ORIGINAL RESEARCH
Me a-analysis o Genome-Wide Associa ion S udies
o Ex a e sion: Findings om he Gene ics o Pe sonali y
Conso ium
S e
´phanie M. an den Be g
1
•Ma leen H. M. de Moo
2,3,4
•Ka in J. H. Ve weij
5,6
•
Robe F. K uege
7
•Michelle Luciano
8,9
•Alejand o A ias Vasquez
10,11,12,13
•
Lindsay K. Ma eson
7
•Jaime De inge
14
•To
˜nu Esko
15
•Naja Amin
16
•
Sco D. Go don
5
•Na elle K. Hansell
5
•Amy B. Ha
17
•Ilkka Seppa
¨la
¨
18
•
Jenni e E. Hu man
19
•Be ina Kon e
20
•Ja i Lah i
21,22
•Minyoung Lee
23
•
Mike Mille
7
•Te esa Nu ile
24
•Toshiko Tanaka
25
•Alexande Teume
26
•
Alexande Vik o in
27
•Juho Wedenoja
28
•Abdel Abdellaoui
2
•Goncalo R. Abecasis
29
•
Daniel E. Adkins
30
•A pana Ag awal
31
•Ju
¨ i Allik
32,33
•Ka ja Appel
34
•
Timo hy B. Bigdeli
23
•Fabio Busone o
35
•Ha y Campbell
36
•Paul T. Cos a
37
•
Geo ge Da ey Smi h
38
•Gail Da ies
8,9
•Ha ie de Wi
39
•Jun Ding
67
•
Ba ba a E. Engelha d
40
•Johan G. E iksson
22,41,42,43,44
•I yna O. Fedko
2
•
Luigi Fe ucci
25
•Ba ba a F anke
10,11,12
•Ina Giegling
20
•Richa d G ucza
31
•
Anne e M. Ha mann
20
•And ew C. Hea h
31
•Ka i Heinonen
21
•Anjali K. Hende s
5
•
Geo g Homu h
45
•Jouke-Jan Ho enga
2
•William G. Iacono
7
•Joos Janzing
11
•
Ma kus Jokela
21
•Robe Ka lsson
27
•John P. Kemp
38,46
•Ma hew G. Ki kpa ick
39
•
An i La ala
41,28
•Te ho Leh ima
¨ki
18
•Da id C. Liewald
8,9
•Pamela A. F. Madden
31
•
Chia a Mag i
47
•Pa ik K. E. Magnusson
27
•Jona han Ma en
19
•And ea Maschio
35
•
Hamdi Mba ek
2
•Sa ah E. Medland
5
•E elin Mihailo
15,48
•Yu i Milaneschi
49
•
Edi ed by S acey Che ny.
S e
´phanie M. an den Be g and Ma leen H. M. de Moo sha ed i s
au ho ship.
Elec onic supplemen a y ma e ial The online e sion o his
a icle (doi:10.1007/s10519-015-9735-5) con ains supplemen a y
ma e ial, which is a ailable o au ho ized use s.
&S e
´phanie M. an den Be g
[email p o ec ed]
1
Depa men o Resea ch Me hodology, Measu emen and
Da a-Analysis (OMD), Facul y o Beha iou al, Managemen ,
and Social Sciences, Uni e si y o Twen e, PO Box 217,
7500 AE Enschede, The Ne he lands
2
Depa men o Biological Psychology, VU Uni e si y
Ams e dam, Ams e dam, The Ne he lands
3
Depa men o Clinical Child and Family S udies, VU
Uni e si y Ams e dam, Ams e dam, The Ne he lands
4
Depa men o Me hods, VU Uni e si y Ams e dam,
Ams e dam, The Ne he lands
5
QIMR Be gho e Medical Resea ch Ins i u e, B isbane,
Aus alia
6
Depa men o De elopmen al Psychology and EMGO
Ins i u e o Heal h and Ca e Resea ch, VU Uni e si y
Ams e dam, Ams e dam, The Ne he lands
7
Depa men o Psychology, Uni e si y o Minneso a,
Minneapolis, USA
8
Depa men o Psychology, Uni e si y o Edinbu gh,
Edinbu gh, UK
9
Cen e o Cogni i e Ageing and Cogni i e Epidemiology,
Uni e si y o Edinbu gh, Edinbu gh, UK
10
Donde s Ins i u e o Cogni i e Neu oscience, Radboud
Uni e si y Nijmegen, Nijmegen, The Ne he lands
11
Depa men o Psychia y, Radboud Uni e si y Nijmegen
Medical Cen e , Nijmegen, The Ne he lands
12
Depa men o Human Gene ics, Radboud Uni e si y
Nijmegen Medical Cen e , Nijmegen, The Ne he lands
13
Depa men o Cogni i e Neu oscience, Radboud Uni e si y
Nijmegen Medical Cen e , Nijmegen, The Ne he lands
14
Depa men o Psychology, Uni e si y o Illinois a U bana-
Champaign, Champaign, IL, USA
15
Es onian Genome Cen e , Uni e si y o Ta u, Ta u, Es onia
123
Beha Gene (2016) 46:170–182
DOI 10.1007/s10519-015-9735-5
G an W. Mon gome y
5
•Ma hias Nauck
50
•Michel G. Ni a d
2
•Klaasjan G. Ouwens
2
•
Aa no Palo ie
51,52
•E ik Pe e sson
27
•Oz en Polasek
53
•Yong Qian
67
•
Lau a Pulkki-Ra
˚back
21
•Olli T. Rai aka i
54,55
•Anu Realo
32
•Richa d J. Rose
56
•
Daniela Ruggie o
24
•Ca s en O. Schmid
26
•Wendy S. Slu ske
57
•Rossella So ice
24
•
John M. S a
9,58
•Bea e S Pou cain
38,59,60
•Angelina R. Su in
25,61
•
Nicholas J. Timpson
38
•Holly T oche
19
•Si a Ve meulen
12,62
•Ee o Vuoksimaa
28
•
Elisabe h Widen
52
•Jaspe Wouda
1,2
•Ma ga e J. W igh
5
•Lina Zgaga
36,63
•
Gene a ion Sco land
64
•Da id Po eous
65
•Alessand a Minelli
47
•
Ab aham A. Palme
17,39
•Dan Rujescu
20
•Ma ina Ciullo
24
•Ca oline Haywa d
19
•
Igo Rudan
36
•And es Me spalu
15,33
•Jaakko Kap io
41,28,52
•Ian J. Dea y
8,9
•
Ka i Ra
¨ikko
¨nen
21
•James F. Wilson
19,36
•Liisa Kel ikangas-Ja
¨ inen
21
•
Lau a J. Bie u
31
•John M. He ema
23
•Hans J. G abe
34,66
•B enda W. J. H. Penninx
49
•
Co nelia M. an Duijn
16
•Da id M. E ans
38
•Da id Schlessinge
67
•
Nancy L. Pede sen
27
•An onio Te acciano
22,25
•Ma McGue
7,68
•
Nicholas G. Ma in
5
•Do e I. Boomsma
2
Recei ed: 30 Oc obe 2014 / Accep ed: 10 Augus 2015 / Published online: 11 Sep embe 2015
ÓThe Au ho (s) 2015. This a icle is published wi h open access a Sp inge link.com
Abs ac Ex a e sion is a ela i ely s able and he i able
pe sonali y ai associa ed wi h nume ous psychosocial,
li es yle and heal h ou comes. Despi e i s subs an ial he i-
abili y, no gene ic a ian s ha e been de ec ed in p e ious
genome-wide associa ion (GWA) s udies, which may be
due o ela i ely small sample sizes o hose s udies. He e,
we epo on a la ge me a-analysis o GWA s udies o
ex a e sion in 63,030 subjec s in 29 coho s. Ex a e sion
i em da a om mul iple pe sonali y in en o ies we e ha -
monized ac oss in en o ies and coho s. No genome-wide
signi ican associa ions we e ound a he single nucleo ide
polymo phism (SNP) le el bu he e was one signi ican hi
a he gene le el o a long non-coding RNA si e
(LOC101928162). Genome-wide complex ai analysis in
wo la ge coho s showed ha he addi i e a iance
explained by common SNPs was no signi ican ly di e en
16
Depa men o Epidemiology, E asmus Uni e si y Medical
Cen e , Ro e dam, The Ne he lands
17
Depa men o Human Gene ics, Uni e si y o Chicago,
Chicago, IL, USA
18
Depa men o Clinical Chemis y, Fimlab Labo a o ies and
School o Medicine, Uni e si y o Tampe e, Tampe e,
Finland
19
MRC Human Gene ics Uni , MRC IGMM, Wes e n Gene al
Hospi al, Uni e si y o Edinbu gh, Edinbu gh, UK
20
Depa men o Psychia y, Uni e si y o Halle, Halle,
Ge many
21
Ins i u e o Beha iou al Sciences, Uni e si y o Helsinki,
Helsinki, Finland
22
Folkha
¨lsan Resea ch Cen e , Helsinki, Finland
23
Depa men o Psychia y, Vi ginia Ins i u e o Psychia ic
and Beha io al Gene ics, Vi ginia Commonweal h
Uni e si y, Richmond, VA, USA
24
Ins i u e o Gene ics and Biophysics ‘‘A. Buzza i-T a e so’’ –
CNR, Naples, I aly
25
Na ional Ins i u e on Aging, NIH, Bal imo e, MD, USA
26
Ins i u e o Communi y Medicine, Uni e si y Medicine
G ei swald, G ei swald, Ge many
27
Depa men o Medical Epidemiology and Bios a is ics,
Ka olinska Ins i u e , S ockholm, Sweden
28
Depa men o Public Heal h, Uni e si y o Helsinki,
Helsinki, Finland
29
Depa men o Bios a is ics, Cen e o S a is ical Gene ics,
Uni e si y o Michigan School o Public Heal h, Ann A bo ,
MI, USA
30
Pha maco he apy & Ou comes Science, Vi ginia
Commonweal h Uni e si y, Richmond, VA, USA
31
Depa men o Psychia y, Washing on Uni e si y School o
Medicine, S . Louis, MO, USA
32
Depa men o Psychology, Uni e si y o Ta u, Ta u,
Es onia
33
Es onian Academy o Sciences, Tallinn, Es onia
34
Depa men o Psychia y and Psycho he apy, Uni e si y
Medicine G ei swald, G ei swald, Ge many
35
Is i u o di Rice ca Gene ica e Biomedica (IRGB), CNR,
Monse a o, I aly
36
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
37
Beha io al Medicine Resea ch Cen e , Duke Uni e si y
School o Medicine, Du ham, NC, USA
38
Medical Resea ch Council In eg a i e Epidemiology Uni ,
School o Social and Communi y Medicine, Uni e si y o
B is ol, B is ol, UK
Beha Gene (2016) 46:170–182 171
123
om ze o, bu polygenic isk sco es, weigh ed using link-
age in o ma ion, signi ican ly p edic ed ex a e sion sco es
in an independen coho . These esul s show ha
ex a e sion is a highly polygenic pe sonali y ai , wi h an
a chi ec u e possibly di e en om o he complex human
ai s, including o he pe sonali y ai s. Fu u e s udies a e
equi ed o u he de e mine which gene ic a ian s, by
wha modes o gene ac ion, cons i u e he he i able na u e
o ex a e sion.
Keywo ds Pe sonali y Pheno ype ha moniza ion 
Common gene ic a ian s Impu a ion Polygenic isk
In oduc ion
Ex a e sion is a pe sonali y ai cha ac e ized by he
endency o expe ience posi i e emo ions, o be ac i e and
eel ene ge ic, o be alka i e and o enjoy social in e ac-
ions. Ex a e sion is associa ed wi h nume ous psy-
chosocial, li es yle and heal h ou comes, such as academic
and job pe o mance, well-being, obesi y, subs ance use,
physical ac i i y, bipola diso de , bo de line pe sonali y
diso de , Alzheime ’s disease, and longe i y (De Moo
e al. 2006,2011; Dis el e al. 2009a; Fu nham e al. 2013;
Judge e al. 2013; Middeldo p e al. 2011; Rhodes and
Smi h 2006; Su in e al. 2011; Te acciano e al. 2008;
Te acciano e al. 2014; Weiss e al. 2008).
Ex a e sion can be measu ed wi h mul iple in en o ies
ha ha e been de eloped as pa o di e en pe sonali y
heo ies. Fo example, ex a e sion is one o he i e pe -
sonali y domains as assessed wi h he Neu o icism–Ex-
a e sion–Openness o Expe ience (NEO) pe sonali y
in en o ies (Cos a and McC ae 1992). Ex a e sion is also
included in Eysenck’s h ee-dimensional heo y o pe -
sonali y (Eysenck and Eysenck 1964,1975; Eysenck e al.
1985). In Cloninge ’s heo y on empe amen s and cha -
ac e s (Cloninge 1987; Cloninge e al. 1993), Ha m
A oidance, No el y Seeking and Rewa d Dependence a e
ela ed o ex a e sion (De F uy e al. 2000). Tellegen’s
pe sonali y heo y posi s he highe o de domain o Posi-
i e Emo ionali y (Pa ick e al. 2002), which esembles
and is highly co ela ed wi h ex a e sion (Chu ch 1994).
We showed ecen ly, by pe o ming an I em Response
Theo y (IRT) analysis using es linking (Kolen and
B ennan 2004), ha i em da a on Ex a e sion, Rewa d
dependence and Posi i e Emo ionali y can be ha monized
o b oadly assess he same unde lying ex a e sion con-
s uc ( an den Be g e al. 2014). This ha moniza ion was
pe o med in o e 160,000 indi iduals om 23 coho s
pa icipa ing in he Gene ics o Pe sonali y Conso ium
(GPC). B ie ly, ha moniza ion was ca ied ou in each
coho sepa a ely by i s i ing an IRT model o da a om
39
Depa men o Psychia y and Beha io al Neu oscience,
Uni e si y o Chicago, Chicago, USA
40
Depa men o Bios a is ics and Bioin o ma ics, Duke
Uni e si y, Du ham, NC, USA
41
Na ional Ins i u e o Heal h and Wel a e (THL), Helsinki,
Finland
42
Depa men o Gene al P ac ice and P ima y Heal h Ca e,
Uni e si y o Helsinki, Helsinki, Finland
43
Uni o Gene al P ac ice and P ima y Heal h Ca e, Uni e si y
o Helsinki, Helsinki, Finland
44
Vasa Cen al Hospi al, Vaasa, Finland
45
In e acul y Ins i u e o Gene ics and Func ional Genomics,
Uni e si y o G ei swald, G ei swald, Ge many
46
T ansla ional Resea ch Ins i u e, Uni e si y o Queensland
Diaman ina Ins i u e, B isbane, Aus alia
47
Depa men o Molecula and T ansla ional Medicine,
Uni e si y o B escia, B escia, I aly
48
Depa men o Bio echnology, Uni e si y o Ta u, Ta u,
Es onia
49
Depa men o Psychia y, EMGO?Ins i u e, Neu oscience
Campus Ams e dam, VU Uni e si y Medical Cen e ,
Ams e dam, The Ne he lands
50
Ins i u e o Clinical Chemis y and Labo a o y Medicine,
Uni e si y Medicine G ei swald, G ei swald, Ge many
51
Wellcome T us Sange Ins i u e, Wellcome T us Genome
Campus, Hinx on, Camb idge, UK
52
Ins i u e o Molecula Medicine Finland (FIMM), Uni e si y
o Helsinki, Helsinki, Finland
53
Depa men o Public Heal h, Facul y o Medicine,
Uni e si y o Spli , Spli , C oa ia
54
Depa men o Clinical Physiology and Nuclea Medicine,
Tu ku Uni e si y Hospi al, Tu ku, Finland
55
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
56
Depa men o Psychological & B ain Sciences, Indiana
Uni e si y, Blooming on, IN, USA
57
Depa men o Psychological Sciences and Missou i
Alcoholism Resea ch Cen e , Uni e si y o Missou i,
Columbia, MO, USA
58
Alzheime Sco land Demen ia Resea ch Cen e, Uni e si y o
Edinbu gh, Edinbu gh, UK
59
School o O al and Den al Sciences, Uni e si y o B is ol,
B is ol, UK
60
School o Expe imen al Psychology, Uni e si y o B is ol,
B is ol, UK
61
College o Medicine, Flo ida S a e Uni e si y, Tallahassee,
FL, USA
172 Beha Gene (2016) 46:170–182
123
indi iduals who had comple ed a leas wo di e en pe -
sonali y ques ionnai es. Nex , based on calib a ed i em
pa ame e s, pe sonali y sco es we e es ima ed based on all
a ailable da a o each indi idual, i espec i e o wha
pe sonali y ques ionnai e was used. The ha monized
ex a e sion pheno ype was he i able. A b oad-sense he i-
abili y o 49 % was es ima ed, based on a me a-analysis in
six win coho s ha a e included in he GPC (29,501 win
pai s), o which 24 % was due o addi i e gene ic a iance
and 25 % due o non-addi i e gene ic a iance. The b oad-
sense he i abili y es ima e is simila o he i abili y es i-
ma es ob ained o ex a e sion as assessed wi h single
measu emen ins umen s (Boucha d and Loehlin 2001;
Dis el e al. 2009b; Finkel and McGue 1997; Kelle e al.
2005; Re ew e al. 2008; Yamaga a e al. 2006). Some
e idence o quali a i e sex di e ences in he gene ic
in luences on ex a e sion was sugges ed by a gene ic
co ela ion in opposi e-sex win pai s o 0.38 ( an den Be g
e al. 2014). Ex a e sion becomes mo e gene ically s able
du ing adolescence un il i is almos pe ec ly gene ically
s able in adul hood (B iley and Tucke -D ob 2014; Kandle
2012), ha is, he same genes a e esponsible o
ex a e sion measu ed a di e en ages.
A hand ul o genome-wide associa ion (GWA) s udies o
ex a e sion ha e been published, aimed a de ec ing
speci ic single nucleo ide polymo phisms (SNPs) ha
explain pa o he he i abili y. The i s GWA s udy o
pe sonali y, which ocused on he i e NEO pe sonali y
ai s, was conduc ed in 3972 adul s (Te acciano e al.
2010). No genome-wide signi ican SNP associa ions we e
ound o ex a e sion, al hough some in e es ing associa-
ions wi h P- alues 10
-5
we e seen wi h SNPs in wo
cadhe in genes and he b ain-de i ed neu o ophic ac o
(BDNF) gene. A subsequen me a-analysis o GWA esul s
o he NEO pe sonali y ai s, conduc ed in 17,375 subjec s,
also did no yield any genome-wide signi ican associa ions
o ex a e sion (De Moo e al. 2012). Two o he GWA
s udies epo ed a simila lack o genome-wide signi icance
o Cloninge ’s empe amen scales (Se ice e al. 2012;
Ve weij e al. 2010). In e es ingly, a s udy ha pe o med a
gene ic complex ai analysis (GCTA; Yang e al. 2010) o
neu o icism and ex a e sion in a ound 12,000 un ela ed
indi iduals epo ed ha 12 % (SE =3 %) o he a iance
in ex a e sion was explained by common SNPs o addi i e
e ec (Vinkhuyzen e al. 2012). Taken oge he , he esul s
om win and genome-wide s udies sugges ha common
SNPs o addi i e e ec a e impo an , ha gene ic non-ad-
di i i y may play a ole, and ha la ge sample sizes a e likely
o be equi ed o iden i y speci ic a ian s.
In his pape , we epo he esul s o he la ges me a-
analysis o GWA esul s o ex a e sion so a , ca ied ou
in 29 coho s ha pa icipa e in he GPC. A o al o 63,030
subjec s wi h ha monized ex a e sion and genome-wide
geno ype da a we e included in he me a-analysis. A 30 h
coho was used o eplica ion. In his conso ium we
epo ed ea lie on a genome-wide signi ican hi o neu-
o icism (De Moo e al. 2015), indica ing ha we may
begin o analyze da a om su icien ly la ge samples, o
ob ain he i s signi ican indings om GWA s udies o
pe sonali y. In addi ion o me a-analysis o GWA esul s,
we compu ed weigh ed polygenic sco es in an independen
coho and associa ed hem wi h ex a e sion, and es i-
ma ed a iance explained by SNPs in wo la ge coho s.
Ma e ials and me hods
Coho s
The ull me a-analysis was pe o med on 63,030 subjec s
om 29 disco e y coho s. All samples we e o Eu opean
o igin. Twen y-one coho s we e om Eu ope, six om he
Uni ed S a es and wo om Aus alia. Sample sizes o he
indi idual coho s anged om 177 o 7210 subjec s. Please
no e ha some coho s we e also pa o p e iously published
GWA s udies on ex a e sion. The Gene a ion Sco land:
Sco ish Family Heal h S udy (GS:SFHS) coho was
included as a eplica ion sample (9,783 subjec s). A b ie
o e iew o all coho s is p o ided in Table 1. A desc ip ion
o each indi idual coho is ound in he Supplemen a y
ma e ials and me hods (see also De Moo e al. 2015).
Pheno yping
A ha monized la en ex a e sion sco e was es ima ed o
all pa icipan s in all 29 coho s ha we e included in he
GWA me a-analysis. This sco e was based on all a ailable
ex a e sion i em da a o each indi idual ( o a de ailed
62
Depa men o Heal h E idence, Radboud Uni e si y
Medical Cen e , Nijmegen, The Ne he lands
63
Depa men o Public Heal h and P ima y Ca e, T ini y
College Dublin, Dublin, I eland
64
Sco ish Family Heal h S udy, A Collabo a ion Be ween he
Uni e si y Medical Schools and NHS,
Abe deen, Dundee, Edinbu gh and Glasgow, UK
65
Medical Gene ics Sec ion, Cen e o Genomics and
Expe imen al Medicine, Ins i u e o Gene ics and Molecula
Medicine, Wes e n Gene al Hospi al, The Uni e si y o
Edinbu gh, Edinbu gh, UK
66
Depa men o Psychia y and Psycho he apy, HELIOS
Hospi al S alsund, S alsund, Ge many
67
Labo a o y o Gene ics, Na ional Ins i u e on Aging, Na ional
Ins i u es o Heal h, Bal imo e, MD, USA
68
Ins i u e o Public Heal h, Uni e si y o Sou he n Denma k,
Odense, Denma k
Beha Gene (2016) 46:170–182 173
123
desc ip ion see an den Be g e al. 2014). Ex a e sion
i em da a came om he ex a e sion scales o he NEO
Pe sonali y In en o y, he NEO Fi e Fac o In en o y, he
50-i em Big-Fi e e sion o he In e na ional Pe sonali y
I em Pool in en o y, he Eysenck Pe sonali y Ques ion-
nai e and he Eysenck Pe sonali y In en o y, om he
Rewa d Dependence scale o he Cloninge ’s T idimen-
sional Pe sonali y Ques ionnai e, and om he Posi i e
Emo ionali y scale o he Mul idimensional Pe sonali y
Ques ionnai e (see an den Be g e al. 2014 and Supple-
men a y ma e ials and me hods). In he GS:SFHS coho
ha was included o eplica ion o op signals, ex a e -
sion was based on he summed sco e o he ex a e sion
scale o he EPQ Re ised Sho Fo m.
Geno yping and impu a ion
Geno yping in all coho s was ca ied ou on Illumina o
A yme ix pla o ms, a e which quali y con ol (QC) was
pe o med, ollowed by impu a ion o geno ypes. QC o
geno ype da a was pe o med in each coho sepa a ely,
wi h compa able bu coho speci ic c i e ia. S anda d QC
checks included es s o Eu opean ances y, sex inconsis-
encies, Mendelian e o s, and high genome-wide
homozygosi y. Checks o ela edness we e conduc ed in
hose coho s ha aimed o include un ela ed indi iduals
only. O he checks o geno ype da a we e based on mino
allele equencies (MAF), SNP call a e (% o subjec s wi h
missing geno ypes pe SNP), sample call a e (% o miss-
ing SNPs pe subjec ) and Ha dy–Weinbe g Equilib ium
(HWE). Geno ype da a we e impu ed using he 1000Gen-
omes phase 1 e sion 3 (build37, hg19) e e ence panel
wi h s anda d so wa e packages such as IMPUTE, MACH,
o Minimac, see Supplemen a y Table 1.
S a is ical analyses
GWA analysis pe coho
GWA analyses we e conduc ed independen ly in each
coho . Since he coho s used di e en esea ch designs
(case–con ol, popula ion win s udies, ex ended pedig ees,
e c.), GWA me hods we e op imized o each coho .
Ex a e sion sco es we e eg essed on each SNP unde an
addi i e model, wi h sex and age included as co a ia es.
Co a ia es such as ances y P incipal Componen s (PCs)
we e added i deemed necessa y o a pa icula coho . In
all analyses, he unce ain y o he impu ed geno ypes was
aken in o accoun , ei he using dosage sco es o mix u es
o dis ibu ions. In hose coho s ha included ela ed
indi iduals, he dependency among pa icipan s was
accoun ed o using coho -speci ic me hods. S anda d
so wa e packages o GWA analyses we e used (see
Supplemen a y Table 1).
Me a-analysis o GWA esul s ac oss coho s
A me a-analysis o he GWA esul s was conduc ed
wi h he weigh ed in e se a iance me hod in METAL
(h p://www.sph.umich.edu/csg/abecasis/me al/index.h ml).
Excluded om me a-analysis we e poo ly impu ed SNPs
(
2
0.30 o p ope _in o 0.40) and SNPs wi h low
Table 1 O e iew o 29 disco e y coho s and 1 eplica ion coho
o he Gene ics o Pe sonali y Conso ium
Coho # Subjec s
a
# SNPs
b
1 ALSPAC 4705 6,454,153
2 BLSA 820 4,989,411
3 BRESCIA 177 3,549,919
4 CHICAGO 311 3,755,416
5 CILENTO 627 1,123,089
6 COGA 647 5,127,101
7 COGEND 1279 5,932,838
8 EGCUT 1184 5,574,695
9 ERF 2300 5,142,865
10 FTC EPI 567 4,870,096
11 FTC NEO 813 5,092,018
12 HBCS 1456 5,612,790
13 CROATIA-Ko cula 808 5,094,034
14 LBC1921 437 4,363,611
15 LBC1936 952 5,168,754
16 MCTFR 7099 6,569,999
17 MGS 2101 5,900,898
18 NBS 1832 5,603,447
19 NESDA 2227 4,707,569
20 NTR 6416 5,339,798
21 ORCADES 1650 4,265,590
22 PAGES 476 4,547,293
23 QIMR adolescen s 2842 5,957,064
24 QIMR adul s 7210 6,343,920
25 Sa diNIA 4332 6,291,135
26 SHIP 2213 5,913,428
27 STR 4903 6,519,094
28 CROATIA-Vis 909 5,327,671
29 YFS 1737 5,914,679
To al 63,030 7,460,147
30 GS:SFHS 9783 74
NA No Applicable o eplica ion coho because only op hi s we e
sough o eplica e
a
Numbe o subjec s wi h alid la en sco e o Ex a e sion and
SNP da a (a e impu a ion and cleaning)
b
Numbe o SNPs (a e impu a ion and cleaning) wi h alid asso-
cia ion esul s ha en e ed he me a-analysis
174 Beha Gene (2016) 46:170–182
123

MAF (MAF H(5/N), which co esponds o less han 5
es ima ed indi iduals in he leas equen geno ype g oup,
unde he assump ion o HWE). This esul ed in a o al
numbe o 7,460,147 unique SNPs in he inal me a-anal-
ysis (wi h 1.1–6.6 M SNPs ac oss coho s). Fo 2182 SNPs,
SNP loca ions could no be ma ched wi h s names. Fo an
addi ional 516,362 SNPS, esul s we e based on one coho
only and he e o e le ou o he analysis, so ha he esul s
a e based on 6,941,603 SNPs. Genomic con ol in la ion
ac o s (lambda), Manha an plo s and quan ile–quan ile
plo s pe coho a e p o ided in Supplemen a y Table 2
and Supplemen a y Figs. 1, 2. A P alue o 5 910
-8
was
used as he h eshold o genome-wide signi icance.
The me a-analysis esul s (P- alues pe SNP) we e used
as he inpu o compu e P- alues a he gene le el. We
pe o med hese analyses in KGG (Li e al. 2012). A P-
alue o 2.87 910
-6
was used as he h eshold o gen-
ome-wide signi icance in hese gene-wide analyses, based
on con olling o he alse-disco e y a e (Benjamini and
Hochbe g 1995).
All GWAS SNP op hi s wi h a P- alue smalle han
1910
-5
we e selec ed o eplica ion in he GS:SFHS
coho .
Polygenic isk sco e analysis
Addi ional analyses we e conduc ed o es whe he
ex a e sion could be p edic ed in an independen a ge
coho based on he GWA me a-analysis esul s. The a ge
coho was he Ne he lands Twin Regis e (NTR) coho
(8648 subjec s). Polygenic isk sco es o his coho we e
es ima ed using LDp ed (Vilhjalmsson e al. 2015) ha
akes in o accoun linkage disequilib ium among he SNPs.
The es ima ion was based on a GWA me a-analysis in
which he NTR and NESDA coho s we e excluded ( u -
he e e ed o as he disco e y se ). Wi h he LD-co -
ec ed polygenic isk sco es, gene alized es ima ing
equa ion (GEE) modeling was applied o es whe he he
polygenic isk sco es p edic ed ex a e sion in he a ge
coho . The co a ia es age, sex and en PCs we e included
as ixed e ec s in he model. The model also included a
andom in e cep wi h amily numbe as he clus e a i-
able, o accoun o dependency among amily membe s.
Ou lie s on he PCs, including e hnic ou lie s, we e
excluded om he analysis.
Va iance explained by SNPs
In he NTR coho and he QIMR Be gho e Medical
Resea ch Ins i u e (QIMR) adul coho (see also Supple-
men a y ma e ials and me hods), GCTA so wa e (Vissche
e al. 2010; Yang e al. 2010) was used o es ima e he
p opo ion o a iance in ex a e sion ha can be explained
by common SNPs o addi i e e ec . In he NTR, his
analysis was ca ied ou in a se o 3597 un ela ed indi-
iduals and in he QIMR adul coho his was done in 3369
un ela ed indi iduals (in each coho one membe pe
amily was selec ed wi h ha monized ex a e sion and
genome-wide SNP da a). GCTA analysis was based on bes
guess geno ypes ob ained in PLINK using a h eshold o a
maximum geno ype p obabili y [0.70, and addi ionally
il e ing on -squa ed [0.80. Nex , in es ima ing he GRM
ma ix in he GCTA so wa e, SNPs wi h MAF 0.05 we e
excluded. The addi i e gene ic ela ionship ma ices
(GRM) es ima ed based on SNPs o all indi iduals o med
he basis o es ima e he p opo ion o pheno ypic a iance
explained by SNPs in he NTR and QIMR coho s. In o he
wo ds, i was de e mined o wha ex en pheno ypic simi-
la i y be ween indi iduals co esponds o gene ic simila i y
(a he SNP le el). Fo bo h NTR and QIMR, sex, age and a
se o popula ion-speci ic PCs we e included as co a ia es.
Resul s
Me a-analysis o GWA esul s
Me a-analysis o GWA esul s ac oss he 29 disco e y
coho s did no yield genome-wide signi ican SNPs asso-
cia ed wi h ex a e sion. The lowes P- alue obse ed was
2.9 910
-7
o a SNP loca ed on ch omosome 2. The e
we e 74 SNPs wi h P- alues 1910
-5
. The Manha an
and quan ile–quan ile plo s a e p o ided in Figs. 1and 2.A
lis wi h he op i e SNPs is gi en in Table 2. A lis wi h
all SNPs ha eached he le el o sugges i e genome-wide
signi icance (P 1910
-5
) is ound in Supplemen a y
Table 3. The esul s o all SNPs can be downloaded om
www. weelingen egis e .o g/GPC. A gene-based es
showed one signi ican hi o LOC101928162, a long non-
coding RNA si e, P=2.87 910
-6
. A lis wi h he op i e
genes om he gene-based analysis is p o ided in Table 3.
Supplemen a y Table 4 p o ides he op 30 genes. Among
he op 30 genes was B ain-De i ed Neu o ophic Fac o
(BDNF,P=0.0003), a gene also implica ed, hough no
genome-wide signi ican , in Te acciano e al. (2010), as
was he BDNF an i-sense RNA gene (P=0.0001).
Resul s o he ollow-up analysis o he op i e SNPs in
he GS:SFHS coho can be ound in Table 2. O he op
i e SNPs, none showed a signi ican e ec . Fo an o e -
iew o he eplica ion esul s o all op SNPs wi h P- alue
1910
-5
see Supplemen a y Table 3. O he 74 SNPs
es ed in he eplica ion coho , h ee SNPs showed nomi-
nal e idence o associa ion (P 0.05), which is less han
he numbe expec ed based on chance alone
(0.05 974 =3.7).
Beha Gene (2016) 46:170–182 175
123
Polygenic isk sco e analysis
The e we e 8201 pe sons indi iduals wi h polygenic sco es
o p edic ion o ex a e sion. The LDp ed-based gene ic
isk sco es signi ican ly p edic ed ex a e sion in he a ge
coho , B=0.059, X
2
(1) =27.30, P 0.001.
Va iance explained by SNPs
In he NTR coho , an es ima ed 5.0 % (SE =7.2) o he
a iance in ex a e sion was explained by all SNPs, bu
his es ima e was no signi ican ly di e en om ze o
(P=0.24). In he QIMR coho , 0.0001 % (SE =15) o
he a iance was explained by SNPs (P=0.46).
Discussion
This s udy assessed he in luence o common gene ic
a ian s on ex a e sion in 63,030 indi iduals om 29
coho s in he GPC. Fi s , a me a-analysis o GWA anal-
yses ac oss 29 disco e y coho s showed no genome-wide
signi ican SNPs. Top SNPs de ec ed in he me a-analysis
o GWA esul s in he disco e y phase we e no eplica ed
in he GS:SFHS coho . The SNPs wi h lowes P- alues
ha e no p e iously epo ed ela ionship wi h pe sonali y,
psychopa hology o b ain unc ioning. Polygenic isk
sco es based on he me a-analysis esul s p edic ed
ex a e sion in an independen da a se . SNP-based
Fig. 1 Manha an plo o me a-analysis esul s o 29 disco e y coho s o ex a e sion in he Gene ics o Pe sonali y Conso ium
Fig. 2 Quan ile-Quan ile plo s o me a-analysis esul s o 29
disco e y coho s o ex a e sion in he Gene ics o Pe sonali y
Conso ium
Table 2 Top SNPs om he me a-analysis o GWA esul s in 29 disco e y coho s o ex a e sion, and hei eplica ion in he GS:SFHS
coho , in he Gene ics o Pe sonali y Conso ium
SNP Ch _BP Alleles Closes gene Disco e y esul s Replica ion esul s
E ec SE P- alue E ec SE P- alue
s2024488 2_217662968 A/G LOC101928250 -0.0303 0.0059 2.939 x 10
-7
0.0285 0.0164 0.08244
s2712162 2_217661788 T/C LOC101928250 -0.0300 0.0059 3.872 x 10
-7
0.0278 0.0164 0.08947
s797182 12_10900487 A/G NA[-0.0277 0.0056 6.673 x 10
-7
-0.0135 0.0153 0.37721
s8010306 14_37150160 A/G SLC25A21 0.0629 0.0128 8.730 x 10
-7
0.0180 0.0314 0.56650
s117292860 19_2227621 A/C DOT1L 0.0553 0.0113 9.191 x 10
-7
-0.0350 0.0239 0.14368
176 Beha Gene (2016) 46:170–182
123
he i abili ies o ex a e sion we e no signi ican ly di -
e en om ze o in wo la ge coho s o he GPC.
Al hough he e we e no genome-wide signi ican esul s
o indi idual SNPs, in he gene-based analysis, he e was
a signi ican hi o one locus, LOC101928162. This is
long noncoding RNA si e whose unc ion emains elusi e.
In e es ingly, among he op 30 genes we e genes p e i-
ously implica ed in ex a e sion o in psychia ic diso de s
associa ed wi h ex a e sion. The low P- alue o
CRTAC1 (P=2.97 x 10
-5
), ha ks back o an in e es ing
ex a e sion SNP ( s7088779) in a p e ious GWAS on
pe sonali y (Amin e al. 2013) ha is loca ed
be ween CRTAC1 and C10o 28.RELN (P=5.69 x 10
-5
)
has been epo ed o inc ease he isk o schizoph enia and
bipola diso de (Kuang e al. 2011; O adia and Shi man
2011), while ADAM12 (7.65 x 10
-5
) was p e iously ound
o be in ol ed in schizoph enia (Fa kas e al. 2010),
and bipola diso de ea men (Nad i e al.
2007). The BDNF gene was also implica ed in a p e ious
ex a e sion GWAS (Te acciano e al. 2010), hough no
genome-wide signi ican . Liu e al. (2005) epo ed a end
owa ds associa ion o BDNF a ian s wi h subs ance
abuse, Jiao e al. (2011) epo ed an associa ion wi h obe-
si y, and Lang e al. (2007) and Beu en e al. (2005) e-
po ed associa ions wi h smoking beha io . As
ex a e sion is known o be associa ed wi h li es yle,
obesi y and subs ance abuse, we deem BDNF o be an
in e es ing candida e gene o ex a e sion in u u e s ud-
ies, along wi h CRTAC,ADAM12 and RELN.
Wi h he cu en me a-analysis we mo e han ipled he
sample size as compa ed o he la ges p e iously published
me a-analysis o ex a e sion (De Moo e al. 2012). In
con as o neu o icism, no genome-wide signi ican SNPs
we e ound. Some ha e a gued (Tu kheime e al. 2014) ha
he he i abili y o pe sonali y ai s ep esen s nonspeci ic
gene ic backg ound, which is composed o so many gene ic
a ian s wi h ex emely small e ec sizes ha indi idually
hese ha e no causal biological in e p e a ion. I may be ha
ex a e sion di e s in his espec om neu o icism. One
o he di e ence was indica ed om he analyses o he IRT-
based ex a e sion and neu o icism sco es: whe eas o
neu o icism no e idence o geno ype x sex in e ac ion was
seen ( an den Be g e al. 2014), o ex a e sion he e was
signi ican e idence o sex limi a ion. I also is in e es ing o
no e ha despi e he ac ha o ex a e sion no genome-
wide signi ican indings eme ged o single SNPs, we we e
able o p edic ex a e sion in an independen da ase , based
on he polygenic isk coho s om he disco e y se . This
indica es ha some ue signal is en ailed in he me a-anal-
ysis esul s.
The esul s o he polygenic isk sco e analysis a e in
con as wi h he esul s om he GCTA analysis, in which
no signi ican p opo ion o a iance explained by SNPs
was de ec ed in wo la ge coho s o he GPC. Ou s udy on
neu o icism epo ed a SNP-based he i abili y o 15 % (De
Moo e al. 2015). The cu en ex a e sion GCTA indings
a e also somewha a odds wi h wo p e ious GCTA s udies
o pe sonali y ai s. One s udy ocused on neu o icism
and ex a e sion as measu ed wi h di e en ins umen s in
ou coho s, and ound on a e age 12 % explained a i-
ance o ex a e sion, al hough ac oss coho s hese es i-
ma es a ied widely (0–27 %) (Vinkhuyzen e al. 2012).
Es ima es o neu o icism also a ied, bu we e gene ally
lowe han o ex a e sion in his s udy, wi h an a e age o
6 % explained a iance. In ano he s udy, be ween 4.2 and
9.9 % o explained a iances we e ound o he ou
Cloninge empe amen s in a combined sample o ou
coho s (Ve weij e al. 2012). The p opo ions o a iances
o Ha m A oidance, No el y Seeking and Pe sis ence
we e signi ican a P 0.05, whe eas in e es ingly he
p opo ion o a iance o Rewa d Dependence was no . I
should be no ed ha bo h hese s udies included he QIMR
coho in hei analyses, so he e is some o e lap in sub-
jec s ac oss s udies. The di e ence is ha in he ea lie
s udies ex a e sion and ewa d dependence we e based on
single pe sonali y in en o ies, while in ou s udy
ex a e sion sco es ha monized among di e en pe sonal-
i y in en o ies we e analyzed. Wha ou esul s and he
esul s in he p e ious s udies ha e in common hough, is
ha he es ima es a e conside ably smalle han he he i-
abili y es ima es based on win s udies. Gi en ha abou
hal o he he i abili y o ex a e sion consis s o non-ad-
di i e gene ic a iance ( an den Be g e al. 2014), i is no
unlikely ha his disc epancy is caused by he in luence o
Table 3 Top genes om he me a-analysis o GWA esul s in 29 disco e y coho s o Ex a e sion in he Gene ics o Pe sonali y Conso ium
Gene Full gene name Pa hways P- alue
LOC101928162 [Long non-coding RNA] Unknown 0.00000287
LOC729506 [Long non-coding RNA] Unknown 0.00000893
PLEKHJ1 Plecks in Homology Domain Con aining, Family J
Membe 1
Phospholipid binding, ci cadian clock
unc ioning
0.0000132
POU2F3 POU Class 2 Homeobox 3 In luenza A 0.0000179
CRTAC1 Ca ilage Acidic P o ein 1 Unknown 0.0000297
Beha Gene (2016) 46:170–182 177
123
common a ian s ha in e ac wi hin loci (dominance) o
ac oss loci (epis asis). In addi ion, he in luence o a e
a ian s may be implica ed. The ela i ely limi ed in lu-
ence o common addi i e gene ic a ia ion, as well as a
p e iously epo ed inding ha highe le els o inb eeding
a e associa ed wi h less socially desi able pe sonali y ai
le els, has led o he idea ha he gene ic a ia ion in
pe sonali y ai s may ha e been main ained by mu a ion–
selec ion balance (Ve weij e al. 2012), and ou esul s a e
consis en wi h his idea.
This s udy comes wi h some limi a ions. Geno yping,
QC, and impu a ion we e ca ied ou sepa a ely in each
coho . Any di e ence in p ocedu es may ha e caused
some loss o s a is ical powe o de ec SNPs in he me a-
analysis. Simila ly, ex a e sion i em da a we e ha mo-
nized as much as possible ( an den Be g e al. 2014), bu
he Rewa d Dependence i em da a om he TCI we e leas
success ully linked o he ex a e sion da a om he o he
in en o ies. This may also ha e caused some loss in powe .
Impo an ly howe e , i should be no ed ha by combining
geno ype and pheno ype da a ac oss coho s as pe o med
in his s udy, a subs an ial inc ease in sample size was
ob ained. I is non i ial ha he gain in powe associa ed
wi h his inc ease in sample size la gely ou weighs any
po en ial loss in powe due o any emaining geno yping o
pheno yping di e ences ac oss coho s.
In conclusion, ex a e sion is a he i able, highly poly-
genic pe sonali y ai wi h a gene ic backg ound ha may
be quali a i ely di e en om ha o o he complex
beha io al ai s. Fu u e s udies a e equi ed o inc ease ou
knowledge o which ypes o gene ic a ian s, by which
modes o gene ac ion, cons i u e he he i able na u e o
ex a e sion. Ul ima ely, his knowledge can be used o
inc ease ou unde s anding o how ex a e sion is ela ed
o a ious impo an psychosocial and heal h ou comes.
Acknowledgmen s We would like o hank all pa icipa ing sub-
jec s. Analyses we e ca ied ou on he Gene ic Clus e Compu e
(h p://www.gene icclus e .o g), which is inancially suppo ed by he
Ne he lands O ganiza ion o Scien i ic Resea ch (NWO 480-05-003).
ALSPAC We a e ex emely g a e ul o all he amilies who ook
pa in his s udy, he midwi es o hei help in ec ui ing hem and
he whole ALSPAC eam, which includes in e iewe s, compu e and
labo a o y echnicians, cle ical wo ke s, esea ch scien is s, olun-
ee s, manage s, ecep ionis s and nu ses. The UK Medical Resea ch
Council (G an 74882), he Wellcome T us (G an 076467) and he
Uni e si y o B is ol p o ide co e suppo o ALSPAC. We hank
23andMe o unding he geno yping o he ALSPAC child en’s
sample. This publica ion is he wo k o he au ho s, and hey will
se e as gua an o s o he con en s o his pape .
BLSA We acknowledge suppo om he In amu al Resea ch
P og am o he NIH, Na ional Ins i u e on Aging. We hank Robe
McC ae.
BRESCIA We acknowledge suppo om he I alian Minis y o
Heal h (RC and RF2007 Con . 42) and Regione Lomba dia (ID:
17387 SAL-13). We hank Ila ia Gandin o impu a ion analysis
suppo .
CHICAGO This wo k was suppo ed by NIH G an s, DA007255
(ABH), HG006265 ( o BEE), DA02812 ( o HdW), and DA021336
and DA024845 ( o AAP). BEE was also unded h ough he Bioin-
o ma ics Resea ch De elopmen Fund, suppo ed by Ka h yn and
Geo ge Gould. We wish o hank And ew D. Skol o p o iding
ad ice abou geno ype calling.
CILENTO We acknowledge D Ma ia Enza Amendola o he es
adminis a ion and hank he pe sonnel wo king in he o ganiza ion o
he s udy in he illages. MC ecei ed unding suppo om he
I alian Minis y o Uni e si ies (FIRB - RBNE08NKH7, INTERO-
MICS Flaghip P ojec ), he Assesso a o Rice ca Regione Campania,
he Fondazione con il SUD (2011-PDR-13), and he Fondazione
Banco di Napoli.
SAGE –COGA/CONGEND Funding suppo o he S udy o
Addic ion: Gene ics and En i onmen (SAGE) was p o ided h ough
he NIH Genes, En i onmen and Heal h Ini ia i e [GEI] (U01
HG004422). SAGE is one o he genome-wide associa ion s udies
unded as pa o he Gene En i onmen Associa ion S udies (GEN-
EVA) unde GEI. Assis ance wi h pheno ype ha moniza ion and
geno ype cleaning, as well as wi h gene al s udy coo dina ion, was
p o ided by he GENEVA Coo dina ing Cen e (U01 HG004446).
Assis ance wi h da a cleaning was p o ided by he Na ional Cen e
o Bio echnology In o ma ion. Suppo o collec ion o da ase s and
samples was p o ided by he Collabo a i e S udy on he Gene ics o
Alcoholism (COGA; U10 AA008401) and he Collabo a i e Gene ic
S udy o Nico ine Dependence (COGEND; P01 CA089392). Funding
suppo o geno yping, which was pe o med a he Johns Hopkins
Uni e si y Cen e o Inhe i ed Disease Resea ch, was p o ided by
he NIH GEI (U01HG004438), he Na ional Ins i u e on Alcohol
Abuse and Alcoholism, he Na ional Ins i u e on D ug Abuse, and he
NIH con ac ‘‘High h oughpu geno yping o s udying he gene ic
con ibu ions o human disease’’(HHSN268200782096C). The Col-
labo a i e S udy on he Gene ics o Alcoholism (COGA), P incipal
In es iga o s B. Po jesz, V. Hesselb ock, H. Edenbe g, L. Bie u ,
includes en di e en cen e s: Uni e si y o Connec icu (V. Hessel-
b ock); Indiana Uni e si y (H.J. Edenbe g, J. Nu nbe ge J ., T.
Fo oud); Uni e si y o Iowa (S. Kupe man, J. K ame ); SUNY
Downs a e (B. Po jesz); Washing on Uni e si y in S . Louis (L.
Bie u , A. Goa e, J. Rice, K. Bucholz); Uni e si y o Cali o nia a San
Diego (M. Schucki ); Ru ge s Uni e si y (J. Tisch ield); Texas
Biomedical Resea ch Ins i u e (L. Almasy), Howa d Uni e si y (R.
Taylo ) and Vi ginia Commonweal h Uni e si y (D. Dick). O he
COGA collabo a o s include: L. Baue (Uni e si y o Connec icu );
D. Kolle , S. O’Conno , L. We he ill, X. Xuei (Indiana Uni e si y);
G ace Chan (Uni e si y o Iowa); S. Kang, N. Manz, M. Rangaswamy
(SUNY Downs a e); J. Roh baugh, J-C Wang (Washing on Uni e si y
in S . Louis); A. B ooks (Ru ge s Uni e si y); and F. Alie (Vi ginia
Commonweal h Uni e si y). A. Pa sian and M. Reilly a e he NIAAA
S a Collabo a o s. This na ional collabo a i e s udy is suppo ed by
NIH G an U10AA008401 om he Na ional Ins i u e on Alcohol
Abuse and Alcoholism (NIAAA) and he Na ional Ins i u e on D ug
Abuse (NIDA). The Collabo a i e Gene ic S udy o Nico ine
Dependence (COGEND) p ojec is a collabo a i e esea ch g oup and
pa o he NIDA Gene ics Conso ium. Subjec collec ion was sup-
po ed by NIH G an P01 CA089392 (L.J. Bie u ) om he Na ional
Cance Ins i u e. Pheno ypic and geno ypic da a a e s o ed in he
NIDA Cen e o Gene ic S udies (NCGS) a h p://zo k.wus l.edu/
unde NIDA Con ac HHSN271200477451C (J. Tisch ield and J.
Rice). Jaime De inge was suppo ed by NIH T32 MH016880.
EGCUT AM and TE ecei ed suppo om FP7 G an s (201413
ENGAGE, 212111 BBMRI, ECOGENE (No. 205419, EBC)) and
OpenGENE. AM and TE also ecei ed a ge ed inancing om
Es onian Go e nmen SF0180142s08 and by EU ia he Eu opean
Regional De elopmen Fund, in he ame o Cen e o Excellence in
Genomics. The geno yping o he Es onian Genome P ojec samples
we e pe o med in Es onian Biocen e Geno yping Co e Facili y, AM
178 Beha Gene (2016) 46:170–182
123