBIM1
( ansmemb ane BAX inhibi o mo i con aining 1). In iguingly his suscep ibili y single-nucleo ide polymo phism (SNP) is
in s ong linkage disequilib ium (
2
¼0.90, D0¼0.96) wi h he p e iously disco e ed GWAS SNP s2382817 o in lamma o y
bowel disease (IBD). Following on om his obse a ion we examined o pleio opy, o sha ed gene ic suscep ibili y, be ween
CRC and he 200 es ablished IBD isk loci, iden i ying an addi ional 11 signi ican associa ions ( alse disco e y a e
[FDR])<0.05). Ou indings p o ide u he insigh in o he biological basis o inhe i ed gene ic suscep ibili y o CRC, and
iden i y isk ac o s ha may in luence he de elopmen o bo h CRC and IBD.
In oduc ion
Colo ec al cance (CRC), a leading cause o cance - ela ed dea h
wo ldwide, has a he i able basis (1,2). Recen genome-wide associ-
a ion s udies (GWAS) ha e success ully iden i ied a numbe o
common single-nucleo ide polymo phisms (SNPs) in luencing CRC
isk he eby indica ing he asse ion ha pa o he he i able isk
is polygenic (3–7). These s udies ha e also p o ided insigh s in o
he biology o CRC, highligh ing he impo ance o bone mo phoge-
ne ic p o ein signalling pa hway genes (BMP2, BMP4, GREM1 and
SMAD7) (4,5), candida e genes (CDH1), as well as genes no p e i-
ously implica ed in CRC (POLD3, TERC, CDKN1A, VIT1A and
SHROOM2) (6,7). I is well es ablished ha in lamma o y bowel dis-
ease (IBD), which p ima ily p esen s as C ohn’s disease o ulce a-
i e coli is, is associa ed wi h an inc eased CRC isk (8–11). Despi e
IBD being s ongly he i able (12), li le e idence o sha ed gene ic
suscep ibili y o di e en ial e ec s o gene ic a ia ion on IBD and
CRC isk has been epo ed, al hough he p esump ion is ha he
di ec ion o e ec will be consis en be ween bo h diseases.
A ailu e o unco e pleio opy may be e lec i e o a lack o
powe o CRC GWAS conduc ed hus a . Indeed s a is ical
modelling o GWAS da a shows ha al hough 19% o he he i a-
bili y o CRC can be asc ibed o common a ia ion, only 10% o
his is explained by cu en ly iden i ied isk SNPs (13). To
empowe he iden i ica ion o new CRC suscep ibili y SNPs in
pe sons o Eu opean ances y, we conduc ed a genome-wide
me a-analysis o a p e iously un epo ed GWAS wi h six pub-
lished da ase s in addi ion o independen eplica ion o alling
13 810 cases and 21 754 con ols.
We epo he iden i ica ion o a new CRC isk associa ion
which also impac s on IBD isk. Ex ending ou analysis o
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es ablished IBD loci, we p o ide e idence o sha ed gene ic sus-
cep ibili y be ween CRC and IBD a 11 addi ional loci.
Resul s
P ima y GWAS
In he p ima y scan ( e med he FIN GWAS), 1172 CRC cases as-
ce ained h ough he Finnish CRC collec ion and Finnish Cance
Regis y we e analysed wi h con ol da a on 8266 indi iduals
om he FINRISK, Heal h2000, Finnish Twin Coho and Helsinki
Bi h Coho S udy coho s. A e applying s ic quali y con ol
c i e ia, 283906 au osomal SNPs we e a ailable o associa ion
wi h CRC isk. A quan ile–quan ile (Q–Q) plo o obse ed e sus
expec ed
2
- es s a is ics showed li le e idence o an in la ion
o es s a is ics, he eby excluding he possibili y o subs an i e
hidden popula ion subs uc u e, c yp ic ela edness among sub-
jec s o di e en ial geno ype calling (in la ion ac o k¼1.07).
Me a-analysis
We pe o med a me a-analysis o ou p ima y scan da a wi h
six o he non-o e lapping GWAS o Eu opean ances y (CCFR1,
CCFR2, COIN, UK1, Sco land1 and VQ58), which ha e been p e i-
ously epo ed (14). To maximize he p ospec s o iden i ying
no el isk a ian s, we impu ed he da a wi h a me ged e e -
ence panel using Sequencing Ini ia i e Suomi (SISu) ( o he FIN
da a) o UK10K ( o he UK da a) in addi ion o 1000 Genomes
P ojec da a. A e quali y con ol p ocedu es, o e 10 million
a ian s, including o e 1 million inse ion–dele ions, we e ana-
lysed in 8749 cases and 18 245 con ols.
Associa ions o he 37 p e iously es ablished Eu opean CRC
isk SNPs showed a di ec ion o e ec consis en wi h p e i-
ously epo ed s udies, wi h 10 o hese SNPs ha ing
P<5.0 10
8
in his me a-analysis (Supplemen a y Ma e ial,
Table S1). Excluding hese known isk SNPs, oge he wi h hose
co ela ed wi h
2
>0.8, om he me a-analysis wo no el e-
gions o linkage disequilib ium (LD), ma ked by s992157 and
s2383207, showed he s onges associa ion wi h CRC a
P<1.0 10
6
(Supplemen a y Ma e ial, Table S2).
To eplica e hese associa ions, we geno yped s992157 and
s2383207 in an addi ional 5061 CRC cases and 3509 con ols,
wi h only s992157 showing e idence o an associa ion wi h
CRC (P¼0.023). In he combined analysis, he associa ion was
signi ican a he genome-wide h eshold (P¼3.15 10
8
; Fig. 1).
The e was no a ia ion due o he e ogenei y (I
2
¼0, P
he
¼0.79).
s992157 is loca ed a 2q35, and is in onic o wo genes: pa ox-
ysmal non-kinesigenic dyskinesia (PNKD) on he o wa d s and
and ansmemb ane BAX inhibi o mo i con aining 1 (TMBIM1)
on he e e se s and (Fig. 2).
Rela ionship be ween geno ype and CRC pheno ype
Using da a on mic osa elli e ins abili y (MSI) s a us om he FIN
(n¼1146), COIN (n¼1239) and NSCCG eplica ion (n¼1282) se ies,
oge he wi h in o ma ion on KRAS and BRAF mu a ion s a us in
umou s in COIN, we explo ed he possibili y ha he associa ion
a s992157 is es ic ed o a speci ic molecula sub ype o CRC
(Supplemen a y Ma e ial, Table S3). The e was no e idence o an
associa ion be ween hese SNPs and any o he a iables a e ad-
jus ing o mul iple es ing (i.e. P>0.05). Addi ionally, we ob-
se ed no consis en associa ion be ween age, sex o umou si e
using da a om he UK1, Sco land1, VQ58, COIN and NSCCG se-
ies (Supplemen a y Ma e ial, Table S3).
IBD SNPs in luence CRC
Ano he associa ion a 2q35 de ined by s2382817 has p e i-
ously been shown o in luence IBD isk (CRC me a P¼1.02 
10
5
), which is also in onic o PNKD and TMBIM1, and is in
s ong LD wi h s992157 (
2
¼0.90, D0¼0.96). Pa adoxically, he
isk o s2382817 in IBD is in e se o he CRC associa ion.
Gi en he compelling e idence o an associa ion be ween IBD
and CRC, we sough e idence o addi ional sha ed suscep i-
bili y be ween he wo diseases. Speci ically, we examined he
isk o CRC in ou me a-analysis a 200 loci ha ha e been
shown in p e ious GWAS o a ec IBD isk (15,16)
(Supplemen a y Ma e ial, Table S4). A Q–Q plo o he obse ed
CRC associa ion P- alues agains he expec ed P- alues o
each o he 200 IBD isk SNPs showed signi ican o e -dispe -
sion (k¼1.33, Fig. 3). This obse a ion is compa ible wi h a ge-
ne ic ela ionship be ween CRC and IBD.
To accoun o mul iple es ing, we imposed an FDR-adjus ed
P- alue o 0.05 as being s a is ically signi ican . A his h eshold,
in addi ion o s2382817, 11 IBD isk SNPs we e associa ed wi h
CRC isk (Table 1), o which i e we e posi i ely associa ed wi h
CRC isk, whe eas he o he se en displayed an in e se ela ion-
ship. A numbe o hese SNPs anno a e genes wi h documen ed
oles ha a e ele an o CRC de elopmen , such as Wn -signal-
ling [WNT4, (17)], umou supp ession [MAPKAPK5,FOXO1 (18,19)]
and cellula ans o ma ion [CDC42,CEBPB (20,21)] (Table 1). We
examined o an associa ion be ween he geno ype o hese 12
SNPs and he molecula sub ype o CRC, and ound no e idence
o a ela ionship (Supplemen a y Ma e ial, Table S3).
Func ional e ec p edic ion analysis
The genomic egion con aining s992157 is he si e o ac i e s uc-
u e and has egula o y mo i s o bo h enhance and p omo o
unc ion in mul iple cell ypes (Fig. 2). Mo eo e ChIP-seq da a
iden i y o e 122 ansc ip ion ac o s binding o he egion, in-
cluding CRC- ela ed ansc ip ion ac o s such as MYC, HNF4A
and TCF7L2 (Supplemen a y Ma e ial, Table S5). We also pe -
o med an exp ession quan i a i e ai loci (eQTL) analysis and
ound no signi ican ela ionship be ween he s992157 geno ype
and PNKD and TMBIM1 exp ession in colo ec al adenoca cinoma
cells (Supplemen a y Ma e ial, Table S6). The isk geno ype was
howe e associa ed wi h al e ed gene exp ession in o he issues,
including lymphoblas oid cells (FDR P- alue<0.05,
Figu e 1. Fo es plo o he odds a ios o he associa ion be ween s992157 and
CRC. S udies we e weigh ed acco ding o he in e se o he a iance o he log o
he OR. Ho izon al lines: 95% con idence in e als (95% CI).Box: OR poin es i-
ma e; i s a ea is p opo ional o he weigh o he s udy. Diamond: o e all sum-
ma y es ima e, wi h con idence in e al gi en by i s wid h. Ve ical line: null
alue (OR ¼1.0).
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Supplemen a y Ma e ial, Table S6). This appa en di e ence in
eQTLs may be e lec i e o he di e ences in epigene ic p o iles a
2q35 be ween CRC and lymphoblas oid cells (Fig. 2).
To u he in es iga e he ela ionship be ween CRC and IBD
isk we pe o med eQTL analysis on he 12 IBD SNPs associa ed
wi h CRC isk in he colo ec al adenoca cinoma da a, and ound
wo signi ican ela ionships be ween s174537 and he exp es-
sion o a y acid desa u ase 2 (FADS2, FDR P- alue ¼3.28 10
6
)
and be ween s516246 and ucosyl ans e ase 2 (FUT2, FDR P-
alue ¼2.08 10
17
) (Supplemen a y Ma e ial, Table S6).
Addi ional e idence o hese eQTLs was ound in o he issues
in he Geu adis, Blood and GTEx da abases (Supplemen a y
Ma e ial, Table S6). Simila ly o s992157, as epo ed abo e,
s2382817 is an eQTL o PNKD and TMBIM1 in bo h lymphoblas-
oid and whole blood issues.
Following on om his we in es iga ed he p esence o
sha ed gene ic pa hways be ween CRC and IBD using he LENS
pa hway ool (22), which allows explo a ion o in e ac ions be-
ween he gene p oduc s in p oximi y o he GWAS SNPs.
Ac oss he 594 CRC p o eins and 1574 IBD p o eins, a ne wo k o
542 o e lapping p o eins was iden i ied. Figu e 4 shows he
common ne wo k and in e ac ions be ween key p o eins. O in-
e es was he di ec ion o associa ion be ween he CRC SNPs
wi h IBD isk. Pa hways wi h e idence o en ichmen (i.e.
P<0.001) wi h a consis en e ec be ween CRC and IBD we e in-
ol ed in immune and in lamma o y esponse, such as co-s im-
ula ion by he CD28 amily, Fc epsilon ecep o signalling and
downs eam B-cell ecep o signalling. In con as , he p o ein
ne wo ks de ined by ecip ocal SNPs associa ion o CRC and
IBD we e en iched o in e leukin and calmodulin signalling.
Figu e 2. Regional plo o associa ion esul s and ecombina ion a es o he 2q35 locus. In he panel, log
10
P alues (y-axis) o he SNPs a e shown acco ding o hei
ch omosomal posi ions (x-axis). The op SNP is shown as a la ge iangle and is labelled by i s sID. The colou in ensi y o each symbol e lec s he ex en o LD wi h
he op SNP: whi e (
2
¼0) h ough o da k ed (
2
¼1.0), wi h
2
es ima ed om he 1000 Genomes Phase 1 da a. Gene ic ecombina ion a es (cM/Mb) a e shown wi h a
ligh blue line. Physical posi ions a e based on NCBI build 37 o he human genome. Also shown a e he ela i e posi ions o genes and ansc ip s mapping o each e-
gion o associa ion. The lowe panel shows he ch oma in s a e segmen a ion ack (Ch omHMM) in HCT116 CRC and GM12878 lymphoblas oid cell lines.
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Pa hways ha we e en iched in bo h, albei in ol ing di e en
p o eins, included hose ela ed o he adap i e immune e-
sponse, cy okine signalling and in e e on signalling
(Supplemen a y Ma e ial, Table S7).
Discussion
In his me a-analysis we combined se en independen GWAS,
and ha e iden i ied a isk locus o CRC isk a 2q35 ma ked by
s992157. As his SNP is in onic o bo h PNKD and TMBIM1, and
hese a e he only ansc ip s wi hin he egion o high LD, i is
a plausible ha he gene ic basis o he 2q35 associa ion o CRC
is h ough unc ional e ec s on one o hese genes a p io i. This
is coupled wi h he ac ha s992157 localizes o a genomic e-
gion wi h egula o y unc ion and he eQTL da a showing allele-
speci ic cis- egula o y ela ionship be ween SNP geno ype and
PNKD and TMBIM1 exp ession. Al hough specula i e, he long
iso o m o PNKD appea s o unc ion in a pa hway o de oxi y al-
pha-ke oaldehyde using glu a hione as a co ac o (23). As glu a-
hione is essen ial o main aining cellula edox s a us,
educed glu a hione le els in cells h ough dys unc ional PNKD
may lead o inc easing oxida i e s ess le els, which ha e been
linked o in lamma ion (24). TMBIM1 has been epo ed o ha e
a ole in egula ing he le el o Fas ligand (25,26), which medi-
a es bo h apop osis and in lamma ion (27). The e o e, bo h gene
p oduc s indi ec ly con ibu e o he egula ion o in lamma-
ion, a physiological p ocess linked wi h he onse o IBD and
CRC.
Ano he SNP in he 2q35 locus ( s2382817), which is in s ong
LD wi h s992157, has p e iously been shown o in luence IBD
isk (15). In addi ion, con empo aneous wi h ou analysis, a e-
cen s udy (28) has also ound e idence, albei no GWAS signi i-
can , o a ela ionship be ween 2q35 a ia ion and CRC isk
(P¼7.0 10
5
), addi ionally inding an in e se ela ionship wi h
isk o IBD. The iden i ied SNP, s11676348, is co ela ed wi h
bo h s992157 and s2382817 (LD me ics,
2
and D0¼0.32, 0.65
and 0.33, 0.71, espec i ely). The opposing e ec s o he
s2382817-C allele wi h inc eased isk o CRC bu dec eased isk
o IBD may ini ially appea pa adoxical, gi en he inc eased isk
o CRC associa ed wi h IBD. The isk o CRC in IBD inc eases
wi h longe du a ion, ex en o coli is and he deg ee o in lam-
ma ion (11). The in lamma o y esponse has been linked o in-
c eased oxida i e s ess, and his oxida i e s a e s imula es
an ioxidan de ences ha p omo e he su i al pa hways in
cance cells, a ou ing umou p oli e a ion (29). None heless,
hese SNPs may indica e sha ed pa hways in which he e a e
opposing ela ionships be ween ca cinogenesis and
in lamma ion.
Mo i a ed by he obse a ion ha he 2q35 locus in luences
IBD isk, we sough addi ional e idence o a common gene ic
basis o bo h diseases by e alua ing he CRC isk a p e iously
es ablished IBD loci (15,16). While no o mally signi ican glob-
ally, he e was an o e - ep esen a ion o associa ion signals o
CRC de ined by he IBD isk SNPs. Th ough his analysis we
iden i ied po en ial isk a ian s o CRC mapped o egions in
he p oximi y o genes encoding WNT4 and CDC42, p e iously
shown o be in ol ed in he isk o CRC (14); MAPKAPK5, a mem-
be o he MAPK amily epo ed o egula e MYC p o ein le els
(18); and he ansc ip ion ac o CEBPB, ound o be highly ex-
p essed in samples de i ed om CRC pa ien s (21). Mo eo e ,
ou eQTL analysis on IBD SNPs showed al e ed exp ession o
FADS2 and FUT2 genes in CRC issues. Bo h he genes ha e p e-
iously been epo ed o ha e a ole in he de elopmen o IBD
(30,31) p o iding u he e idence o possible sha ed genes.
Fu he s udies a e equi ed o delinea e he gene ic basis and
implica e pe u ba ion o a speci ic gene as he unc ional basis
Figu e 3. Quan ile–quan ile (Q–Q) plo o obse ed and expec ed CRC associa ion
P- alues o 200 IBD isk SNPs (15, 16).
Table 1. Table o he IBD SNPs wi h FDR-co ec ed P- alue <0.05 in he CRC GWAS
sID Ch Posi ion Tag genes CRC isk
allele
IBD isk
allele
CRC
RAF
CRC P- alue CRC FDR
co ec ed
CRC OR CRC 95% CI
s12568930 1 22702231 WNT4, CDC42 T T 0.85 6.58 10
05
3.29 10
03
1.12 (1.06; 1.18)
s7554511 1 200877562 GPR25, C1o 106 A C 0.29 6.95 10
04
0.02 1.08 (1.03; 1.13)
s7608910 2 61204856 PUS10, REL A G 0.63 7.28 10
04
0.02 1.07 (1.03; 1.12)
s17229285 2 199523122 PLCL1, SATB2 C C 0.49 2.46 10
03
0.04 1.06 (1.02; 1.1)
s2382817 2 219151218 TMBIM1, PNKD C A 0.62 1.02 10
05
1.02 10
03
1.09 (1.05; 1.14)
s4722672 7 27231762 HOXA13, HOXA11 C C 0.20 2.46 10
03
0.04 1.08 (1.03; 1.13)
s174537 11 61552680 MYRF, TMEM258 G T 0.67 2.63 10
03
0.04 1.06 (1.02; 1.11)
s653178 12 112007756 ATXN2, MAPKAPK5 T C 0.54 2.23 10
05
1.49 10
03
1.09 (1.05; 1.13)
s17085007 13 27531267 GPR12, UPS12 C C 0.19 5.81 10
04
0.02 1.09 (1.04; 1.15)
s941823 13 41013977 MRPS31, FOXO1 T C 0.27 2.47 10
03
0.04 1.07 (1.02; 1.12)
s516246 19 49206172 FUT2, MAMSTR T T 0.54 4.71 10
04
0.02 1.07 (1.03; 1.11)
s913678 20 48955424 CEBPB, PTPN1 C T 0.34 7.30 10
06
1.02 10
03
1.10 (1.05; 1.14)
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o he associa ions. Collec i ely hese da a a e consis en wi h a
deg ee o commonali y in gene ically de ined pa hways in he
de elopmen be ween CRC and IBD, albei ha many o he as-
socia ions ha e opposi e e ec s.
Conside ing he low p e alence o IBD in Eu opean popu-
la ions (<0.5%) (32), oge he wi h he obse a ion ha o he
SNPs ha a e s ongly associa ed wi h isk o IBD we e no
associa ed wi h CRC, i is unlikely ha sampling has biased
ou indings. Mo eo e i he associa ion be ween hese IBD
SNPs and CRC was simply media ed by i s associa ion wi h
IBD pe se, we would ha e expec ed di ec ionali y o he asso-
cia ion o be iden ical bu his was no he case o many o
he SNPs.
In summa y, we ha e iden i ied a new isk associa ion o
CRC which also in luences IBD isk. Ou associa ion signals o
CRC de ined by o he es ablished IBD isk SNPs also se e o
highligh he impo ance o sha ed gene pa hways in he de el-
opmen o CRC and IBD. Deciphe ing he unc ional and biologi-
cal basis o hese SNPs associa ions has he po en ial o
ansla e in o a be e unde s anding o he biological basis o
how IBD ansi ions o CRC. Finally ou analysis se es o illus-
a e ha in e - ela ionships be ween diseases do no necessa -
ily equa e o consis en allelic a chi ec u e in isk, hus adding
an ex a laye o complexi y o in e p e a ion.
Ma e ials and Me hods
E hics
Collec ion o blood samples and clinico-pa hological in o ma-
ion om subjec s was unde aken wi h in o med consen and
e hical e iew boa d app o al a all si es in acco dance wi h he
ene s o he Decla a ion o Helsinki.
P ima y GWAS
The Finnish GWAS (FIN) was based on 1172 CRC cases and 8266
cance ee con ols asce ained h ough Finnish Hospi als (33)
and h ough he Finnish Cance Regis y. Cases we e geno yped
using Illumina HumanOmni 2.5M8 1 acco ding o he manu ac-
u e ’s ecommenda ions. Fo con ols, we made use o
Illumina HumanHap 670k and 610k a ay da a on indi iduals
om he FINRISK (34), Heal h 2000 (35), Finnish Twin Coho (36)
and Helsinki Bi h Coho S udies (37). Indi iduals we e ex-
cluded wi h: <90% success ully geno yped SNPs, disco dan sex
in o ma ion, duplica ion o c yp ic ela edness (iden i y by de-
scen >0.2). We excluded SNPs om he analysis wi h: call
a e <95%, (mino allele equency [MAF]) <0.01 and depa u e
om Ha dy–Weinbe g equilib ium in con ols a P<10
6
. The
adequacy o he case–con ol ma ching and he possibili y o
di e en ial geno yping o cases and con ols we e assessed us-
ing quan ile–quan ile (Q–Q) plo s o es s a is ics.
Published GWAS o me a-analysis
We made use o six p e iously published GWAS: UK1 (CORGI
s udy) (7) comp ised 940 cases wi h colo ec al neoplasia and 965
con ols; Sco land1 (COGS s udy) (7) included 1012 CRC cases
and 1012 con ols; VQ58 comp ised 1800 CRC cases om he
UK-based VICTOR and QUASAR2 adju an chemo he apy clini-
cal ials (38) and 2690 popula ion con ol geno ypes om he
Wellcome T us Case Con ol Conso ium 2 (WTCCC2) 1958
bi h coho (39); CCFR1 comp ised 1290 amilial CRC cases and
1055 con ols om he Colon Cance Family Regis y (CCFR) (40);
CCFR2 included a u he 796 cases om he CCFR and 2236 con-
ols om he Cance Gene ic Ma ke s o Suscep ibili y (CGEMS)
s udies o b eas and p os a e cance (41,42); and he COIN
Figu e 4. Hi e plo o common p o ein–p o ein in e ac ions be ween CRC and IBD de ined by isk SNPs. Each a c ep esen s an in e ac ion be ween wo p o eins, and
he dis ance om he cen e o he plo co esponds o a g ea e numbe o p o ein–p o ein in e ac ions (highe deg ee o he node). The le a m ep esen s p o eins
ha we e only iden i ied using he CRC SNPs, he igh a m ep esen s p o eins ha we e only iden i ied using he IBD SNPs, and he cen al a m ep esen s he com-
mon p o eins, highligh ing he p e iously associa ed ag genes.
2354 |Human Molecula Gene ics, 2016, Vol. 25, No. 11
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GWAS (14) was based on 2244 CRC cases asce ained h ough
wo independen Medical Resea ch Council clinical ials o ad-
anced/me as a ic CRC (COIN and COIN-B) (43) and con ols
comp ised 2162 indi iduals om he UK Blood Se ice Con ol
G oup geno yped as pa o he WTCCC2 (39).
The VQ58, UK1 and Sco land1 GWAS se ies we e geno yped
using Illumina Hap300, Hap240S, Hap370, Hap550 o Omni2.5M
a ays. 1958BC geno yping was pe o med as pa o he
WTCCC2 s udy on Hap1.2M-Duo Cus om a ays. The CCFR sam-
ples we e geno yped using Illumina Hap1M, Hap1M-Duo o
Omni-exp ess a ays. CGEMS samples we e geno yped using
Illumina Hap300 and Hap240 o Hap550 a ays. The COIN cases
we e geno yped using A yme ix Axiom A ays and he Blood
Se ice con ols we e geno yped using A yme ix 6.0 a ays.
A e applying he same quali y con ol as ha pe o med o
FIN, da a on 8749 CRC cases and 18 245 con ols we e a ailable
o he me a-analysis.
The adequacy o he case–con ol ma ching and possibili y
o di e en ial geno yping o cases and con ols we e assessed
using Q–Q plo s o es s a is ics. k
GC
alues (44) o he UK1,
Sco land1, VQ58, CCFR1, CCFR2 and COIN s udies we e 1.02,
1.01, 1.01, 1.02, 1.03 and 1.05, espec i ely. Any e hnic ou lie s o
indi iduals iden i ied as ela ed we e excluded.
Replica ion se ies
In o al, 5061 CRC cases om he Na ional S udy o Colo ec al
Cance Gene ics (NSCCG) (45) we e geno yped. Con ols
(n¼3509) we e om NSCCG and he Gene ic Lung Cance
P edisposi ion S udy (46). None o he con ols had a known his-
o y o malignancy a asce ainmen . All subjec s we e B i ish
esiden s wi h sel - epo ed Eu opean e hnici y and he e we e
no ob ious demog aphic di e ences be ween cases and con-
ols. DNA was ex ac ed om EDTA- enous blood samples us-
ing con en ional me hodologies and PicoG een quan i ied
(In i ogen Co po a ion, Ca lsbad, CA, USA). Geno yping o wo
SNPs was conduc ed using KASPa compe i i e allele-speci ic
PCR chemis y (LGC, Hoddesdon, UK; p ime sequences and
condi ions a ailable on eques ). To moni o quali y con ol, du-
plica e samples we e included in assays, and conco dance be-
ween duplica e samples was >99%.
Impu a ion and me a-analysis
Analyses we e unde aken using R ( 3.02) (47) and PLINK ( 1.9)
(48) so wa e. Phasing o GWAS SNP geno ypes was pe o med us-
ing SHAPEIT ( 2. 644 and 2. 790 o FIN) (49). P edic ion o he
un yped SNPs was ca ied ou using IMPUTE ( 2.3.1) (50). The FIN
da ase used a me ged e e ence panel based on da a om he
1000 Genomes P ojec (Phase 1 3) (51) oge he wi h an addi ional
popula ion ma ched e e ence panel o 3882 SISu haplo ypes. The
UK samples used a me ged e e ence panel using da a om he
1000 Genomes P ojec and UK10K (Ap il 2014 elease). The ideli y
o impu a ion, as assessed by he conco dance be ween impu ed
and sequenced SNPs, was examined in a subse o 200 UK cases
(14). The associa ion be ween each SNP and he isk o CRC was
assessed by a equen is associa ion es unde an addi i e
model, using SNPTEST ( 2.5.1) (52), u ilizing he geno ype p oba-
bili ies om IMPUTE whe e an SNP was no di ec ly yped.
Popula ion s a i ica ion was con olled in he FIN samples using
sex and six p incipal componen s. Associa ion me a-analyses
only included ma ke s wi h in o sco es >0.8, impu ed call a es/
SNP >0.9 and MAFs >0.005. Me a-analyses we e ca ied ou using
META ( 1.6) (53). We calcula ed Coch an’s Qs a is ic o es o
he e ogenei y and he I
2
s a is ic o quan i y he p opo ion o he
o al a ia ion ha was caused by he e ogenei y (54). I
2
al-
ues 75% a e conside ed cha ac e is ic o la ge he e ogenei y (54).
Cha ac e iza ion o cance pheno ype
Associa ions by sex, age and clinico-pa hological pheno ypes
we e examined by logis ic eg ession. MSI s a us was de e mined
using BAT25 and BAT26 ma ke s, and samples showing5no el
alleles when compa ed wi h no mal DNA a ei he o bo h
ma ke s we e assigned as MSI-H (co esponding o MSI-high) (55).
Tumou s we e sc eened o KRAS codons 12, 13 and 61 and BRAF
codon 600 mu a ions by py osequencing (43). Addi ionally, KRAS
(all h ee codons) and BRAF (codons 594 and 600) we e sc eened
o mu a ions by MALDI-TOF mass a ay (Sequenom, San Diego,
CA, USA) (56). Di e ences be ween he a ious si es o he umou
(colonic [ICD-9:153], ec al [ICD-9:154.1] and ec o sigmoid junc-
ion [ICD9:154.0]) we e also analysed.
Func ional p edic ion
To explo e epigene ic p o iles o genomic loca ion associa ed
wi h CRC, we used ENCODE his one modi ica ion da a, HaploReg
and RegulomeDB (57,58) o examine whe he any o he SNPs o
hei p oxies (i.e.
2
>0.8 in he 1000 Genomes EUR e e ence
panel) anno a e ansc ip ion ac o binding o enhance ele-
men s. Addi ionally, we made use o ChIP-seq da a on he LoVo
CRC cell line (59). We used Ch omHMM o in eg a e DNase,
H3K4me3, H3K4me1, H3K27ac, Pol2 and CTCF s a es om he
CRC cell line HCT116 using a mul i a ia e Hidden Ma ko Model
(60). Ch omHMM acks o lymphoblas oid cells we e ob ained
om ENCODE (61). We assessed sequence conse a ion using:
Phas Cons (62) (>0.3 indica i e o conse a ion) and Genomic
E olu iona y Ra e P o iling (63) (>2 indica i e o conse a ion).
SNAP plo s we e c ea ed using he isPIG ool (64).
eQTL analysis
To examine o a ela ionship be ween SNP geno ype and
mRNA exp ession in CRC, we analysed Tumo Cance Genome
A las (TCGA) RNA-seq exp ession and A yme ix 6.0 SNP da a
(dbGaP accession numbe : phs000178. 7.p6) on 416 colo ec al
adenoca cinoma samples (65). Associa ion be ween no malized
RNA coun s pe -gene and SNP geno ype was quan i ied using
he K uskal–Wallis end es . To look o a ela ionship be-
ween SNP geno ype and exp ession le els in o he issues, we
used publicly a ailable exp ession da a gene a ed om he
MuTHER (66), eQTL Blood B owse (67), GTEx (68) and Geu adis/
1000 Genomes (69) esou ces. Fo he Geu adis da a, he ela-
ionship be ween SNPs and exp ession o genes loca ed wi hin
1 Mb was analysed using he Ma ix eQTL (70) package unde a
linea model. When he SNPs we e no di ec ly yped, a p oxy
SNP was used (
2
0.8). In all he da ase s, eQTL esul s we e in-
cluded whe e FDR P<0.05.
Rela ionship be ween es ablished isk SNPs o IBD and
CRC
To in es iga e pleio opic (sha ed gene ic suscep ibili y) be-
ween CRC and IBD, we examined he 201 SNPs iden i ied in
GWAS ha ha e been shown o a ec IBD isk (15,16). One SNP
( s71559680) is an indel ha was no p esen in he CRC
2355Human Molecula Gene ics, 2016, Vol. 25, No. 11 |
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geno yping a ays o he e e ence panels, and was hus e-
mo ed om he analysis. We ob ained he lead SNPs om he
IBD GWAS and ex ac ed he P- alues o he co esponding
SNPs in ou CRC me a-analysis.
Pa hway analysis
To in es iga e he possibili y o sha ed gene ic suscep ibili y be-
ween CRC and IBD, we pe o med pa hway analysis. Fi s , we
selec ed he wo closes coding genes o he leading SNPs in
each GWAS and hen pe o med pa hway analysis using LENS
ool (22), which iden i ies gene p oduc and p o ein–p o ein in-
e ac ions om HPRD (71) and BioGRID (72). En ichmen o pa h-
ways was assessed using Fishe ’s exac es , compa ing he
o e lap o he genes in he ne wo k wi h he genes in he pa h-
way. Pa hway da a we e ob ained om REACTOME (73).
Cy oscape was used o pe o m ne wo k analyses (74), and he
Hi e Plo was d awn using Hi eR (academic.depauw.edu/
hanson/Hi eR/Hi eR.h ml, las accessed Ma ch 29, 2016).
Supplemen a y Ma e ial
Supplemen a y Ma e ial is a ailable a HMG online.
Acknowledgemen s
We would like o hank Ami Sud o his c i ical eading o he
manusc ip . We a e g a e ul o all indi iduals who pa icipa ed
in he a ious s udies. This s udy made use o geno yping da a
om he 1958 Bi h Coho , kindly made a ailable by he
Wellcome T us Case Con ol Conso ium 2. A ull lis o he in-
es iga o s who con ibu ed o he gene a ion o he da a is
a ailable a h p://www.w ccc.o g.uk/, las accessed Ma ch 29,
2016. The esul s published he e a e in whole o pa based
upon da a gene a ed by The Cance Genome A las pilo p ojec
es ablished by he NCI and NHGRI. In o ma ion abou TCGA and
he in es iga o s and ins i u ions ha cons i u e he TCGA e-
sea ch ne wo k can be ound a h p://cance genome.nih.go /,
las accessed Ma ch 29, 2016.
Con lic o In e es s a emen . None decla ed.
Funding
In Finland, his wo k was suppo ed by g an s om he
Academy o Finland [Finnish Cen e o Excellence P og am
2012–2017, 250345], he Jane and Aa os E kko Founda ion, he
Finnish Cance Socie y [pe sonal g an o K.P.], he Eu opean
Resea ch Council [ERC; 268648], he Sig id Juselius Founda ion,
SYSCOL, he No dic In o ma ion o Ac ion eScience Cen e
(NIASC), he No dic Cen e o Excellence inanced by No dFo sk
[p ojec 62721, pe sonal g an o K.P.] and S a e Resea ch
Funding o Kuopio Uni e si y Hospi al [B1401]. We acknowledge
he compu a ional esou ces p o ided by he ELIXIR node,
hos ed a he CSC–IT Cen e o Science, Finland, and unded by
he Academy o Finland [g an s 271642 and 263164], he
Minis y o Educa ion and Cul u e, Finland. V.S. was suppo ed
by he Finnish Academy [g an numbe 139635]. Sample collec-
ion and geno yping in he Finnish Twin Coho has been sup-
po ed by he Wellcome T us Sange Ins i u e, ENGAGE—
Eu opean Ne wo k o Gene ic and Genomic Epidemiology, FP7-
HEALTH-F4-2007 [g an ag eemen numbe 201413], he
Na ional Ins i u e o Alcohol Abuse and Alcoholism [g an s AA-
12502 and AA-00145 o Richa d J. Rose and K02AA018755 o
Danielle M. Dick] and he Academy o Finland [g an s 100499,
205585, 265240 and 263278 o J.K.].
A he Ins i u e o Cance Resea ch, his wo k was suppo ed
by Cance Resea ch UK [C1298/A8362—Bobby Moo e Fund o
Cance Resea ch UK]. Addi ional suppo was p o ided by he
Na ional Cance Resea ch Ne wo k and he NHS ia he
Biological Resea ch Cen e o he Na ional Ins i u e o Heal h
Resea ch a he Royal Ma sden Hospi al NHS T us . In
Edinbu gh, he wo k was suppo ed by P og amme G an und-
ing om Cance Resea ch UK [C348/A12076]. In Ox o d, addi-
ional unding was p o ided by he Ox o d Comp ehensi e
Biomedical Resea ch Cen e [ o C.P. and I.P.M.T.] and he EU FP7
CHIBCHA g an [I.P.M.T.]. Co e in as uc u e suppo o he
Wellcome T us Cen e o Human Gene ics, Ox o d was p o-
ided by g an [090532/Z/09/Z]. We a e g a e ul o many col-
leagues wi hin UK Clinical Gene ics Depa men s ( o CORGI)
and o many collabo a o s who pa icipa ed in he VICTOR and
QUASAR2 ials. We also hank colleagues om he UK Na ional
Cance Resea ch Ne wo k ( o NSCCG). Suppo om he
Eu opean Union [FP7/207-2013, g an 258236] and FP7 collabo a-
i e p ojec SYSCOL and COST Ac ion in he UK is also acknowl-
edged [BM1206]. The COIN and COIN-B ials we e unded by
Cance Resea ch UK and he Medical Resea ch Council and we e
conduc ed wi h he suppo o he Na ional Ins i u e o Heal h
Resea ch Cance Resea ch Ne wo k. COIN and COIN-B ansla-
ional s udies we e suppo ed by he Bobby Moo e Fund om
Cance Resea ch UK, Teno us, he Kidani T us , Cance
Resea ch Wales and he Na ional Ins i u e o Social Ca e and
Heal h Resea ch Cance Gene ics Biomedical Resea ch Uni
(2011–2014) [all awa ded o J.P.C.]. N.A.A., B.F.M. and S.M.W.
we e unded and suppo ed by KFSHRC.
The wo k o he Colon Cance Family Regis y (CCFR) was sup-
po ed by om he Na ional Cance Ins i u e [g an UM1
CA167551], Na ional Ins i u es o Heal h and h ough coope a-
i e ag eemen s wi h he ollowing CCFR cen es: Aus alasian
Colo ec al Cance Family Regis y [U01 CA074778, U01/U24
CA097735], USC Conso ium Colo ec al Cance Family Regis y
[U01/U24 CA074799], Mayo Clinic Coope a i e Familial Regis y
o Colon Cance S udies [U01/U24 CA074800], On a io Familial
Colo ec al Cance Regis y [U01/U24 CA074783], Sea le
Colo ec al Cance Family Regis y [U01/U24 CA074794] and
Uni e si y o Hawaii Colo ec al Cance Family Regis y [U01/U24
CA074806].
The CCFR Illumina GWAS was suppo ed by unding om he
Na ional Cance Ins i u e, Na ional Ins i u es o Heal h [U01
CA122839 and R01 CA143237 o G.C.]. Sea le CCFR esea ch was
also suppo ed by he Cance Su eillance Sys em o he F ed
Hu chinson Cance Resea ch Cen e [Con ol Nos. N01-CN-67009
(1996–2003), N01-PC-35142 (2003–2010)] and he Su eillance,
Epidemiology and End Resul s (SEER) P og am o he Na ional
Cance Ins i u e [Con ac No. HHSN2612013000121 (2010–2017)]
wi h addi ional suppo om he F ed Hu chinson Cance
Resea ch Cen e . The collec ion o cance incidence da a o
he S a e o Hawai’i used in his s udy was suppo ed by he
Hawai‘i Depa men o Heal h as pa o he s a ewide cance
epo ing p og am manda ed by Hawai‘i Re ised S a u es;
he Na ional Cance Ins i u e’s Su eillance, Epidemiology
and End Resul s P og am (SEER) awa ded o he Uni e si y o
Hawai‘i [Con ol Nos. N01-PC-67001 (1996–2003), N01-PC-35137
(2003–2010), Con ac Nos. HHSN26120100037C (2010–2013),
HHSN261201300009I (2010–cu en )]. The ideas and opinions ex-
p essed he ein a e hose o he au ho (s) and endo semen by he
S a e o Hawai‘i, Depa men o Heal h, he Na ional Cance
Ins i u e, SEER P og am o hei Con ac o s and Subcon ac o s
2356 |Human Molecula Gene ics, 2016, Vol. 25, No. 11
a Tampe e Uni e si y Lib a y. Depa men o Heal h Sciences on Oc obe 31, 2016h p://hmg.ox o djou nals.o g/Downloaded om
is no in ended no should be in e ed. The collec ion o cance
incidence da a used in his s udy was suppo ed by he Cali o nia
Depa men o Public Heal h as pa o he s a ewide cance e-
po ing p og am manda ed by Cali o nia Heal h and Sa e y Code
Sec ion 103885; he Na ional Cance Ins i u e’s Su eillance,
Epidemiology and End Resul s P og am [unde con ac
HHSN261201000035C] awa ded o he Uni e si y o Sou he n
Cali o nia, and [con ac HHSN261201000034C] awa ded o he
Public Heal h Ins i u e; and he Cen e s o Disease Con ol and
P e en ion’s Na ional P og am o Cance Regis ies, unde ag ee-
men [U58DP003862-01] awa ded o he Cali o nia Depa men o
Public Heal h. The ideas and opinions exp essed he ein a e hose
o he au ho (s) and endo semen by he S a e o Cali o nia,
Depa men o Public Heal h he Na ional Cance Ins i u e, and
he Cen e s o Disease Con ol and P e en ion o hei
Con ac o s and Subcon ac o s is no in ended no should be in-
e ed. The con en o his manusc ip does no necessa ily e-
lec he iews o policies o he Na ional Cance Ins i u e o any
o he collabo a ing cen es in he CCFR, no does men ion o
ade names, comme cial p oduc s, o o ganiza ions imply en-
do semen by he US Go e nmen o he CCFR. Funding o pay
he Open Access publica ion cha ges o his a icle was p o ided
by COAF: Cha i y Open Access Fund.
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2357Human Molecula Gene ics, 2016, Vol. 25, No. 11 |
a Tampe e Uni e si y Lib a y. Depa men o Heal h Sciences on Oc obe 31, 2016h p://hmg.ox o djou nals.o g/Downloaded om