Regula o y a ian o he TPH2 gene and ea ly li e
s ess a e associa ed wi h heigh ened a en ion o
social signals o ea in in an s
Linda Fo ssman,
1
Mikko J. Pel ola,
2,3,4
San e i Y iaho,
1
Kaija Puu a,
5
Nina Mononen,
6
Te ho Leh im€
aki,
6
and Jukka M. Lepp€
anen
1
1
School o Medicine, Uni e si y o Tampe e, Tampe e, Finland;
2
School o Social Sciences and Humani ies, Uni e si y
o Tampe e, Tampe e, Finland;
3
Cen e o Child and Family S udies, Leiden Uni e si y, Leiden, Ne he lands;
4
Leiden
Ins i u e o B ain and Cogni ion, Leiden Uni e si y, Leiden, Ne he lands;
5
Depa men o Child Psychia y, Tampe e
Uni e si y Hospi al, Tampe e, Finland;
6
Depa men o Clinical Chemis y, Fimlab Labo a o ies and School o
Medicine, Uni e si y o Tampe e and Tampe e Uni e si y Hospi al, Tampe e, Finland
Backg ound: C oss-species e idence sugges s ha gene ic and expe ien ial ac o s ac ea ly in de elopmen o
es ablish indi idual emo ional ai s, bu li le is known abou he mechanisms ha eme ge du ing his pe iod o
media e long- e m ou comes. He e, we es ed he hypo hesis ha known gene ic and en i onmen al isk condi ions
may heigh en in an s’ na u al endency o a end o h ea -ale ing s imuli, esul ing in a cogni i e bias ha may
con ibu e o emo ional ulne abili y. Me hods: Da a om wo samples o 5–7-mon h-old in an s (N=139) we e
used o examine whe he es ablished candida e a ia ions in he se o onin-sys em genes, i.e., TPH2 SNP s4570625
(-703 G/T) and HTR1A SNP s6295 (-1019 G/C), and ea ly ea ing condi ion (ma e nal s ess and dep essi e
symp oms) a e associa ed wi h al e a ions in in an s’ a en ion o acial exp essions. In an s we e es ed wi h a
pa adigm ha assesses he abili y o disengage a en ion om a cen ally p esen ed s imulus (a non ace con ol
s imulus o a neu al, happy, o ea ul acial exp ession) owa d he loca ion o a new s imulus in he isual
pe iphe y (a geome ic shape). Resul s: TPH2 -703 T-ca ie geno ype (i.e., TT homozygo es and he e ozygo es),
p esence o ma e nal s ess and dep essi e symp oms, and a combina ion o he T-ca ie geno ype and ma e nal
dep essi e symp oms we e associa ed wi h a ela i ely g ea e di icul y disengaging a en ion om ea ul acial
exp essions. No associa ions we e ound wi h in an s’ empe amen al ai s. Conclusions: Al e a ions in in an s’
na u al a en ional bias owa d ea ul acial exp essions may eme ge p io o he mani es a ion o emo ional and
social beha io s and p o ide a sensi i e ma ke o ea ly emo ional de elopmen . Keywo ds: A en ion, acial
exp ession, ea , yp ophan hyd oxylase 2 gene, in ancy, ma e nal s ess.
In oduc ion
The i s yea s o li e appea o cons i u e a pe iod o
heigh ened plas ici y when an o ganism’s biological
sys ems a e pa icula ly sensi i e o gene ic and
expe ien ial in luences, and may unde go unc ional
al e a ions ha a e ounda ional o indi idual
emo ional ai s (He zman & Boyce, 2010). S udies
examining how de elopmen al p ocesses du ing his
pe iod a e in luenced by gene ic and en i onmen al
ad e si y (e.g., Feldman e al., 2009; Holmboe
e al., 2010) may hence p o ide impo an new
ma ke s o iden i ying indi iduals a isk and o
unde s anding he on ogene ic o igins o emo ional
ulne abili y.
One ac able, bu as ye li le examined, aspec o
ea ly de elopmen ela es o unc ional eme gence o
mechanisms ha media e a en ional igilance o
biologically ele an s imuli (LeDoux, 2012). In
human in an s, he i s signs o such igilance a e
obse ed du ing he second hal o he i s yea o
li e when in an s begin o disc imina e be ween acial
exp essions and exhibi an a en ional bias owa d
aces ha exp ess ea (Pel ola, Hie anen, Fo ssman,
& Lepp€
anen, 2013). Simila igilance o dange -
ale ing cues is obse ed in se e al species (Olsson
& Phelps, 2007), sugges ing a conse ed mechanism
ha may se e as an adap i e unc ion in de ec ing
ha m ul s imuli. Ye , he e a e also indica ions ha
gene ic and expe ien ial ac o s may exace ba e
such species- ypical pe cep ual p edisposi ions
(Shackman, Shackman, & Pollak, 2007), and ha a
di icul y disengaging a en ion om h ea - ela ed
acial exp essions is co ela ed wi h ai anxie y
(Geo giou e al., 2005) and p edic s ulne abili y o
anxie y in child en and adul s (Ba -Haim, Mo ag, &
Glickman, 2011; Fox, Hane, & Pine, 2007; Pine,
2007).
In he p esen s udy, we examined whe he he
de elopmen o a en ion o emo ional cues is
modula ed by es ablished gene ic and en i onmen al
isk ac o s. Al hough a en ional biases canno be
di ec ly linked wi h pa icula gene ic o en i on-
men al ac o s, we easoned ha he apid de elop-
men o hese p ocesses du ing he i s yea o li e
may make hem suscep ible o modula o y e ec s by
ac o s ha a e mo e nonspeci ic in na u e (c .
Leona do & Hen, 2007).
Con lic o in e es s a emen : No con lic s decla ed.
©2013 The Au ho s. Jou nal o Child Psychology and Psychia y published by John Wiley & Sons L d on behal o Associa ion o Child and
Adolescen Men al Heal h.
This is anopen access a icle unde he e ms o he C ea i e Commons A ibu ion-NonComme cial-NoDe i s License, which pe mi s use and dis ibu ion
in any medium, p o ided he o iginal wo k is p ope ly ci ed, he use is non-comme cial and no modi ica ions o adap a ions a e made.
Jou nal o Child Psychology and Psychia y 55:7 (2014), pp 793–801 doi:10.1111/jcpp.12181
The p ima y ocus o ou gene ic analyses was a
common G o T base subs i u ion ( s4570625) in he
p omo e egion o a gene ha encodes yp ophan
hyd oxylase-2 (TPH2), a b ain-speci ic enzyme o
se o onin syn hesis. The T-allele o his single
nucleo ide polymo phism (SNP) has been associa ed
wi h al e ed TPH2 mRNA exp ession (Chen,
Vallende , & Mille , 2008), enhanced amygdala and
co ical esponsi eness o emo ional cues (B own
e al., 2005; He mann e al., 2007), educed a en-
ion con ol (S obel e al., 2007), and inc eased
suscep ibili y o dep essi e diso de s (Gao e al.,
2012). The possibili y ha hese gene ic e ec s a e
es ablished h ough al e ed neu ode elopmen is
suppo ed by e idence showing ha TPH2 exp ession
commences e y ea ly in he de eloping b ain (emb y-
onic day 11 in mice, Waide , A a agi, Gu knech , &
Lesch, 2011) and he esul s o ou p e ious s udy
showing ha he THP2 -703 T-ca ie geno ype (i.e.,
T-ca ie s, including bo h TT homozygo es and he -
e ozygo es) a e associa ed wi h inc eased di icul y
disengaging a en ion om happy and ea ul exp es-
sions in 7-mon h-old in an s (Lepp€
anen e al., 2011).
Ou goal in he p esen s udy was o examine he
eplicabili y o hese esul s in a new sample o in an s.
A second gene ic a ia ion examined in he p esen
s udy was a polymo phism in he se o onin au o e-
cep o 1A gene (HTR1A SNP s6295 -1019 G/C). The
C/C geno ype o his SNP has been associa ed wi h
inc eased se o one gic one and heigh ened amyg-
dala eac i i y o acial exp essions (Fak a e al.,
2009). In ou p e ious s udy (Lepp€
anen e al., 2011),
no signi ican associa ion o his SNP on a en ion
disengagemen in in an s was ound, bu he esul s
showed a end-le el associa ion be ween he C/C
geno ype and inc eased di icul y disengaging.
To examine whe he he p edic ed e ec s o he
TPH2 SNP s4570625 (-703 G/T) geno ype and
in an s’ a en ional bias o ea ul acial exp essions
a e dependen on ea ly ea ing condi ions, we exam-
ined ma e nal s ess and dep essi e symp oms.
Ma e nal s ess and dep ession ha e been associ-
a ed wi h ad e se changes in se e al aspec s o
child de elopmen (Bo ns ein, A e be y, Mash, &
Manian, 2011; Feldman e al., 2009), wi h some
s udies (Bagne , Pe i , Lewinsohn, & Seeley, 2010),
al hough no all (Naicke , Wickham, & Colman,
2012), sugges ing ha dep essi e symp oms du ing
p egnancy and i s pos na al mon hs a e especially
s ongly associa ed wi h ad e se ou comes. I is
no ewo hy ha s ess and dep essi e symp oms,
as assessed by ypical sel - epo ques ionnai es, a e
likely o be linked wi h se e al changes in he child’s
gene ic p edisposi ions as well as p e- and pos na al
en i onmen (e.g., Feldman e al., 2009). Ou s udy
was no aimed a easing apa hese ac o s bu
a he o examine whe he ma e nal s ess as an
es ablished isk condi ion is linked wi h an
ea ly-eme ging and heigh ened a en ion bias owa d
signals o nega i e emo ion.
Me hods
Pa icipan s
The p esen analyses included da a om wo ongoing
longi udinal s udies. Mos o he pa icipan s in he
wo s udies came om u ban, middle-class amilies o
Finnish o igin. The i s sample (Coho 1) consis ed o
7-mon h-old in an s (n=66) om a s udy ha was
s a ed in Oc obe 2007 and consis ed o labo a o y
assessmen s a 7, 24, and 48 mon hs o age. The
me hodology and esul s o he 7-mon h assessmen
we e epo ed in a p e ious publica ion (Lepp€
anen
e al., 2011) and we e used he e in pooled analyses o
TPH2 SNP s4570625 e ec s ac oss wo samples. The
second sample (Coho 2) consis ed o 5–7-mon h-old
in an s om a s udy ha began in Ap il 2012 and
include labo a o y assessmen s a 5, 7, 12, 24, and
48 mon hs o age. DNA samples we e a ailable om
73 ull- e m (≥37 weeks) in an s (35 emales) wi h
sco able a en ion assessmen s a 5 (M=151.58
days, SD =3.28 days) and 7 (M=213.44 days,
SD =4.61 days) mon hs o age. Ma e nal s ess and
dep ession da a we e a ailable o 87 in an s wi h
sco able a en ion da a a 5 (M=151.84 days,
SD =3.26 days) and 7 (M=213.13 days, SD =3.23
days) mon hs o age. Addi ional in an s en olled in he
s udy we e excluded om one o he analyses because
o missing DNA (n=20) o ques ionnai e da a (n=5),
and bo h analyses because o p ema u e bi h (n=1),
ussiness (n=6) o echnical p oblems du ing es ing
(n=6), expe imen e ’s e o (n=1), d opping ou
(n=1), o p o iding insu icien gaze da a (<50% ials
in one o se e al condi ions a one o bo h ime poin s;
n=12). Gene ic and s ess- ela ed da a om Coho
2 ha e no been epo ed p e iously, bu he a en ion
da a o subg oup o in an s in his sample we e used in
a p e ious epo by Pel ola e al. (2013).
E hical pe mission o he s udy was ob ained
om he E hical Commi ee o Tampe e Uni e si y
Hospi al and a w i en in o med consen was gi en
by he pa en s o he pa icipan s be o e he s a o
he s udy.
DNA ex ac ion and geno yping
A olume o 3.0 ml EDTA-whole blood was aken
om he pa icipan s when hey we e 7 mon hs by
an expe ienced labo a o y nu se and s o ed a
20°C. DNA was ex ac ed by using QIAamp*DNA
Blood Miniki and BioRobo s*M48 (Qiagen, Hilden,
Ge many). Consis en wi h he analyses conduc ed
o Coho 1 (Lepp€
anen e al., 2011), he i s DNA
analyses o Coho 2 ocused on single nucleo ide
polymo phisms (SNPs) in he TPH2 ( s4570625)
and HTR1A -1019 ( s6295) genes. Geno yping was
pe o med by using Taqman*SNP Geno yping Assays
and ABI P ism 7900HT Sequence De ec ion Sys em
(Applied Biosys ems, Fos e Ci y, CA, USA) wi h he
ollowing assays: C_226207_10 ( s4570625) and
C_11904666_10 ( s6295). No disc epancies we e
©2013 The Au ho s. Jou nal o Child Psychology and Psychia y published by John Wiley & Sons L d on behal o Associa ion o
Child and Adolescen Men al Heal h.
794 Linda Fo ssman e al. J Child Psychol Psychia 2014; 55(7): 793–801
de ec ed in he geno yping esul s o duplica e sam-
ples.
Ma e nal s ess and dep essi e symp oms
Assessmen o s ess ul li e e en s and ma e nal
dep essi e symp oms was pe o med h ough
ques ionnai es. The child’s biological mo he o bo h
pa en s we e epo ed as he p ima y ca egi e o he
child o all excep wo dyads wi h a he as he
p ima y ca egi e . The mo he s we e gi en he
ques ionnai es a e he 7-mon h-labo a o y isi ,
we e asked o ill hem ou wi hin 2 weeks om he
isi , and e u n hem o he labo a o y in a p epaid
en elope. The ecen li e e en s ques ionnai e (based
on B ugha, Bebing on, Tennan , & Hu y, 1985)
consis ed o 18 s ess ul li e e en s and one open-
esponse i em (a ull desc ip ion o he e en s is
p o ided in Table S3). The mo he s we e asked o
ick a ‘yes’ box i he e en had occu ed du ing he
pas 12 mon hs, and ick a ‘s ill a ec s me’ box i he
e en was s ill ha ing an e ec on hei li e. The sum
o all ‘yes’ esponses and ‘s ill a ec s me’ esponses
(excep esponses o he i em ela ed o child
bi h) we e calcula ed sepa a ely and we e used as
measu es o ma e nal s ess. To assess ma e nal
pos na al dep essi e symp oms, mo he s illed ou
he 10-i em Edinbu gh Pos na al Dep ession Scale
(EPDS, Re . Cox, Holden, & Sago sky, 1987). The
sum sco es om he EPDS we e used o index
dep essi e symp oms, wi h highe alues indica ing
highe le els o dep essi e symp oms.
Assessmen o a en ion o acial exp essions
A de ailed desc ip ion o he pa adigm ha was used
o assess a en ion disengagemen can be ound in
Pel ola e al. (2013). Du ing he labo a o y assess-
men a 5 and 7 mon hs o age, he in an s sa on
hei pa en s lap a a ~60-cm iewing dis ance in
on o a 23-inch moni o ha was pa o a
co neal- e lec ion eye- acke (Tobii TX300; Tobii
Technology, S ockholm, Sweden). E e y expe imen-
al ial was p eceded by a p esen a ion o an
a en ion-g abbing s imulus (a ed ci cle ha
expanded om 0.4° o 4.3°in a con inuous ashion)
o a ac he in an ’s a en ion o he cen e o he
sc een. The expe imen e moni o ed he in an ’s gaze
di ec ion h ough a hidden ideo came a, and when
he child was a ending o he ed ci cle, p essed a
bu on o s a he ial. On each ial, he in an s
we e p esen ed wi h a con ol s imulus (i.e., a
sc ambled ace) o one o h ee di e en acial
exp essions (i.e., neu al, happy, o ea ul acial
exp ession) on he cen e o he sc een. A e
1000 ms, he cen al s imulus was lanked by a
la e al s imulus (a black-and-whi e pic u e o e i-
cally a anged ci cles o a checke boa d pa e n)
13.6°equip obably on he le o igh o 3000 ms,
as shown in Figu e 1. The p esen analyses a e
based on he in an s’ a en ion disengagemen om
he cen al s imuli du ing he i s pa o he es ing
session (24 ials; 6 ials/condi ion). The second
pa o s imulus p esen a ion was added o he
pu poses o EEG measu emen and will be epo ed
in a sepa a e publica ion.
Iden ical o Coho 1, ideo eco dings o each
in an ’s beha io in Coho 2 we e coded ame-by--
ame by an obse e who was blind o he s imulus
condi ion. In cases whe e he ideo eco ding was
missing o in alid (e.g., ideo came a did no eco d
due o echnical e o s, ideo eco ding showed a
de ia ion in ame a e, o he child was ou o iew),
da a poin s we e eplaced wi h gaze da a om he
eye- acke eco ding. A ial was conside ed in alid
i he in an did no look a he cen al s imulus o a
leas 75% du ing he ini ial 1000 ms p esen a ion, i
he in an made an an icipa o y eye mo emen (i.e.,
eye mo emen commenced <160 ms a e he onse
o he la e al s imulus), o an eye mo emen owa d
an inco ec loca ion (i.e., no owa d he la e al
s imulus). O he sco able ials, he numbe o
missing a en ion shi s (i.e., no eye mo emen
owa d he la e al s imulus du ing a ime window
om 160 o 1000 ms a e he onse o he la e al
s imulus) we e calcula ed and se ed as he depen-
den a iable in he s udy.
1000 ms
3000 ms
Figu e 1 The sequence o e en s and s imuli in he pa adigm
used o assess in an s’ a en ion. The p opo ion o missing
saccades om he cen al s imulus o he la e al s imulus was
used as a measu e o a en ion disengagemen
©2013 The Au ho s. Jou nal o Child Psychology and Psychia y published by John Wiley & Sons L d on behal o Associa ion o
Child and Adolescen Men al Heal h.
doi:10.1111/jcpp.12181 TPH2 gene and li e s ess a e associa ed wi h a en ion o ea 795
Assessmen o empe amen
Pa en s a ed hei child’s empe amen using he
In an Beha io Ques ionnai e (Ro hba , 1981)
when hei child was 7 mon hs.
S a is ical analysis
Ou i s analysis was aimed a examining whe he
he p e iously epo ed associa ion be ween he
T-allele o he TPH2 SNP s4570625 (-703 G/T)
and a en ion disengagemen (numbe o missing
a en ion shi s) was eplica ed in Coho 2. As in he
p e ious s udy (Lepp€
anen e al., 2011), a dominan
e ec o he T-allele was es ed by di iding he
pa icipan s in o G/G homozygo es and T-ca ie s,
and by conduc ing a Gene alized Es ima ing Equa-
ions (a Poisson log linea model, SPSS 20) wi h
Geno ype, Age, and Facial Exp ession as ac o s, he
numbe o missing saccades as a dependen a iable
(a Kolmogo o –Smi no es showed ha he numbe
o missing saccades ollowed a Poisson dis ibu ion,
ps>. 06), and a na u al log o he numbe o ials as
an o se a iable. A co esponding analysis was
conduc ed o examine he associa ion be ween
HTR1A SNP s6295 (-1019 G/C geno ypes (G-ca i-
e s s. C/C homozygo es) and a en ion disengage-
men in Coho 2. Following he s a is ical app oach
o he p e ious s udy (Lepp€
anen e al., 2011), an
unadjus ed alpha le el o .05 was used o bo h
s a is ical analyses.
Second, we examined whe he he numbe o
ma e nal s ess ul li e e en s we e associa ed wi h
he a en ional bias owa d acial exp essions. Da a
on s ess ul li e e en s we e a ailable o Coho 2
only. In he p ima y analysis, a iables desc ibing
he numbe o li e e en s and he numbe o li e
e en s ‘s ill a ec ing’ he mo he we e di ided in o
h ee g oups (i.e., g oups wi h 0, 1, and 2 o mo e li e
e en s), and hei e ec s we e examined by Gene -
alized Es ima ing Equa ions wi h Li e E en s, Age,
and Facial Exp ession as ac o s in a Poisson log
linea model and he numbe o missing saccades as
a dependen a iable. In a seconda y co ela ion
analysis (Spea man ho), in ended o supplemen
he o iginal analysis by using he o iginal ung ouped
a iables, we co ela ed he aw numbe o li e e en s
wi h a a iable ha desc ibed a en ional bias
owa d ea ul acial exp essions (i.e., he di e ence
in he p opo ion o missing a en ions shi s o all
non ea ul s imuli and ea ul acial exp essions).
Thi d, we examined whe he he e ec s o TPH2
SNP s4570625 (-703 G/T) we e dependen on ea -
ing condi ion. Fo his analysis, da a om Coho s 1
and 2 we e pooled o a ain a maximal sample size,
and mo he ’s a ings o dep essi e symp oms ha
we e a ailable om bo h coho s we e used as
a a iable e lec ing he ea ly ea ing condi ions.
A uni a ia e analysis o a iance (ANOVA) was
pe o med wi h geno ype (be ween ac o ; GG: n=88
s. T-ca ie s: n=51) as an independen a iable,
EPDS sco es as a con inuous co a ia e, and he ea
bias sco e as a dependen a iable. Es ima es o
e ec sizes o independen a iables (i.e., p opo ion
o a iance explained by he a iable) a e gi en as
pa ial g
2
as p o ided by SPSS. The ea bias sco es
me he s anda d c i e ia o uni a ia e no mali y
(skewness =.26; ku osis =.63).
Finally, al hough he p ima y pu pose o his
s udy was o examine whe he he selec ed gene ic
and psychosocial ac o s we e associa ed wi h he
ea ly de elopmen o a en ion disengagemen , co -
esponding analyses we e also conduc ed o examine
whe he pa allel associa ions a e obse ed in mea-
su es o in an empe amen . Fo hese analyses,
indi idual - es s we e used o compa e TPH2 SNP
s4570625 (-703 G/T) geno ypes wi h espec o
di e en empe amen al scales (Ro hba , 1981),
and Pea son co ela ions we e calcula ed o examine
he associa ions be ween ma e nal s ess ul li e
e en s and in an empe amen dimensions in
Coho 2, as well as ma e nal dep essi e symp oms
and in an empe amen al ai s using pooled da a
om Coho 1 and 2.
Resul s
TPH2 SNP s4570625 (-703 G/T) and a en ion
disengagemen
The allelic equencies o he TPH2 SNP s4570625
(-703 G/T) we e in Ha dy–Weinbe g equilib ium in
he eplica ion sample, =.06, p=.79, and in an s in
he G/G (n=45) and T-ca ie (n=28; G/T: n=26,
T/T: n=2) g oups did no di e in gende a io, age,
bi h-weigh , ma e nal dep essi e sco es, s ess ul
li e e en s sco es, o numbe o sco able ials (Table
S2). The mino allele equency o s4570625 in he
p esen sample (.2055) was compa able o ha in
gene al Finnish popula ion sampling (.1953, Rai ak-
a i e al., 2008). A Gene alized Es ima ing Equa ions
(Poisson) model wi h geno ype, acial exp ession, and
age as ac o s e ealed no signi ican main e ec o
TPH2 SNP s4570625 (-703 G/T) on numbe o
missing a en ion shi s, p<.10, bu he e was a
signi ican main e ec o acial exp ession,
2
=126.05, d =3, p<.001, and a signi ican in e -
ac ion be ween geno ype and acial exp ession,
2
=10.89, d =1, p=.012. Inspec ion o he mean
p opo ion o missing a en ion shi s in he wo
geno ype g oups shows ha he wo geno ype g oups
did no di e in o e all le els o missing a en ion
shi s, bu he T-ca ie s displayed a la ge ela i e
inc ease in numbe o missing saccades o ea ul
acial exp essions compa ed o he o he condi ions
(M
inc ease
=.14, SD =.15 in he GG g oup s.
M
inc ease
=.23, SD =.16 in he T-ca ie g oup). Thus,
bo h G/G homozygo es and T-ca ie s show he
ypical pa e ns o inc eased numbe o missing
a en ions shi s in he con ex ea ul acial
©2013 The Au ho s. Jou nal o Child Psychology and Psychia y published by John Wiley & Sons L d on behal o Associa ion o
Child and Adolescen Men al Heal h.
796 Linda Fo ssman e al. J Child Psychol Psychia 2014; 55(7): 793–801
exp essions (see Figu e S1), bu he ypical pa e n o
inc eased numbe o missing shi s o ea is signi -
ican ly la ge in he T-ca ie s. The e was no in e ac-
ion be ween TPH2 -703 geno ype, emo ion, and age,
p>.13, indica ing ha he e ec s o geno ype g oup
and acial exp ession we e no age- ela ed. Toge he ,
hese esul s show ha he ela i e inc ease in miss-
ing a en ion shi s o happy exp essions in T-ca i-
e s (Lepp€
anen e al., 2011) did no eplica e in he new
sample, bu he inc ease in missing saccades o
ea ul acial exp ession was consis en ly la ge in
T-ca ie s ac oss he wo s udies. Figu e 2 illus a es
he geno ype e ec on p opo ion o missing a en ion
shi s om he neu al and a ec i ely salien s imuli
in he o al sample (Coho s 1 and 2 combined).
Co esponding analysis o he HTR1A SNP s 6295
(-1019 G/C) showed no di e ences be ween he
G-ca ie s (n=55; C/G: n=34, G/G: n=21) and
C/C (n=18) geno ypes on a en ion disengagemen .
This SNP was le ou om all subsequen da a
analyses in he s udy.
Ma e nal s ess and a en ion disengagemen
The mean numbe o s ess ul li e e en s epo ed by
he mo he s was 1.4 ( ange 0–5), wi h 23 mo he s
epo ing no li e e en s, 33 one e en , and 31 wo o
mo e li e e en s. The mean numbe o e en s s ill
a ec ing he mo he was 0.6 ( ange 0–3), wi h 54
mo he s epo ing no a ec ing e en s, 19 epo ing
one s ill a ec ing e en , and 14 epo ing wo o mo e
a ec ing e en s. S ess ul li e e en s we e no asso-
cia ed wi h he numbe o sco able ials in a en ion
ask, all ps>.10, indica ing ha ma e nal s ess
was no ela ed o he success o quali y o he da a
collec ion pe se.
A Gene alized Es ima ing Equa ions (Poisson)
model wi h he numbe o s ess ul li e e en s,
acial exp ession, and age as ac o s e ealed no
signi ican main e ec o li e e en s no a signi ican
in e ac ion be ween he numbe o li e e en s and
acial exp ession on missing a en ion shi s,
p=.12. A simila analysis using he numbe o li e
e en s ‘s ill a ec ing’ he mo he e ealed a signi -
ican in e ac ion be ween he numbe o e en s and
acial exp ession,
2
=18.82, d =6, p=.004. As
shown in Figu e 3, inc eased numbe o li e e en s
‘s ill a ec ing’ he mo he was associa ed wi h a
linea inc ease in missing a en ion in he ea ul
acial exp ession condi ion (i.e., ela i ely la ge ea
bias sco es). The in e ac ion be ween he numbe o
e en s and acial exp ession was u he quali ied
by an in e ac ion wi h age,
2
=12.9, d =6,
p=.045. Sepa a e analysis (uni a ia e ANOVAs)
showed ha he associa ion be ween li e e en s
and ea bias sco es was weake a 5 mon hs
(p=.16) han a 7 mon hs o age (p=.003). The
associa ion be ween s ess ul li e e en s and
in an s’ ea bias sco es was also seen in co ela-
ions be ween he aw (ung ouped) numbe s o li e
e en s and ea bias sco es. The epo ed numbe o
s ess ul li e e en s and he numbe o e en s ‘s ill
a ec ing’ we e bo h signi ican ly associa ed wi h he
s eng h o he ea bias in in an s, Spea man’s ho
.32 and .37, ps<.004.
TPH2 SNP s4570625 (-703 G/T), ma e nal
dep ession, and in an s’ ea bias
To examine whe he he obse ed e ec o he TPH2
SNP s4570625 (-703 G/T) geno ype on missing
a en ion shi s was dependen on exposu e o
Condi ion
Fea HappyNeu alNon- ace
Missing a en ion shi s (p)
0.50
0.40
0.30
0.20
0.10
0.00
T-ca ie
GG
TPH2-703
TPH2 Geno ype
T-ca ie GG
Fea bias sco e
1.00
0.75
0.50
0.25
0.00
–0.25
131 173
151
Figu e 2 Le : Mean p opo ion o missing a en ion shi s in he o al sample (Coho 1 and 2) om he cen al o he la e al s imulus in
he a en ion disengagemen ask g ouped by acial exp essions and TPH2 SNP s4570625 (-703 G/T; G/G n=88; T-ca ie n=51). E o
ba s ep esen 1 s anda d e o . Righ : A boxplo showing he e ec o TPH2 SNP s4570625 (-703 G/T) geno ypes on a en ion bias
owa d ea ul acial exp essions, calcula ed as he di e ence in missing saccades o non ea ul (i.e., con ol, neu al, and happy s imuli)
and ea ul acial exp essions ( ea bias sco e)
©2013 The Au ho s. Jou nal o Child Psychology and Psychia y published by John Wiley & Sons L d on behal o Associa ion o
Child and Adolescen Men al Heal h.
doi:10.1111/jcpp.12181 TPH2 gene and li e s ess a e associa ed wi h a en ion o ea 797

ma e nal dep essi e symp oms, we ca ied ou a
uni a ia e ANOVA wi h geno ype (be ween ac o ; GG
homozygo es s. T-ca ie s) as an independen a -
iable and ma e nal dep essi e sco e as a co a ia e
using pooled da a om Coho 1 and 2. This analysis
showed a signi ican main e ec o TPH2 SNP
s4570625 (-703 G/T), F(1, 130) =7.0, p=.009,
pa ial g
2
=.05, and ma e nal dep ession, F(1,
130) =8.3, p=.005, pa ial g
2
=.06, on he p opo ion
o missing a en ion shi s o ea . These main
e ec s we e quali ied by a signi ican in e ac ion
be ween geno ype and ma e nal dep ession, F(1,
129) =8.5, p<.001, pa ial g
2
=.12. As shown
in Figu e 4, T-ca ie s wi h mo he s who sco ed
ela i ely highe on pos na al dep ession exhibi ed
highes le els o missing a en ion shi s o ea ul
acial exp ession. No signi ican main e ec o in e -
ac ions we e ound o Coho (be ween ac o ;
Coho 1 s. Coho 2, p- alues =.14–.92.) o any
subs an ial change o he abo e desc ibed esul s,
when he ANOVA was conduc ed wi h his ac o as
an independen a iable.
TPH2 SNP s4570625 (-703 G/T), ma e nal s ess, and
in an empe amen
No associa ion be ween geno ype and any o he
empe amen al dimensions we e ound in pooled
analysis o da a om Coho 1 and 2 (n=157), o
be ween ma e nal s ess and in an empe amen
in Coho 2 (n=117), ps>.05. Ma e nal dep es-
si e symp oms we e co ela ed wi h in an empe -
amen al o ien ing, dis ess o limi a ions, and
nega i e a ec i i y, s .18–.23, ps<.05 (unco -
ec ed), in pooled analysis o da a om Coho 1
and 2.
Discussion
The e has been inc easing ecen in e es in he
possibili y ha a ia ions in he TPH2 gene may al e
ea ly neu ode elopmen , pa ially con ingen on
exposu e o ad e se expe iences. Consis en wi h
his possibili y, ou esul s showed ha he T-ca ie
geno ype o he TPH2 SNP s4570625 (-703 G/T) is
associa ed wi h a simila end o ela i ely g ea e
Condi ion
Fea ulHappyNeu alNon- ace
Missing a en ion shi s (p)
0.60
0.50
0.40
0.30
0.20
0.10
0.00
2 o mo e
1
0
S ess ul li e
e en s "s ill
a ec ing"
S ess ull li e e en s "s ill a ec ing"
2 o mo e10
Fea bias sco e
0.60
0.40
0.20
0.00
–0.20
–0.40
Figu e 3 Le : Numbe o s ess ul li e e en s ‘s ill a ec ing’ he mo he and mean p opo ions o in an s’ missing saccades in di e en
s imulus condi ions. Righ : A boxplo showing he associa ion be ween ‘s ill a ec ing’ s ess ul e en s and ea bias sco es
Condi ion
Fea HappyNeu alNon- ace
Missing a en ion shi s (p)
0.70
0.60
0.50
0.40
0.30
0.20
0.10
0.00
T-ca ie & high EPDS
T-ca ie & low EPDS
GG & high EPDS
GG & low EPDS
G oup
Figu e 4 Mean p opo ion o missing a en ion shi s in he o al
sample (Coho 1 and 2) om he cen al s imulus (Non ace,
Neu al, Happy, o Fea ul acial exp ession) o he la e al a ge
g ouped by ma e nal dep ession sco e (Edinbu gh Pos na al
Dep ession Scale; EPDS; Median-spli : high s. low) and TPH2
SNP s4570625 (-703 G/T) geno ypes (G/G and low EPDS n=42; G/
G and high EPDS n=42; T-ca ie and low EPDS n=34; T-ca ie
and high EPDS n=15). E o ba s ep esen 1 s anda d e o
©2013 The Au ho s. Jou nal o Child Psychology and Psychia y published by John Wiley & Sons L d on behal o Associa ion o
Child and Adolescen Men al Heal h.
798 Linda Fo ssman e al. J Child Psychol Psychia 2014; 55(7): 793–801
di icul y disengaging a en ion om ea ul acial
exp essions in wo independen samples o 5- o
7-mon h-old in an s. We also ound ha his asso-
cia ion was dependen on he in an ’s ea ing condi-
ions in a p edic ed way, being mos p onounced in
T-ca ie s whose mo he s epo ed highe le els o
dep essi e symp oms. I con i med, he po en ial
dominan associa ion o he T-allele o he TPH2 SNP
s4570625 (-703 G/T) wi h inc eased se o onin syn-
hesis and se o one gic one (Chen & Mille , 2012),
and he dependence o TPH2 exp ession on ea ly
expe iences (Ga dne e al., 2009) may p o ide a
neu obiologically plausible mechanism o enhanced
a en ion o ea . Indeed, a andomized con olled
s udy in human adul s has shown ha inc eased
yp ophan and se o one gic unc ion heigh ens
pe cep ual sensi i i y o ea ul acial exp essions
(A enbu ow e al., 2003). A p esen , his in e p e-
a ion mus be wi h cau ion, howe e , gi en he
absence o di ec e idence o he unc ional signi -
icance o he TPH2 SNP s4570625 (-703 G/T).
Fu he mo e, he p esen s udy ocused on a single
polymo phism in he TPH2 gene while i is likely ha
mul iple SNPs, genes, and neu o ansmi e sys ems
a e in ol ed in ea ly a en ional de elopmen .
In u u e esea ch, i will be impo an o examine
whe he he obse ed gene ic associa ions we e
a ec ed by gene ic ances y by analyzing ances y
in o ma i e gene ic ma ke s and by eplica ing he
s udy in samples om di e en ances ies. I
should also be no ed ha he cu en analyses do
no ule ou he possibili y ha he obse ed gene ic
associa ions in he in an s may be pa ly a ibu -
able o indi ec e ec s a ising om he ac ha he
pa en s a e likely o sha e he same geno ype and
associa ed beha io al ai s (such as heigh ened
dep ession).
S ess ul li e e en s (pa icula ly when pe cei ed
as ‘s ill a ec ing’ he mo he ) we e also associa ed
wi h a selec i e di icul y disengaging a en ion om
ea ul acial exp essions in in an s. Besides sha ed
gene ic in luences be ween he mo he and he child,
he e a e se e al plausible expe ience- ela ed mech-
anisms ha may media e he associa ion be ween
ma e nal s ess and heigh ened in an a en ion o
ea ul acial exp essions. Ma e nal s ess may pose
a nonspeci ic isk condi ion ha is associa ed wi h a
numbe o p e- and pos na al ad e se in luences
(e.g., educed ma e nal sensi i i y) and co-occu ing
condi ions, each o which may lead o exace ba ions
in in an s s ess eac i i y and ela ed p ocesses,
possibly also inc easing in an s a en i eness o
social signals o ea (Loman & Gunna , 2010). A
ela ed possibili y is ha expe ienced s ess
inc eases ca egi e s’ p o ec i e and p ecau iona y
beha io s (Hahn-Holb ook, Holb ook, & Hasel on,
2011). P esumably, one o he p ima y means by
which ca egi e s exe such beha io s is by acial
signaling o ea . I con inued o e ime, epea ed
exposu e o such beha io s may inc ease bo h
adul s’ and in an s’ sensi i i y o ea cues (see
Shackman e al., 2007 o a simila explana ion o
p esumably adap i e enhancemen in a en ion o
ang y acial exp essions in mal ea ed child en).
Ou esul s we e limi ed by he eliance on
sel - epo s as he only sou ce o in o ma ion ega ding
ma e nal s ess and dep essi e symp oms, as well as
ma e nal epo s as he only sou ce o in o ma ion
conce ning in an s’ empe amen . Ne e heless,
ques ionnai es ha e been ex ensi ely used in de el-
opmen al esea ch and we e conside ed o p o ide a
su icien p oxy o ea ing condi ion and in an s’
empe amen o he pu poses o he p esen s udy.
I is clea , howe e , ha u he esea ch wi h a
b oade app oach o s udying he ole o in an s’
ea ing en i onmen o he de elopmen o a en ion
o social signals, o example h ough di ec home
obse a ions and he assessmen o mo he –child
in e ac ion, du ing he i s mon hs o li e will be
impo an o unco e ing he mechanisms ha
unde lie he associa ion be ween s ess and heigh -
ened ea bias. Also, i will be impo an o ule ou
he possibili y ha ma e nal dep ession biases he
a ings o in an empe amen by using mo e objec-
i e measu es o empe amen .
In summa y, he p esen s udy sugges s ha
in an s’ na u al a en ional bias owa d ea ul acial
exp essions may be exace ba ed by gene ic and
psychosocial isk ac o s wi hin a ela i ely sho
ime pe iod in ea ly de elopmen . These al e a ions
in a en ional biases may p o ide a sensi i e and
accessible ma ke o ea ly emo ional de elopmen ,
as al e a ions in a en ion we e obse ed wi hou any
concomi an changes in mo he - epo ed empe a-
men al ai s. Al hough we did no examine he
long- e m unc ional signi icance o heigh ened ea
bias in he cu en s udy (such analyses will be
conduc ed when longi udinal assessmen s ha e
been comple ed), i is in iguing o no e ha a weal h
o ecen e idence sugges s ha exagge a ed a en-
ion o h ea -ale ing cues may ep esen one o he
key on ogene ic mechanisms ha ca alyzes he
de elopmen o ea - ela ed empe amen al ai s
and inc eases ulne abili y o anxie y diso de s
(e.g., Ba -Haim e al., 2011). Na u ally, he in e ence
o such causal associa ions be ween a en ion and
emo ion equi es no only longi udinal da a bu ,
ul ima ely, con olled expe imen s wi h echniques
o a enua e maladap i e a en ion biases (Ba -
Haim e al., 2011). Recen s udies ha e shown ha
eye- acking sys ems can be used o enhance a en-
ion disengagemen in in an s (Wass, Po ayska-
Poms a, & Johnson, 2011), bu i is no ye known
whe he such e ec s ex end o in an s a en ion
biases owa d h ea -ale ing cues.
Suppo ing in o ma ion
Addi ional Suppo ing In o ma ion may be ound in he
online e sion o his a icle:
©2013 The Au ho s. Jou nal o Child Psychology and Psychia y published by John Wiley & Sons L d on behal o Associa ion o
Child and Adolescen Men al Heal h.
doi:10.1111/jcpp.12181 TPH2 gene and li e s ess a e associa ed wi h a en ion o ea 799
Figu e S1 Dis ibu ion o missing saccades o ea ul
acial exp essions ac oss he wo samples.
Table S1 Mean p opo ion o missing saccades in he
a en ion disengagemen ask.
Table S2 Demog aphic in o ma ion, sum sco es o
ma e nal a ing on he Edinbu gh Pos na al Dep ession
Scale.
Table S3 Li e e en s ques ionnai e.
Appendix S1. Regula o y a ian o he TPH2 gene and
ea ly li e s ess a e associa ed wi h heigh ened a en-
ion o social signals o ea in in an s.
Acknowledgemen s
This esea ch was suppo ed by g an s om he Acad-
emy o Finland (#218284), he Eu opean Resea ch
Council (# 283763), he Tampe e Uni e si y Hospi al
Medical Funds (g an 9M048 o 9N035 o T.L), Finnish
Founda ion o Ca dio ascula Resea ch, Tampe e
Tube culosis Founda ion and Emil Aal onen Founda-
ion.
The au ho s g a e ully acknowledge he e o s o he
amilies who pa icipa ed in he s udies. The au ho s
decla e hey ha e no po en ial o compe ing con lic o
in e es s.
Co espondence
Linda Fo ssman, Tampe e Cen e o Child Heal h
Resea ch, School o Medicine, Uni e si y o Tampe e,
FIN-33014 Tampe e, Finland; Email: linda. o ssman@
u a. i
Key poin s
•The ea ly s ages o human de elopmen a e highly sensi i e o gene ic and en i onmen al in luences, and
unc ional adap a ions du ing his pe iod may be ounda ional o li e ime emo ional ai s.
•Li le is known abou he mechanisms ha eme ge du ing his pe iod o media e long- e m ou comes.
•Ou s udy shows ha in an s’ na u al a en ional bias owa d ea ul acial exp essions is heigh ened in
associa ion wi h es ablished gene ic and psychosocial isk ac o s.
•Heigh ened a en ional bias owa d ea may p o ide a sensi i e and accessible ma ke o he assessmen o
ea ly de elopmen and po en ially also o unde s anding he mechanisms ha media e emo ional
ulne abili y.
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Accep ed o publica ion: 17 Oc obe 2013
Published online: 5 Decembe 2013
©2013 The Au ho s. Jou nal o Child Psychology and Psychia y published by John Wiley & Sons L d on behal o Associa ion o
Child and Adolescen Men al Heal h.
doi:10.1111/jcpp.12181 TPH2 gene and li e s ess a e associa ed wi h a en ion o ea 801