SHORT REPORT
Me a-analysis o 49 549 indi iduals impu ed wi h he
1000 Genomes P ojec e eals an exonic damaging
a ian in ANGPTL4 de e mining as ing TG le els
Elisabe h M an Leeuwen,
1
Aniko Sabo,
2
Joshua C Bis,
3
Jenni e E Hu man,
4,5
Ani Manichaikul,
6
Albe V Smi h,
7,8
Ma y F Fei osa,
9
Se kalem Demissie,
10
Pe e K Joshi,
11
Qing Duan,
12
Jona han Ma en,
4
Jan B an Klinken,
13
Ida Su akka,
14
Ilja M Nol e,
15
Weihua Zhang,
16,17
Hamdi Mba ek,
18
Rui ang Li-Gao,
19
S ella T ompe ,
20,21
Niek Ve weij,
22
E angelos E angelou,
16,23
Leo-Pekka Lyy ikäinen,
24,25
Bamidele O Tayo,
26
Jo is Deelen,
27
Pe e J an de Mos ,
15
Sande W an de Laan,
28
Dan E A king,
29
Alanna Mo ison,
30
Abbas Dehghan,
1
Osca H F anco,
1
Albe Ho man,
1
Fe nando Ri adenei a,
31
E ic J Sijb ands,
31
And e G Ui e linden,
1,31
Josy C Mychaleckyj,
6
A chie Campbell,
32
Lynne J Hocking,
33
Sandosh Padmanabhan,
34
Jenni e A B ody,
3
Kenne h M Rice,
35
Cha les C Whi e,
36
Tama a Ha is,
37
Aa on Isaacs,
1
Ha y Campbell,
11
Leslie A Lange,
12
Igo Rudan,
38
I ana Kolcic,
39
Pau Na a o,
4
Ta ijana Zemunik,
39
Veikko Salomaa,
40
The Li eLines
Coho S udy Angad S Koone ,
41
Jaspal S Koone ,
17,41,42
Benjamin Lehne,
16
William R Sco ,
16,17
Sian-Tsung Tan,
41
Eco J de Geus,
18
Yu i Milaneschi,
43
B enda W J H Penninx,
43
Gonneke Willemsen,
18
Renée de Mu se ,
19
Ian Fo d,
44
Ron T Ganse oo ,
45
Ma celo P Segu a-Lepe,
16
Olli T Rai aka i,
46,47
Jo ma S Viika i,
48,49
Kjell Nikus,
50,51
Te ence Fo es e ,
52
Colin A McKenzie,
52
An on J M de C aen,
21
Hes e M de Ruij e ,
28
CHARGE Lipids Wo king G oup
Ge a d Pas e kamp,
28,53
Ha old Sniede ,
15
Albe ine J Oldehinkel,
54
P Eline Slagboom,
27
Richa d S Coope ,
26
Mika Kähönen,
55,56
Te ho Leh imäki,
24,25
Paul Ellio ,
57
Pim an de Ha s ,
22,58
J Wou e Jukema,
20
Dennis O Mook-Kanamo i,
19,59,60
Do e I Boomsma,
18
John C Chambe s,
16,17,42
Mo is Swe z,
58,61
Samuli Ripa i,
14,62,63
Ko Willems an Dijk,
13,64
Ve onique Vi a ,
4
Oz en Polasek,
39
Ca oline Haywa d,
4
James G Wilson,
65
James F Wilson,
4,11
Vilmundu Gudnason,
7,8
S ephen S Rich,
6
B uce M Psa y,
3,66,67,68
Ing id B Bo ecki,
9
E ic Boe winkle,
2,30
Je ome I Ro e ,
69,70,71
L Ad ienne Cupples,
5,9
Co nelia M an Duijn
1
▸Addi ional ma e ial is
published online only. To iew
his file please isi he jou nal
online (h p://dx.doi.o g/10.
1136/jmedgene -2015-
103439)
Fo numbe ed a filia ions see
end o a icle.
Co espondence o
P o esso Co nelia M an
Duijn, Gene ic Epidemiology
Uni , Depa men o
Epidemiology, E asmus Medical
Cen e , Pos bus 2040,
Ro e dam 3000 CA,
The Ne he lands;
c. anduijn@e asmusmc.nl
Recei ed 4 Augus 2015
Re ised 19 No embe 2015
Accep ed 23 No embe 2015
Published Online Fi s
1 Ap il 2016
To ci e: an Leeuwen EM,
Sabo A, Bis JC, e al.J Med
Gene 2016;53:441–449.
ABSTRACT
Backg ound So a , mo e han 170 loci ha e been
associa ed wi h ci cula ing lipid le els h ough genome-
wide associa ion s udies (GWAS). These associa ions a e
la gely d i en by common a ian s, hei unc ion is o en
no known, and many a e likely o be ma ke s o he
causal a ian s. In his s udy we aimed o iden i y mo e
new a e and low- equency unc ional a ian s
associa ed wi h ci cula ing lipid le els.
Me hods We used he 1000 Genomes P ojec as a
e e ence panel o he impu a ions o GWAS da a om
∼60 000 indi iduals in he disco e y s age and ∼90 000
samples in he eplica ion s age.
Resul s Ou s udy esul ed in he iden ifica ion o fi e
new associa ions wi h ci cula ing lipid le els a ou loci.
All ou loci a e wi hin genes ha can be linked
biologically o lipid me abolism. One o he a ian s,
s116843064, is a damaging missense a ian wi hin
he ANGPTL4 gene.
Conclusions This s udy illus a es ha GWAS wi h
high-scale impu a ion may s ill help us un a el he
biological mechanism behind ci cula ing lipid le els.
INTRODUCTION
Genome-wide associa ion s udies (GWAS) o ci cu-
la ing lipid le els (high-densi y lipop o ein choles-
e ol (HDL-C), low-densi y lipop o ein choles e ol
(LDL-C), o al choles e ol (TC) and iglyce ides
(TG)) ha e iden ified o e 170 loci.
1–3
These
Open Access
Scan o access mo e
ee con en
an Leeuwen EM, e al.J Med Gene 2016;53:441–449. doi:10.1136/jmedgene -2015-103439 441
Genome-wide s udies
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s udies ha e been based on impu a ions o he HapMap e e -
ence panel
2
o p ima y e sions o he 1000 Genomes P ojec
(1kG)
1
o geno yping on he Illumina Exome Chip.
3
None has
used impu a ions wi h he Phase 1 in eg a ed elease 3 o he
1kG which allows he impu a ion o a e and low- equency
unc ional a ian s and s uc u al a ia ions wi h mo e p eci-
sion. E idence o a e and low- equency unc ional a ian s
associa ed wi h ci cula ing lipid le els comes om ecen s udies
in which exome sequencing o he NPC1L1 gene iden ified a e
a ian s associa ed wi h educed LDL-C le els and educed isk
o co ona y hea disease.
4
Mo eo e , exome sequencing o
LDLR and APOA5 iden ified a e a ian s associa ed wi h an
inc eased LDL-C and inc eased TG le els
5
and exome sequen-
cing o APOC3 iden ified a e a ian s associa ed wi h educed
TG le els and educed isk o co ona y hea disease.
6
Ou goal in his s udy was o iden i y a e and low- equency
unc ional a ian s associa ed wi h ci cula ing lipid le els in a
la ge sample size compa ed wi h he exome sequencing o can-
dida e gene app oach. To his end, we impu ed geno ypes o
s udy samples pa icipa ing in he coho s o he Coho s o
Hea and Aging Resea ch in Genomic Epidemiology
(CHARGE) conso ium using he Phase 1 in eg a ed elease V. 3
o he 1kG and conduc ed a me a-analysis o abou app oxi-
ma ely 60 000 indi iduals, ollowed by a eplica ion in an inde-
penden se o 90 000 indi iduals.
METHODS
Please see online supplemen a y me hods o comple e desc ip-
ions o he me hods. In summa y, o he disco e y s age o his
p ojec , we used he da a om 20 coho s o he CHARGE con-
so ium (see online supplemen a y me hods). All coho s we e
impu ed wi h e e ence o he 1kG e e ence panel ( e sion
Phase 1 in eg a ed elease V.3). The o al numbe o indi iduals
in he disco e y s age was 59 409 o HDL-C, 48 780 o
LDL-C, 60 024 o TC and 49 549 o TG. Online supplemen-
a y ables S1 and S2 con ain he baseline cha ac e is ics pe
coho and mo e de ails abou SNP geno yping and geno ype
impu a ions.Wi hin each coho , each a ian was es ed o
associa ion wi h each o he lipid ai s, assuming an addi i e
gene ic model. The associa ion esul s o all coho s o all a -
ian s we e combined using in e se a iance weigh ing. We used
he ollowing fil e s o he a ian s: 0.3<R
2
(measu emen o
he impu a ion quali y) ≤1.0 and expec ed mino allele coun
(expMAC=2×MAF (mino allele equency)×R
2
×sample size)
>10 p io o me a-analysis. A e me a-analysis o all a ailable
a ian s, we excluded he a ian s ha we e no p esen in a
leas ou coho s, o p e en alse posi i e findings. In o de o
selec only a ian s ha we e independen ly associa ed wi h
each o he lipid ai s, we used he genome-wide complex ai
analysis (GCTA)
7
ool, V.1.13. To iden i y no el loci we selec ed
om he lis o a ian s iden ified by GCTA, hose a ian s
loca ed mo e han 0.5 Mb away om p e iously iden ified
loci o he co esponding ai
23
and which we e significan
(p alue<5×10
−8
) in he ini ial disco e y s age. To p e en he
iden ifica ion o alse posi i e loci, we added a second eplica-
ion s age wi hin 23 independen coho s. The expe imen -wide
significance h eshold equi ed o keep ype I e o a e wi hin
he eplica ion s age a 5% is 2.63×10
−3
(Bon e oni co ec ion
based on 19 a ian s). We also me a-analysed he indi iduals o
he disco e y and eplica ion s age oge he and pe e hnici y
using a fixed-e ec app oach. We also epea ed his analysis
wi h genome-wide associa ion me a analysis (GWAMA) (V.2.0.5)
using a andom e ec app oach as he indi iduals in disco e y
and eplica ion s ages come om mul iple e hnici ies.
RESULTS
The associa ion o all a ian s wi h HDL-C, LDL-C, TC and
TG was es ed in all disco e y coho s (see online supplemen-
a y figu es S1 and S2). The associa ion esul s o all disco e y
coho s o all a ian s we e combined in a fixed-e ec
me a-analysis using METAL (see online supplemen a y figu es
S3 and S4). We significan ly eplica ed 88.1% o he loci
desc ibed by Teslo ich e al
2
despi e a sample size o abou 80%
(see online supplemen a y figu e S5 and supplemen a y able
S3). We also significan ly eplica ed 43.4% o he loci desc ibed
by he Global Lipids Gene ics Conso ium (GLGC)
3
despi e a
sample size o abou 30% (see online supplemen a y figu e S6
and supplemen a y able S4).
A condi ional and join analysis using GCTA iden ified 185
independen a ian s o HDL-C, 174 o LDL-C, 214 o TC
and 119 o TG. Nex , we excluded all a ian s ha we e no
genome-wide significan (p alue<5×10
−8
) in he ini ial disco -
e y s age, which esul ed in 56 a ian s o HDL-C, 50 o
LDL-C, 66 o TC and 37 o TG. And we excluded all a ian s
which a e wi hin 0.5 Mb o a loci p e iously published by
Teslo ich e al
2
o GLGC,
3
which esul ed in h ee a ian s o
HDL-C, h ee o LDL-C, se en o TC and six o TG. These
a ian s a e loca ed a 17 di e en loci and include one dele ion
(figu e 1 and able 1).
These 19 a ian s we e selec ed o eplica ion. The o al
numbe o indi iduals in he eplica ion s age was 84 598,
72 486, 83 739 and 73 519 o HDL-C, LDL-C, TC and TG,
espec i ely (see online supplemen a y ables S1 and S2 o
baseline cha ac e is ics and in o ma ion abou SNP geno yping
and impu a ion de ails).The sample size in he eplica ion s age
was la ge han he ini ial disco e y sample o 17 ou o he 19
a ian s. The equencies o he a ian s we e simila be ween
he disco e y and eplica ion coho s. The di ec ions o e ec
we e he same in he disco e y and eplica ion coho s o 16
ou o he 19 a ian s (see online supplemen a y figu e S7).
We used a Bon e oni co ec ed h eshold o significance
(p alue<2.63×10
−3
). Fi e ou o he 19 a ian s we e
significan ly eplica ed ( able 1): s6457374 (TC), s186696265
(LDL-C and TC), s77697917 (HDL-C) and s116843064 (TG).
The equency o hese a ian s anged be ween 0.012 and 0.249
wi hin he disco e y sample. Online supplemen a y able S5
shows he he e ogenei y o he 19 a ian s a e he me a-analysis
o all disco e y coho s and o all eplica ion coho s. We also
me a-analysed all a ian s in he indi iduals o he disco e y
coho s and eplica ion coho s combined ( able 1 and see online
supplemen a y ables S5 and S6) and pe e hnici y (see online
supplemen a y able S6) using a fixed-e ec me a-analysis
app oach. We ound ha he fi e significan ly eplica ed a ian s
we iden ified in his s udy a e only significan wi hin he
Eu opean samples, he eby no icing ha he e a e much mo e
Eu opean samples in his s udy, compa ed wi h he A ican and
Asian samples. When using a andom-e ec me a-analysis o
accoun o he mul iple e hnici ies in ou sample (see online sup-
plemen a y able S7), we ound ha o he fi e eplica ed a ian s,
one a ained genome-wide significance (p alue<5×10
−8
) and
he o he ou nominal significance (p alue<0.05).
DISCUSSION
We conduc ed a GWAS ha included GWAS da a impu ed o
he 1kG o iden i y a e and low- equency, po en ially unc-
ional, a ian s associa ed wi h ci cula ing lipid le els. To his
end, we impu ed geno ypes in app oxima ely 60 000 indi iduals
om 20 coho s in he CHARGE conso ium wi h he 1kG
442 an Leeuwen EM, e al.J Med Gene 2016;53:441–449. doi:10.1136/jmedgene -2015-103439
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e e ence panel. The me a-analysis, ollowed by GCTA analysis
e ealed 19 associa ions wi h MAF anging om 0.01 o 0.48.
O he 19 associa ions, we we e able o eplica e fi e in an inde-
penden sample o app oxima ely 90 000 indi iduals.
One o he fi e associa ions we iden ified is be ween TG and
s116843064, an exonic a ian in he ANGPTL4 gene on
ch omosome 19 (figu e 2C). This missense a ian changes he
amino acid glu amic acid in o lysine (Glu40Lys) and is p edic ed
o be damaging o he s uc u e and unc ion o he p o ein by
Polyphen2,
8
Mu a ionTas e
9
and likelihood a io es (LRT).
10
ANGPTL4 is significan ly associa ed wi h he Kyo o Encyclopedia
o Genes and Genomes (KEGG) e m a y acid me abolism, he
GO p ocess lipid s o age and he gene on ology (GO) cellula
componen lipid pa icle (p alue o 1.10×10
−6
, 1.31×10
−10
and 2.87×10
−18
, espec i ely, genene wo k.nl). ANGPTL4 has
been associa ed wi h HDL-C be o e using he GWAS app oach
2
and wi h TG be o e using an exome sequencing app oach
11
and
mo e ecen ly using he GWAS app oach.
1
We he e o e do no
claim his finding as no el, hough his is he smalles s udy in
which his a ian was genome-wide significan ly associa ed wi h
TG and eplica ed in an independen sample.
The second new finding we iden ified is he associa ion
be ween TC and s6457374, an in e genic a ian loca ed
on ch omosome 6 be ween he genes HLA-C and HLA-B
(figu e 2A). Bo h genes a e associa ed wi h he KEGG e m ATP
binding casse e (ABC) anspo e s (p alue o 4.29×10
−5
and
3.84×10
−5
o HLA-C and HLA-B, espec i ely, genene wo k.
nl) which is in line wi h, among o he s, a p e iously published
associa ion be ween TC and an exonic a ian in he ABCA6
gene which is also an ABC anspo e .
12
ABC anspo e s
anspo a wide a ie y o subs a es ac oss ex acellula and
in acellula memb anes, including lipids.
13
The hi d finding o his s udy is he associa ion be ween
HDL-C and s77697917, an in e genic a ian on ch omosome
17 be ween he genes SOST and DUSP3 (figu e 2B). DUSP3 is
associa ed wi h he egula ion and unc ion o
ca bohyd a e- esponsi e elemen -binding p o ein (ChREBP) in
he li e (p alue=3.03×10
−5
, genene wo k.nl). ChREBP med-
ia es he ac i a ion o se e al egula o y enzymes in ol ed in
lipogenesis.
14–18
This a ian is in high linkage disequilib ium
(D0=0.936) in he 1 kG wi h s72836561, an exonic a ian in
he gene CD300LG (MAF=0.027, β=−2.437, se
β
=0.381, p
alue=1.51×10
−10
in he disco e y s age). This missense
a ian changes he amino acid a ginine in o cys eine
(A g82Cys) and is p edic ed o be damaging o he s uc u e
and unc ion o he p o ein by Polyphen2,
8
Mu a ionTas e
9
and LRT.
10
This amino acid polymo phism has been associa ed
wi h HDL-C in exome-wide associa ion s udies
19
and TG in
GWAS
1
be o e.
The ou h a ian we iden ified is s186696265, which is
loca ed on ch omosome 6 and associa ed wi h LDL-C and TC
(figu e 2D, E). This in e genic a ian is be ween he LPA
(Lipop o ein, Lp(A)) gene and he PLG (Plasminogen) gene.
The LPA gene has been associa ed be o e wi h LDL-C and TC
be o e.
2
The epo ed lead SNP was s1564348, which in he
newe human genome e sions is anno a ed o he SLC22A1
(Solu e Ca ie Family 22 (O ganic Ca ion T anspo e ),
Membe 1) gene ins ead o he LPA gene. This explains why we
again iden ified a locus nea he LPA gene, which has been iden-
ified by o he s as well.
1
Fou een ou o he 19 a ian s we e no eplica ed despi e
simila sample sizes and simila equencies wi hin he eplica-
ion s age as compa ed wi h he disco e y s age. O hose 14
a ian s, 11 exhibi ed e ec sizes in he same di ec ion in bo h
s ages. A possible explana ion migh be ha he eplica ion
sample size is much la ge compa ed wi h ha o he disco e y
sample size. Two a ian s migh ha e lacked significan eplica-
ion due o small sample size, s60839105 and s151198427.
Figu e 1 Manha an plo s o HDL-C (A), LDL-C (B), TC (C) and TG (D) a e he me a-analysis o all disco e y coho s. Va ian s ha we e p esen
in a leas ou coho s and ha a e no wi hin 0.5 Mb o a p e iously published loci
23
we e included. The black line indica es he genome-wide
significan line (5×10
−8
), he black and ed do s he a ian s iden ified by GCTA which a e no genome-wide significan and which a e
genome-wide significan , espec i ely. HDL-C, high-densi y lipop o ein choles e ol; LDL-C, low-densi y lipop o ein choles e ol; TC, o al choles e ol;
TG, iglyce ides.
an Leeuwen EM, e al.J Med Gene 2016;53:441–449. doi:10.1136/jmedgene -2015-103439 443
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Table 1 The esul s o he 19 a ian s a e he me a-analysis o all disco e y coho s, all eplica ion coho s and all coho s combined
Disco e y coho s Replica ion coho s All coho s combined
T ai Ch :Posi ion s iden i ie nea es gene A1/A2 F eq N βSE
β
p Value F eq N βSE
β
p Value F eq βSE
β
p Value
HDL-C 3:72 067 255 s75909755 PROL2-EIF4E3 T/C 0.03 62 607 1.593 0.275 7.27E-09 0.03 86 252 −0.019 0.031 5.45E-01 0.03 0.002 0.031 9.57E-01
TC 6:31 272 261 s6457374 HLA-B T/C 0.75 46 839 2.339 0.339 5.32E-12 0.81 74 417 0.057 0.016 4.23E-04 0.81 0.062 0.016 1.18E-04
LDL-C 6:31 325 323 s9266229 HLA-B C/G 0.53 37 981 −2.201 0.344 1.62E-10 0.41 61 582 −0.025 0.014 7.37E-02 0.41 −0.029 0.014 4.04E-02
TG 6:36 648 275 –CDKN1A CAG/C 0.45 53 425 −0.019 0.003 7.63E-09 0.49 59 018 −0.003 0.004 5.20E-01 0.46 −0.013 0.003 5.93E-07
TG 6:13 983 949 8 s608736 –C/G 0.48 53 425 −0.019 0.003 5.67E-09 0.49 73 512 −0.008 0.003 2.67E-02 0.48 −0.013 0.002 9.10E-09
TG 6:16 085 176 6 s376563 SLC22A3 T/C 0.46 47 036 −0.02 0.003 3.37E-09 0.46 73 512 −0.001 0.003 8.22E-01 0.46 −0.010 0.002 1.36E-05
LDL-C 6:16 111 170 0 s186696265 LPA-PLG T/C 0.01 49 221 11.247 1.241 1.31E-19 0.01 59 497 0.263 0.076 5.42E-04 0.01 0.304 0.076 6.17E-05
TC 6:16 111 170 0 s186696265 LPA-PLG T/C 0.01 59 859 10.004 1.162 7.20E-18 0.01 75 821 0.238 0.075 1.46E-03 0.01 0.278 0.075 1.93E-04
HDL-C 7:80 492 357 s60839105 SEMA3C T/C 0.07 7882 3.355 0.571 4.26E-09 0.08 4971 1.067 1.228 3.85E-01 0.07 2.948 0.518 1.25E-08
TC 8:68 351 787 s151198427 CPA6 A/G 0.11 17 361 6.552 1.147 1.12E-08 0.13 1419 −2.858 2.396 2.33E-01 0.11 4.797 1.035 3.56E-06
LDL-C 9:78 728 065 s146369471 PCSK5 T/C 0.99 43 398 8.529 1.449 3.99E-09 0.99 51 367 0.068 0.103 5.11E-01 0.99 0.110 0.103 2.84E-01
TC 9:78 728 065 s146369471 PCSK5 T/C 0.99 53 787 7.978 1.413 1.64E-08 0.99 70 241 0.015 0.103 8.84E-01 0.99 0.057 0.103 5.79E-01
TC 12:51 207 704 s829112 ATF1 A/G 0.68 56 924 1.448 0.258 2.02E-08 0.73 87 659 0.009 0.012 4.63E-01 0.73 0.012 0.012 3.18E-01
TG 13:11 454 402 4 s7140110 GAS6 T/C 0.71 48 221 −0.021 0.004 3.65E-08 0.72 60 437 −0.006 0.005 2.68E-01 0.72 −0.015 0.003 5.13E-07
TG 15:43 726 625 s150844304 TP53BP1 A/C 0.97 52 720 −0.083 0.01 2.52E-17 0.95 63 884 −0.026 0.015 8.85E-02 0.96 −0.066 0.008 9.52E-16
TC 17:18 046 290 s8065026 MYO15A T/C 0.79 56 924 −1.644 0.292 1.76E-08 0.81 76 913 −0.026 0.013 4.93E-02 0.81 −0.029 0.013 2.66E-02
HDL-C 17:41 840 849 s77697917 SOST-DUSP3 T/C 0.02 45 052 −2.717 0.407 2.38E-11 0.03 67 843 −0.222 0.036 4.27E-10 0.03 −0.241 0.035 1.04E-11
TG 19:8 429 323 s116843064 ANGPTL4 A/G 0.03 35 643 −0.101 0.016 6.46E-11 0.03 44 194 −0.065 0.019 4.53E-04 0.03 −0.087 0.012 3.83E-13
TC 20:17 844 684 s2618566 BANF2-SNX5 T/G 0.65 63 300 −1.566 0.251 4.68E-10 0.60 88 946 −0.024 0.011 2.83E-02 0.60 −0.027 0.011 1.38E-02
The a ian s in bold a e he signi ican ly eplica ed a ian s.
A1 is allele 1 and A2 is allele 2, F eq is he equency o A1, βis he e ec o A1.
HDL-C, high-densi y lipop o ein choles e ol; LDL-C, low-densi y lipop o ein choles e ol; TC, o al choles e ol; TG, iglyce ides.
444 an Leeuwen EM, e al.J Med Gene 2016;53:441–449. doi:10.1136/jmedgene -2015-103439
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Bo h a ian s only pass quali y con ol in he coho s in he
disco e y s age ha con ain indi iduals o A ican ances y
(see online supplemen a y figu e S7). Al hough he e a e se e al
coho s wi h indi iduals o A ican ances y in he eplica ion
s age, bo h a ian s did no pass quali y con ol in mos coho s
which leads o he conclusion ha hese a ian s migh be
popula ion-specific. This is also sugges ed by he 1 kG da a
(Phase 3) as he equency o he C-allele is 92% in A ican
samples and 100% in he Eu opean samples o s60839105
and he equency o he G-allele is 86% in he A ican samples
and 100% in he Eu opean samples o s151198427.
Impu a ions o coho s wi h indi iduals o A ican ances y
wi h he A ican Genome Va ia ion P ojec
20
migh confi m
he associa ion o s60839105 wi h HDL-C and s151198427
wi h TC.
To ou knowledge, his is he fi s GWAS o ci cula ing lipid
le els using he Phase 1 in eg a ed elease V.3 o he 1 kG, he e-
o e we canno compa e he posi i e eplica ion a e wi h o he
s udies. Howe e , we did eplica e 88.1% o he findings o
Teslo ich e al
2
and 43.4% o he findings o GLGC
3
despi e
ou smalle sample. A high eplica ion a e is expec ed based on
he high o e lap o ou samples wi h he samples o Teslo ich
e al
2
and wi h he samples o GLGC
3
hough i indica es ha
when using he 1000 Genomes ins ead o he HapMap e e -
ence panel, we can achie e a high eplica ion a e using a
smalle sample size. We also ied o eplica e findings om
Figu e 2 The egional associa ion esul s o he ini ial me a-analysis o all disco e y coho s o (A) TC on ch omosome 6, (B) HDL-C on
ch omosome 17, (C) TG on ch omosome 19, (D) LDL-C on ch omosome 6 and (E) TC on ch omosome 6. HDL-C, high-densi y lipop o ein choles e ol;
LDL-C, low-densi y lipop o ein choles e ol; TC, o al choles e ol; TG, iglyce ides.
an Leeuwen EM, e al.J Med Gene 2016;53:441–449. doi:10.1136/jmedgene -2015-103439 445
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exome sequencing o candida e genes. The p.A g406X mu a ion
in he NPC1L1 gene ( s145297799), which was epo ed o be
associa ed wi h educed LDL-C le els and educed isk o co -
ona y hea disease,
4
is no a ailable in he 1kG e e ence panel
and, he e o e, we we e no able o eplica e his finding. Do
e al
5
desc ibed he exome sequencing o he genes LDLR and
APOA5 and iden ified a e a ian s associa ed wi h an inc eased
isk o myoca dial in a c ion, inc eased LDL-C and TG le els.
O hose a e a ian s, only wo in he LDLR gene and se en in
he APOA5 gene exis in ou disco e y me a-analysis.
Bo h LDLR a ian s a e associa ed wi h TG in ou
disco e y me a-analysis ( s34282181, β=−0.093, SE
β
=0.023,
p alue=4.827×10
−5
and s2075291, β=0.219, SE
β
=0.046,
p alue=2.092×10
−6
), bu no significan ly associa ed wi h
LDL-C ( s34282181, β=−3.939, SE
β
=1.861, p alue=0.034
and s2075291, β=−2.316, SE
β
=3.001, p alue=0.440). None
o he se en APOA5 a ian s we e significan ly associa ed wi h
TG o LDL-C in ou disco e y me a-analysis (lowes p alue is
o LDL-C wi h s72658860, β=−18.430, SE
β
=7.140, p
alue=9.848×10
−3
). The hi d published finding we ied o
eplica e, was he associa ion be ween APOC3 and TG le els.
6
O he se en a ian s epo ed, only one exis ed in ou disco -
e y me a-analysis (ch omosome 11, posi ion 116 701 354),
which is associa ed wi h TG (β=−0.343, SE
β
=0.113, p
alue=2.311×10
−3
). Those au ho s also epo ed an associa ion
be ween an APOA5 a ian ( s3135506) and TG as he mos sig-
nifican finding. This a ian was also significan ly associa ed
wi h TG in ou disco e y me a-analysis (β=0.129, SE
β
=0.007,
p alue=1.099×10
−87
). These eplica ion e o s demons a e
ha many o he published esul s o exome sequencing can be
eplica ed h ough he use o 1 kG impu a ions.
In conclusion, we iden ified and eplica ed fi e a ian s asso-
cia ed wi h ci cula ing lipid le els. These a ian s a e in genes
ha can be linked biologically o lipid me abolism. Al hough
he e we e a la ge numbe o a ian s ha did no eplica e a
he accep ed genome-wide significance h eshold, he low-cos ,
hypo hesis- ee app oach ha we applied unco e ed fi e a -
ian s. This s udy, he e o e, illus a es ha GWAS may s ill help
us un a el he biological mechanisms behind ci cula ing lipid
le els.
Au ho a filia ions
1
Depa men o Epidemiology, E asmus Medical Cen e , Ro e dam, The Ne he lands
2
Human Genome Sequencing Cen e , Baylo College o Medicine, Hous on, USA
3
Depa men o Medicine, Uni e si y o Washing on, Sea le, USA
4
Medical Resea ch Council Human Gene ics Uni , Ins i u e o Gene ics and Molecula
Medicine, Uni e si y o Edinbu gh, Edinbu gh, UK
5
The F amingham Hea S udy, NHLBI Ca dio ascula Epidemiology and Human
Genomics B anch, F amingham, USA
6
Cen e o Public Heal h Genomics, Uni e si y o Vi ginia, Cha lo es ille, USA
7
Icelandic Hea Associa ion, Kopa ogu , Iceland
8
Facul y o Medicine, Uni e si y o Iceland, Reykja ik, Iceland
9
Depa men o Gene ics, Washing on Uni e si y School o Medicine, S Louis, USA
10
Depa men o Bios a is ics, Bos on Uni e si y School o Public Heal h, Bos on,
USA
11
Ushe Ins i u e o Popula ion Heal h Sciences and In o ma ics, Uni e si y o
Edinbu gh, Edinbu gh, UK
12
Depa men o Gene ics, Uni e si y o No h Ca olina, Chapel Hill, USA
13
Depa men o Human Gene ics, Leiden Uni e si y Medical Cen e , Leiden, The
Ne he lands
14
Human Genomics Uni , Ins i u e o Molecula Medicine, Uni e si y o Helsinki,
Helsinki, Finland
15
Depa men o Epidemiology, Uni e si y o G oningen, Uni e si y Medical Cen e
G oningen, G oningen, The Ne he lands
16
Depa men o Epidemiology and Bios a is ics, School o Public Heal h, Impe ial
College London, London, UK
17
Depa men o Ca diology, Ealing Hospi al NHS T us , Middlesex, UK
18
Depa men o Biological Psychology, VU Uni e si y Ams e dam and EMGO+
Ins i u e o Heal h and Ca e Resea ch, Ams e dam, The Ne he lands
19
Depa men o Clinical Epidemiology, Leiden Uni e si y Medical Cen e , Leiden,
The Ne he lands
20
Depa men o Ca diology, Leiden Uni e si y Medical Cen e , Leiden, The
Ne he lands
21
Depa men o Ge on ology and Ge ia ics, Leiden Uni e si y Medical Cen e ,
Leiden, The Ne he lands
22
Depa men o Ca diology, Uni e si y Medical Cen e G oningen, Uni e si y o
G oningen, G oningen, The Ne he lands
23
Depa men o Hygiene and Epidemiology, Uni e si y o Ioannina Medical School,
Ioannina, G eece
24
Depa men o Clinical Chemis y, Fimlab Labo a o ies, Tampe e, Finland
25
Depa men o Clinical Chemis y, Uni e si y o Tampe e School o Medicine,
Tampe e, Finland
26
Public Heal h Sciences, Loyola Uni e si y Chicago S i ch School o Medicine,
Maywood, USA
27
Depa men o Molecula Epidemiology, Leiden Uni e si y Medical Cen e , Leiden,
The Ne he lands
28
Labo a o y o Expe imen al Ca diology, Uni e si y Medical Cen e U ech , U ech ,
The Ne he lands
29
McKusick-Na hans Ins i u e o Gene ic Medicine, Johns Hopkins Uni e si y School
o Medicine, Bal imo e, USA
30
Human Gene ics Cen e , The Uni e si y o Texas School o Public Heal h, Hous on,
USA
31
Depa men o In e nal Medicine, E asmus Medical Cen e , Ro e dam, The
Ne he lands
32
Gene a ion Sco land, Cen e o Genomic and Expe imen al Medicine,
Ins i u e o Gene ics and Molecula Medicine, Uni e si y o Edinbu gh, Edinbu gh,
UK
33
Musculoskele al Resea ch P og amme, Di ision o Applied Medicine, Uni e si y o
Abe deen, Abe deen, UK
34
B i ish Hea Founda ion Glasgow Ca dio ascula Resea ch Cen e, Ins i u e o
Ca dio ascula and Medical Sciences, College o Medical, Ve e ina y and Li e
Sciences, Uni e si y o Glasgow, Glasgow, UK
35
Depa men o Bios a is ics, Uni e si y o Washing on, Sea le, USA
36
B igham and Women’s Hospi al, Bos on, USA
37
Labo a o y o Epidemiology and Popula ion Sciences, Na ional Ins i u e on Aging,
Na ional Ins i u es o Heal h, Be hesda, USA
38
Cen e o Popula ion Heal h Sciences, Uni e si y o Edinbu gh, Edinbu gh, UK
39
Facul y o Medicine, Uni e si y o Spli , Spli , C oa ia
40
Depa men o Heal h, Na ional Ins i u e o Heal h and Wel a e, Helsinki, Finland
41
Ca dio ascula Science, Na ional Hea and Lung Ins i u e, Impe ial College
London, London, UK
42
Impe ial College Heal hca e NHS T us, Impe ial College London, London, UK
43
Depa men o Psychia y, VU Uni e si y Medical Cen e Ams e dam/GGZinGees
and EMGO+ Ins i u e o Heal h and Ca e Resea ch and Neu oscience Campus
Ams e dam, Ams e dam, The Ne he lands
44
Robe son Cen e o Bios a is ics, Uni e si y o Glasgow, Glasgow, UK
45
Depa men o Neph ology, Uni e si y o G oningen, Uni e si y Medical Cen e
G oningen, G oningen, The Ne he lands
46
Depa men o Clinical Physiology, Tu ku Uni e si y Hospi al, Tu ku, Finland
47
Resea ch Cen e o Applied and P e en i e Ca dio ascula Medicine, Uni e si y o
Tu ku, Tu ku, Finland
48
Di ision o Medicine, Tu ku Uni e si y Hospi al, Tu ku, Finland
49
Depa men o Medicine, Uni e si y o Tu ku, Tu ku, Finland
50
Depa men o Ca diology, Hea Hospi al, Tampe e Uni e si y Hospi al, Tampe e,
Finland
51
School o Medicine, Uni e si y o Tampe e, Tampe e, Finland
52
T opical Me abolism Resea ch Uni , T opical Medicine Resea ch Ins i u e, Uni e si y
o he Wes Indies, Mona, Jamaica
53
Labo a o y o Clinical Chemis y and Hema ology, Uni e si y Medical Cen e
U ech , U ech , The Ne he lands
54
Depa men o Psychia y, Uni e si y o G oningen, Uni e si y Medical Cen e
G oningen, G oningen, The Ne he lands
55
Depa men o Clinical Physiology, Tampe e Uni e si y Hospi al, Tampe e, Finland
56
Depa men o Clinical Physiology, Uni e si y o Tampe e School o Medicine,
Tampe e, Finland
57
Depa men o Epidemiology and Bios a is ics, MRC-PHE Cen e o En i onmen
and Heal h, School o Public Heal h, Impe ial College London, London, UK
58
Depa men o Gene ics, Uni e si y o G oningen, Uni e si y Medical Cen e
G oningen, G oningen, The Ne he lands
59
Depa men o Public Heal h and P ima y Ca e, Leiden Uni e si y Medical Cen e ,
Leiden, The Ne he lands
60
Epidemiology Sec ion, Depa men o BESC, King Faisal Medical Hospi al and
Resea ch Cen e, Riyadh, Saudi A abia
61
Genomics Coo dina ion Cen e , Uni e si y o G oningen, Uni e si y Medical Cen e
G oningen, G oningen, The Ne he lands
62
Public Heal h, Uni e si y o Helsinki, Helsinki, Finland
63
Wellcome T us Sange Ins i u e, UK
446 an Leeuwen EM, e al.J Med Gene 2016;53:441–449. doi:10.1136/jmedgene -2015-103439
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64
Depa men o Gene al In e nal Medicine, Leiden Uni e si y Medical Cen e ,
Leiden, The Ne he lands
65
Physiology and Biophysics, Uni e si y o Mississippi Medical Cen e , Jackson, USA
66
Depa men o Epidemiology, Uni e si y o Washing on, Sea le, USA
67
Depa men o Heal h Se ices, Uni e si y o Washing on, Sea le, USA
68
G oup Heal h Coope a i e, G oup Heal h Resea ch Ins i u e, Sea le, USA
69
Ins i u e o T ansla ional Genomics and Popula ion Sciences, Los Angeles
BioMedical Resea ch Ins i u e a Ha bo -UCLA Medical Cen e , To ance, USA
70
Di ision o Genomic Ou comes, Depa men o Pedia ics, Ha bo -UCLA Medical
Cen e , To ance, USA
71
Depa men s o Pedia ics, Medicine, and Human Gene ics, UCLA, Los Angeles,
USA
Acknowledgemen s The au ho s especially hank all olun ee s who pa icipa ed
in he s udy.
The au ho s hank he s a and pa icipan s o he ARIC s udy o hei impo an
con ibu ions. In as uc u e was pa ly suppo ed by G an Numbe UL1RR025005,
a componen o he Na ional Ins i u es o Heal h and NIH Roadmap o Medical
Resea ch.
We a e g a e ul o all s udy pa icipan s and hei ela i es, gene al p ac i ione s
and neu ologis s o hei con ibu ions o he ERF s udy and o P Ve aa o he
help in genealogy, J Ve gee o he supe ision o he labo a o y wo k and P
Snijde s o his help in da a collec ion.
The au ho s hank Beh ooz Alizadeh, Annemieke Boesjes, Ma cel B uinenbe g,
Noo je Fes en, Pim an de Ha s , Ilja Nol e, Lude F anke, Mi a Valimohammadi o
hei help in c ea ing he GWAS da abase, and Rob Bie inga, Joos Kee s, René
Oos e go, Rosalie Visse , Judi h Vonk o hei wo k ela ed o da a collec ion and
alida ion. The au ho s a e g a e ul o he s udy pa icipan s, he s a om he
Li eLines Coho S udy and he con ibu ing esea ch cen es deli e ing da a o
Li eLines and he pa icipa ing gene al p ac i ione s and pha macis s.
MESA and he MESA SHARe p ojec a e conduc ed and suppo ed by con ac s
N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163,
N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168,
N01-HC-95169, UL1-TR-001079 and UL1-TR-000040 om he Na ional Hea ,
Lung, and Blood Ins i u e (NHLBI). Funding o MESA SHARe geno yping was
p o ided by NHLBI Con ac N02-HL6-4278. The p o ision o geno yping da a was
suppo ed in pa by he Na ional Cen e o Ad ancing T ansla ional Sciences, CTSI
g an UL1TR000124, and he Na ional Ins i u e o Diabe es and Diges i e and
Kidney Disease Diabe es Resea ch Cen e (DRC) g an DK063491 o he Sou he n
Cali o nia Diabe es Endoc inology Resea ch Cen e . This publica ion was de eloped
unde a STAR esea ch assis ance ag eemen , No. RD831697 (MESA Ai ), awa ded
by he U.S En i onmen al p o ec ion Agency. I has no been o mally e iewed by
he EPA. The iews exp essed in his documen a e solely hose o he au ho s and
he EPA does no endo se any p oduc s o comme cial se ices men ioned in his
publica ion.
The au ho s o he NEO s udy hank all indi iduals who pa icipa ed in he
Ne he lands Epidemiology in Obesi y s udy, all pa icipa ing gene al p ac i ione s o
in i ing eligible pa icipan s and all esea ch nu ses o collec ion o he da a. The
au ho s hank he NEO s udy g oup, Pe a Noo dijk, Pa an Beelen and Ingebo g de
Jonge o he coo dina ion, lab and da a managemen o he NEO s udy. The
geno yping in he NEO s udy was pe o med a he Cen e Na ional de Géno ypage
(Pa is, F ance), headed by Jean-F ancois Deleuze.
The au ho s o he ORCADES s udy would like o acknowledge he in aluable
con ibu ions o Lo aine Ande son and he esea ch nu ses in O kney, he
adminis a i e eam in Edinbu gh and he people o O kney.
On behal o he Ro e dam S udy, he au ho s hank Pascal A p, Mila Jhamai,
Ma ijn Ve ke k, Lizbe h He e a and Ma jolein Pe e s o hei help in c ea ing he
GWAS da abase, and Ka ol Es ada and Maksim V. S uchalin o hei suppo in
c ea ion and analysis o impu ed da a. The au ho s a e g a e ul o he s udy
pa icipan s, he s a om he Ro e dam S udy and he pa icipa ing gene al
p ac i ione s and pha macis s.
Collabo a o s The Li eLines Coho S udy: see online supplemen a y appendix
1. CHARGE Lipids Wo king G oup: see online supplemen a y appendix 2.
Con ibu o s EM L o ganised he s udy and designed he s udy wi h subs an ial
inpu o AI, LAC and CM D. EM L d a ed he manusc ip wi h subs an ial inpu
om CM D. All au ho s had he oppo uni y o commen on he manusc ip . Da a
collec ion, GWAS and s a is ical analysis was done by SW dL, HMdR, GP (AEGS);
AVS, VG, TBH (AGES); EE, MPS, PE (Ai wa e); AS, DEA, ACM, EB (ARIC); JCB, JAB,
KMC, BMP (CHS); AI, EM L, CM D (ERF); MFF, IBB (FamHS); LPL, KN, MK
(FINCAVAS); IS, VS, SR (FINRISK); SD, CCW, LAC (FHS); JEH, AC, LJH, SP (GS); QD,
LAL, JGW (JHS); JEH, IK, PN, OP (CROATIA Ko cula); IMN, MS (Li elines); JD,
AJMdC, PES (LLS); WZ, JSK, BL, WRS, STT, JCC (LOLIPOP); BOT, TF, CAM, RSC
(Loyola); AM, JCM, SSR, JIR (MESA); RLG, RdM, DOMK (NEO); HM, EJdG, YM,
BWJHP, GW, DIB (NTR-NESDA); PKJ, HC, JFW (ORCADES); NV, RTG, P dH
(PREVEND); ST, IF, JWJ (PROSPER); EM L, AD, OHF, AH, FR, EJS, AGU, CM D (RS);
JEH, TZ, VV (CROATIA Spli ); PJ dM, AJO, HS (TRAILS); JEH, JM, CH, IR (CROATIA
Vis); JSV, OTR, TL (YFS). EM L pe o med he me a-analysis and all ollow-up s eps.
Biological associa ion o loci and bioin o ma ics we e ca ied ou by EM L, JB K,
KW D and CM D.
Funding The AGES S udy has been unded by NIH con ac s N01-AG-1-2100 and
HHSN271201200022C, he NIA In amu al Resea ch P og am, Hja a e nd ( he
Icelandic Hea Associa ion), and he Al hingi ( he Icelandic Pa liamen ).
The Ai wa e S udy is unded by he Home O fice (g an numbe 780-TETRA) wi h
addi ional suppo om he Na ional Ins i u e o Heal h Resea ch (NIHR) Impe ial
College Heal hca e NHS T us (ICHNT) and Impe ial College Biomedical Resea ch
Cen e (BRC). PE is an NIHR Senio In es iga o and is suppo ed by he ICHNT and
Impe ial College BRC, he MRC-PHE Cen e o En i onmen and Heal h and he
NIHR Heal h P o ec ion Resea ch Uni on Heal h Impac o En i onmen al Haza ds.
The ARIC S udy is ca ied ou as a collabo a i e s udy suppo ed by Na ional
Hea , Lung, and Blood Ins i u e (NHLBI) con ac s (HHSN268201100005C,
HHSN268201100006C, HHSN268201100007C, HHSN268201100008C,
HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and
HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; Na ional
Human Genome Resea ch Ins i u e con ac U01HG004402; and Na ional Ins i u es
o Heal h con ac HHSN268200625226C.
Ca dio ascula Heal h S udy: This CHS esea ch was suppo ed by NHLBI con ac s
HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079,
N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and
NHLBI g an s U01HL080295, R01HL087652, R01HL105756, R01HL103612, and
R01HL120393 wi h addi ional con ibu ion om he Na ional Ins i u e o
Neu ological Diso de s and S oke (NINDS). Addi ional suppo was p o ided h ough
R01AG023629 om he Na ional Ins i u e on Aging (NIA). A ull lis o p incipal
CHS in es iga o s and ins i u ions can be ound a CHS-NHLBI.o g. The p o ision o
geno yping da a was suppo ed in pa by he Na ional Cen e o Ad ancing
T ansla ional Sciences, CTSI g an UL1TR000124, and he Na ional Ins i u e o
Diabe es and Diges i e and Kidney Disease Diabe es Resea ch Cen e (DRC) g an
DK063491 o he Sou he n Cali o nia Diabe es Endoc inology Resea ch Cen e . The
con en is solely he esponsibili y o he au ho s and does no necessa ily ep esen
he o ficial iews o he Na ional Ins i u es o Heal h.
CROATIA-Ko cula, CROATIA-Spli and CROATIA-Vis (CR-Ko cula, CR-Spli , CR-Vis)
we e unded by he Medical Resea ch Council UK, The C oa ian Minis y o Science,
Educa ion and Spo s (g an 216-1080315-0302), he Eu opean Union amewo k
p og am 6 EUROSPAN p ojec (con ac no. LSHG-CT-2006-018947) and he
C oa ian Science Founda ion (g an 8875).
The ERF s udy as a pa o EUROSPAN (Eu opean Special Popula ions Resea ch
Ne wo k) was suppo ed by Eu opean Commission FP6 STRP g an numbe 018947
(LSHG-CT-2006-01947) and also ecei ed unding om he Eu opean Communi y’s
Se en h F amewo k P og amme (FP7/2007-2013)/g an ag eemen
HEALTH-F4-2007-201413 by he Eu opean Commission unde he p og amme
“Quali y o Li e and Managemen o he Li ing Resou ces”o 5 h F amewo k
P og amme (no. QLG2-CT-2002-01254). The ERF s udy was u he suppo ed by
ENGAGE conso ium and CMSB. High- h oughpu analysis o he ERF da a was
suppo ed by join g an om Ne he lands O ganisa ion o Scien ific Resea ch and
he Russian Founda ion o Basic Resea ch (NWO-RFBR 047.017.043). Exome
sequencing in ERF was suppo ed by he ZonMw g an (p ojec 91111025).
The Family Hea S udy was suppo ed by he by g an s R01-HL-087700,
R01-HL-088215 and R01-HL-117078 om he Na ional Hea , Lung, and Blood
Ins i u e.
Gene a ion Sco land ecei ed co e unding om he Chie Scien is O fice o he
Sco ish Go e nmen Heal h Di ec o a e CZD/16/6 and he Sco ish Funding Council
HR03006. Geno yping o he GS:SFHS samples was ca ied ou by he Gene ics Co e
Labo a o y a he Wellcome T us Clinical Resea ch Facili y, Edinbu gh, Sco land and
was unded by he UK’s Medical Resea ch Council.
The Li eLines Coho S udy, and gene a ion and managemen o GWAS geno ype
da a o he Li eLines Coho S udy is suppo ed by he Ne he lands O ganiza ion o
Scien ific Resea ch NWO (g an 175.010.2007.006), he Economic S uc u e
Enhancing Fund (FES) o he Du ch go e nmen , he Minis y o Economic A ai s,
he Minis y o Educa ion, Cul u e and Science, he Minis y o Heal h, Wel a e and
Spo s, he No he n Ne he lands Collabo a ion o P o inces (SNN), he P o ince o
G oningen, Uni e si y Medical Cen e G oningen, he Uni e si y o G oningen, Du ch
Kidney Founda ion and Du ch Diabe es Resea ch Founda ion.
The Leiden Longe i y S udy (LLS) has ecei ed unding om he Eu opean Union’s
Se en h F amewo k P og amme (FP7/2007–2011) unde g an ag eemen no
259679. This s udy was suppo ed by a g an om he Inno a ion-O ien ed Resea ch
P og am on Genomics (Sen e No em IGE05007), he Cen e o Medical Sys ems
Biology, and he Ne he lands Conso ium o Heal hy Ageing (g an 050-060-810),
all in he amewo k o he Ne he lands Genomics Ini ia i e, Ne he lands
O ganiza ion o Scien ific Resea ch (NWO), Unile e Colwo h and by BBMRI-NL, a
Resea ch In as uc u e financed by he Du ch go e nmen (NWO 184.021.007).
The LOLIPOP s udy is suppo ed by he Na ional Ins i u e o Heal h Resea ch
(NIHR) Comp ehensi e Biomedical Resea ch Cen e Impe ial College Heal hca e NHS
T us , he B i ish Hea Founda ion (SP/04/002), he Medical Resea ch Council
(G0601966,G0700931), he Wellcome T us (084723/Z/08/Z) he NIHR
an Leeuwen EM, e al.J Med Gene 2016;53:441–449. doi:10.1136/jmedgene -2015-103439 447
Genome-wide s udies
g oup.bmj.com on No embe 11, 2016 - Published by h p://jmg.bmj.com/Downloaded om
(RP-PG-0407-10371),Eu opean Union FP7 (EpiMig an , 279143) and Ac ion on
Hea ing Loss (G51). The wo k was ca ied ou in pa a he NIHR/Wellcome T us
Impe ial Clinical Resea ch Facili y.
The NEO s udy is suppo ed by he pa icipa ing Depa men s, he Di ision and
he Boa d o Di ec o s o he Leiden Uni e si y Medical Cen e , and by he Leiden
Uni e si y, Resea ch P ofile A ea ‘Vascula and Regene a i e Medicine’. Dennis
Mook-Kanamo i is suppo ed by Du ch Science O ganiza ion (ZonMW-VENI G an
916.14.023).
ORCADES was suppo ed by he Chie Scien is O fice o he Sco ish
Go e nmen , he Royal Socie y, he MRC Human Gene ics Uni , A h i is Resea ch
UK and he Eu opean Union amewo k p og am 6 EUROSPAN p ojec (con ac no.
LSHG-CT-2006-018947). DNA ex ac ions we e pe o med a he Wellcome T us
Clinical Resea ch Facili y in Edinbu gh.
The PROSPER s udy was suppo ed by an in es iga o ini ia ed g an ob ained
om B is ol-Mye s Squibb. JWJ is an Es ablished Clinical In es iga o o he
Ne he lands Hea Founda ion (g an 2001 D 032). Suppo o geno yping was
p o ided by he se en h amewo k p og am o he Eu opean commission (g an
223004) and by he Ne he lands Genomics Ini ia i e (Ne he lands Conso ium o
Heal hy Aging g an 050-060-810).
The gene a ion and managemen o GWAS geno ype da a o he Ro e dam
S udy is suppo ed by he Ne he lands O ganisa ion o Scien ific Resea ch NWO
In es men s (n . 175.010.2005.011, 911-03-012). This s udy is unded by he
Resea ch Ins i u e o Diseases in he Elde ly (014-93-015; RIDE2), he Ne he lands
Genomics Ini ia i e (NGI)/Ne he lands O ganisa ion o Scien ific Resea ch (NWO)
p ojec n . 050-060-810. The Ro e dam S udy is unded by E asmus Medical Cen e
and E asmus Uni e si y, Ro e dam, Ne he lands O ganiza ion o he Heal h
Resea ch and De elopmen (ZonMw), he Resea ch Ins i u e o Diseases in he
Elde ly (RIDE), he Minis y o Educa ion, Cul u e and Science, he Minis y o
Heal h, Wel a e and Spo s, he Eu opean Commission (DG XII), and he Municipali y
o Ro e dam.
Pa icipa ing cen es o TRAILS include he Uni e si y Medical Cen e and
Uni e si y o G oningen, he E asmus Uni e si y Medical Cen e Ro e dam, he
Uni e si y o U ech , he Radboud Medical Cen e Nijmegen, and he Pa nassia
Ba o g oup, all in he Ne he lands. TRAILS has been financially suppo ed by a ious
g an s om he Ne he lands O ganiza ion o Scien ific Resea ch NWO (Medical
Resea ch Council p og am g an GB-MW 940-38-011; ZonMW B ainpowe g an
100-001-004; ZonMw Risk Beha io and Dependence g an s 60-60600-97-118;
ZonMw Cul u e and Heal h g an 261-98-710; Social Sciences Council medium-sized
in es men g an s GB-MaGW 480-01-006 and GB-MaGW 480-07-001; Social
Sciences Council p ojec g an s GB-MaGW 452-04-314 and GB-MaGW 452-06-004;
NWO la ge-sized in es men g an 175.010.2003.005; NWO Longi udinal Su ey
and Panel Funding 481-08-013 and 481-11-001), he Du ch Minis y o Jus ice
(WODC), he Eu opean Science Founda ion (Eu oSTRESS p ojec FP-006), Biobanking
and Biomolecula Resou ces Resea ch In as uc u e BBMRI-NL (CP 32), and he
pa icipa ing uni e si ies.
Compe ing in e es s BMP se es on he DSMB o a clinical ial o a de ice
unded by he manu ac u e (Zoll Li eCo ) and on he S ee ing Commi ee o he
Yale Open Da a Access P ojec unded by Johnson & Johnson. OHF wo ks in
E asmusAGE, a cen e o aging esea ch ac oss he li e cou se unded by Nes lé
Nu i ion (Nes ec); Me agenics; and AXA. Nes lé Nu i ion (Nes ec); Me agenics; and
AXA had no ole in design and conduc o he s udy; collec ion, managemen ,
analysis, and in e p e a ion o he da a; and p epa a ion, e iew o app o al o he
manusc ip .
Pa ien consen Ob ained.
E hics app o al All s udies we e pe o med wi h he app o al o he Local
Medical E hics Commi ees.
P o enance and pee e iew No commissioned; ex e nally pee e iewed.
Da a sha ing s a emen All me a-analysis esul s and he esul s o he ollow-up
analysis o his p ojec a e a ailable.
Open Access This is an Open Access a icle dis ibu ed in acco dance wi h he
C ea i e Commons A ibu ion Non Comme cial (CC BY-NC 4.0) license, which
pe mi s o he s o dis ibu e, emix, adap , build upon his wo k non-comme cially,
and license hei de i a i e wo ks on di e en e ms, p o ided he o iginal wo k is
p ope ly ci ed and he use is non-comme cial. See: h p://c ea i ecommons.o g/
licenses/by-nc/4.0/
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