ARTICLE OPEN
P o eomic insigh s in o men al heal h s a us: plasma ma ke s in
young adul s
Alexey M. A onin
1
, Aino-Kaisa Pii onen
1
, Izaque de Sousa Maciel
1
, Ma iia I ano a
1
, A o Ala alo
1
, Alyce M. Whipp
2
,
Lea Pulkkinen
3
, Richa d J. Rose
4
, I ene an Kamp
5
, Jaakko Kap io
2,6
and Ka ja M. Kanninen
1
✉
© The Au ho (s) 2024
Global emphasis on enhancing p e en ion and ea men s a egies necessi a es an inc eased unde s anding o he biological
mechanisms o psychopa hology. Plasma p o eomics is a powe ul ool ha has been applied in he con ex o specific men al
diso de s o bioma ke iden ifica ion. The p- ac o , also known as he “gene al psychopa hology ac o ”, is a concep in
psychopa hology sugges ing ha he e is a common unde lying ac o ha con ibu es o he de elopmen o a ious o ms o
men al diso de s. I has been p oposed ha he p- ac o can be used o unde s and he o e all men al heal h s a us o an
indi idual. He e, we aimed o disco e plasma p o eins associa ed wi h he p- ac o in 775 young adul s in he FinnTwin12 coho .
Using liquid ch oma og aphy– andem mass spec ome y, 13 p o eins wi h a significan connec ion wi h he p- ac o we e
iden ified, 8 o which we e linked o epide mal g ow h ac o ecep o (EGFR) signaling. This explo a o y s udy p o ides new insigh
in o biological al e a ions associa ed wi h men al heal h s a us in young adul s.
T ansla ional Psychia y (2024) 14:55 ; h ps://doi.o g/10.1038/s41398-024-02751-z
INTRODUCTION
Men al heal h issues a e inc easingly becoming a majo conce n
globally [1,2]. In ac , he Wo ld Heal h O ganiza ion es ima es
ha abou one in e e y eigh people ac oss he globe su e om
a men al heal h diso de , making hese diso de s he p ima y
cause o a educed quali y o li e [1]. The ecen COVID-19
pandemic has no ably exace ba ed men al heal h issues, pa icu-
la ly among young adul s aged 18–29. Du ing he pandemic, he
numbe o young adul s expe iencing dep ession symp oms mo e
han doubled in nume ous Eu opean coun ies [3].
Despi e he significan impac o men al heal h diseases on
daily li e and hei conside able economic cos , hese condi ions
o en go undiagnosed and un ea ed [1,3]. This highligh s he
p essing need o ea ly de ec ion o indi iduals a high isk o
psychopa hology, a ge ed p e en a i e measu es, and imp o e-
men s in diagnos ic p ocedu es and ea men s.
Al hough di e en men al diso de s may ha e unique
symp oms, hey ha e been shown o sha e commonali ies in
e ms o unde lying biological, psychological, and social ac o s
[4]. The p- ac o , also known as he “gene al psychopa hology
ac o ,”is a concep in psychopa hology sugges ing ha he e is
a common unde lying ac o ha con ibu es o he de elop-
men o a ious o ms o men al diso de s [5,6]. I has been
p oposed ha his single la en ac o can encapsula e indi i-
duals’p ocli i y o de elop all o ms o psychopa hology
included wi hin he b oad in e nalizing, ex e nalizing, and
hough diso de dimensions [7]. The p- ac o is analogous o
he gene al ac o in in elligence (called he g- ac o ), which
summa izes he obse a ion ha indi iduals who do well on one
ype o cogni i e es end o do well on all o he ypes o
cogni i e es s [5,8]. O he ac o s, such as a gene al ac o o
pe sonali y (GFP) and a gene al ac o o pe sonali y diso de (g-
PD), ha e been p e iously shown o ha e a high co ela ion wi h
he p- ac o [9]. A he indi idual le el, he p- ac o eflec s
meaning ul di e ences be ween pe sons on a single dimension
ha ep esen s he endency o expe ience psychia ic p oblems
as pe sis en and como bid; ha is, high p- ac o indi iduals
expe ience di ficul ies in egula ion/con ol when dealing wi h
o he s, he en i onmen , and he sel [4,5,10].
P e ious s udies ha e shown he p- ac o o be connec ed o
b ain unc ioning in adolescen s, wi h highe p- ac o sco es
associa ed wi h diminished ac i a ion o mul iple b ain zones
du ing execu i e asks [11]. Impo an ly, some s udies ha e
epo ed ha he p- ac o may be a s onge p edic o o men al
heal h ou comes han specific diagnoses o men al diso de s [12].
A ecen s udy showed ha he p- ac o was associa ed wi h
poo e pe o mance on he simple eac ion ime ask and he
inspec ion ime ask, wi h speed o p ocessing being a common
co ela e o psychopa hology ac o s [13]. Likewise, Pulkkinen [14]
has shown ha low emo ion and beha io egula ion obse ed as
ex e nalizing and in e nalizing p oblems in child en a e nega i ely
associa ed wi h he execu i e unc ions o he o eb ain o
inhibi ion and upda ing (con aining wo king memo y and
shi ing). This sugges s ha he p- ac o could be used o be e
unde s and he o e all men al heal h s a us o an indi idual,
a he han jus ocusing on indi idual diagnoses.
Recei ed: 15 June 2023 Re ised: 5 Janua y 2024 Accep ed: 8 Janua y 2024
1
A.I. Vi anen Ins i u e o Molecula Sciences, Uni e si y o Eas e n Finland, Kuopio, Finland.
2
Ins i u e o Molecula Medicine Finland (FIMM), HiLIFE, Uni e si y o Helsinki,
Helsinki, Finland.
3
Depa men o Psychology, Uni e si y o Jy askyla, Jy askyla, Finland.
4
Depa men o Psychological & B ain Sciences, Indiana Uni e si y, Blooming on, IN, USA.
5
Cen e o Sus ainabili y, En i onmen and Heal h, Na ional Ins i u e o Public Heal h and he En i onmen , Bil ho en, he Ne he lands.
6
Depa men o Public Heal h, Uni e si y
o Helsinki, Helsinki, Finland. ✉email: ka ja.kanninen@ue .fi
www.na u e.com/ p
T ansla ional Psychia y
1234567890();,:
Bioma ke disco e y has gained ac ion in ecen yea s as
esea che s seek o unco e he biological unde pinnings o men al
heal h condi ions [15,16]. The de elopmen o “omics” echnolo-
gies and s a e-o - he-a analy ical me hods ha e inc eased in e es
in he capabili ies o plasma p o eomics in bioma ke disco e y. LC-
MS/MS-based p o eomics p o ides a global snapsho o p o ein
exp ession pa e ns ha eflec physiological and pa hological
s a es [17], making comp ehensi e analysis o he plasma
p o eome possible [18]. This has enabled he simul aneous
de ec ion and quan ifica ion o housands o p o eins, expedi ing
bioma ke disco e y e o s and educing he ime and esou ces
equi ed o his p ocess. This holis ic iew o p o eomics allows o
he unbiased disco e y o no el bioma ke s, wi h less need o p io
knowledge o a ge p o eins. This ea u e is pa icula ly impo an
in cases whe e he biology o he p ocess is no ye ully
unde s ood o when new, un o eseen bioma ke s a e needed o
imp o ed diagnos ic o p ognos ic applica ions [19].
P o eomics app oaches ha e been u ilized o he iden ifica ion
o p o ein signa u es associa ed wi h specific psychological
diso de s [20–22]. Fo example, se e al g ow h ac o s (BDNF,
VEGF, NGF) and cy okines (IL-1β, IL-6, IFN-α) ha e been linked o
dep ession [23]. Mo eo e , a ecen mul i-omics s udy epo ed
educed apolipop o ein le els and an inc ease in complemen
e ec o p o eins in he plasma o schizoph enia (SCZ) pa ien s
[24]. Howe e , p o eomics analyses ha e no p e iously been
combined o s udies o he p- ac o o iden ifica ion o ma ke s
associa ed wi h o e all men al heal h s a us.
The FinnTwin12 (FT12) coho , a longi udinal s udy o Finnish
wins bo n be ween 1983 and 1987, has a mul i ude o da a and
biological samples [25,26]. As a aluable esou ce o explo ing
biological p ocesses in ol ed in men al heal h p oblems, we
explo ed he connec ion be ween he p- ac o , p e iously
epo ed in [27], and plasma p o eomics among young adul s
om his coho .
METHODS
Coho desc ip ion
The FT12 coho is a longi udinal popula ion-based coho o Finnish wins
bo n 1983–1987 collec ed o in es iga e beha io al de elopmen and
heal h habi s [25,26]. Ini ially, wins and hei amilies we e iden ified using
he Finnish Cen al Popula ion Regis y, and ques ionnai e collec ion
occu ed o all pa icipan s in he coho a ages 11/12, 14, 17, and 22. The
baseline esponse a e was 87% (N=5600 wins) and has emained high
( esponse a e ange: 85–90%). A age 14, a subse o he wins ( om 1035
amilies) was mo e in ensi ely s udied, including psychia ic in e iews and
addi ional ques ionnai es (ages 14 and 22), as well as blood plasma
samples (age 22). The “age 22”assessmen wa e o hese mo e in ensi ely
s udied wins in ol ed 1347 indi iduals (mean age =22.4 yea s, SD =0.70;
esponse a e 73.0%), 779 o whom a ended in-pe son assessmen s and
p o ided enous blood plasma samples. The blood samples we e collec ed
a e o e nigh as ing, which in ol ed abs aining om alcohol and
obacco since he nigh be o e sampling. Plasma was immedia ely
ex ac ed and s o ed a −80 °C [27].
p- ac o calcula ion
In FT12, beha io al and emo ional cha ac e is ics we e measu ed a all da a
collec ion wa es. The modified Mul idimensional Pee Nomina ion
In en o y (MPNI) measu e aimed a obse ing indi idual di e ences in
emo ion and beha io egula ion was used. I is an ex ension o he
measu e [28] used in he Jy äskylä Longi udinal S udy o Pe sonali y and
Social De elopmen in which he de elopmen o he same indi iduals has
been ollowed om age 8–50, wi h findings ha low sel - egula ion is
associa ed wi h social and psychological dys unc ion [14]. The MPNI scale
has been p e iously ac o analyzed wi h h ee main ac o s e med
Beha io P oblems, Emo ional P oblems, and Adjus men [28].
The MPNI was collec ed in FT12 a ages 12, 14, and 17, om di e en
a e s (7 in o al): pa en s (age 12), eache s (age 12 and 14), win child en
hemsel es (age 14 and 17), and he child’s co- win (age 14 and 17). The
measu e includes subscales o he ex e nalizing p oblem dimension:
agg ession (6 i ems [ o MPNI ages 12, 14, 17]), hype ac i i y-impulsi i y (7
i ems [MPNI ages 12, 14], 6 i ems [MPNI ages 17]), and ina en ion (4 i ems
[MPNI ages 12, 14, 17]), as well as o he in e nalizing p oblem dimension;
dep ession (5 i ems [MPNI ages 12, 14], 2 i ems [MPNI ages 17]), social
anxie y (2 i ems [MPNI ages 12, 14], 3 i ems [MPNI ages 17]), and 1 i em o
ic imiza ion (MPNI ages 12, 14, 17). Each MPNI i em (e.g., “Is es less,
unable o si s ill”) has ou esponse choices ( om “no obse ed in he
child” o “clea ly obse able in he child”, sco ed 0–3 espec i ely). The
MPNI p- ac o sco e was c ea ed by combining all he i ems o he
“ex e nalizing”and “in e nalizing”dimensions oge he in o a sum sco e,
wi h a mos 2 missing i ems allowed. Missing i ems we e impu ed based
on he mean o he emaining i ems, wi h less han 3% o wins ha ing
missing i ems. A composi e “combined”p- ac o sco e was c ea ed using
he p- ac o sco es o all se en o he abo emen ioned a ailable MPNI
a ings (C onbach’s alpha=0.76), because we know ha a ings om
di e en a e s a e no highly co ela ed, howe e , hey can impa unique
in o ma ion [29–31]. Each o he se en sco es we e s anda dized as z
sco es, and hen we ook he mean o a ailable sco es. The p- ac o o he
FT12 coho was p e iously c ea ed and analyzed in ela ion o me aboli es
in [27]. Ele en wins had no o e all p- ac o sco e, lea ing 775 wins. O
hem, 505 (65%) had been sco ed by all a e s a all imes, while 194 (25%)
had only one a e alue missing, he emaining 10% ha ing sco es om
2–4 a e s. To examine he dimensionali y o combining he se en
indi idual p- ac o sco es, we pe o med a ac o analysis on he subse o
pa icipan s who had been a ed on all measu es. The ac o analysis
indica ed one majo ac o , wi h he fi s eigen alue associa ed wi h he
fi s ac o ha ing a alue well o e one. A co ela ion analysis was
pe o med o he newly calcula ed sco e wi h he sum scale based on all
se en p- ac o s, showing a high co ela ion coe ficien o 0.983. The
composi e “combined”p- ac o sco e was used o he subsequen
analyses.
The p edic i e powe o he p- ac o was es ed using he da a on he
psychia ic in e iews o he wins a age 22. Using a logis ic eg ession
model o MDD, p- ac o sco e, adjus ed o sex, p edic s MDD easonably
well wi h an a ea unde he ecei e ope a ing cha ac e is ic cu e (ROC
AUC) o 0.67.
High-abundance p o ein deple ion
Albumin accoun s o 50%, and he op 22 p o eins accoun o 99% o
plasma p o eins by weigh in human plasma samples [19]. The e o e, he
deple ion o high-abundan p o eins is essen ial o he iden ifica ion and
analysis o low-abundan p o eins. A comme cial ki (High Selec ™Top14
Abundan P o ein Deple ion Mini Spin Columns, ca . Numbe : A36370,
The moScien ific) was used o deple e he 14 mos abundan p o eins om
plasma be o e he p o eomic analyses. The deple ed p o eins we e human
se um albumin (HSA), albumin, IgG, IgA, IgM, IgD, IgE, kappa and lambda
ligh chains, alpha-1-acidglycop o ein, alpha-1-an i ypsin, alpha-2-mac o-
globulin, apolipop o ein A1, fib inogen, hap oglobin, and ans e in,
acco ding o manu ac u e ’s manual. B iefly, 10 µL o o al plasma was
added o he mini spin columns and incuba ed o 10 min while o a ing,
ollowed by cen i uga ion o he columns (1,000 × g) o 2 min. The fil a e
was collec ed in 2 ml plas ic ubes and s o ed a −20 °C un il p epa a ion
o mass spec ome y p o eomic analyses, which we e pe o med a he
Tu ku P o eomics Facili y in Finland suppo ed by Biocen e Finland.
P o ein p ecipi a ion and diges ion
The p o eins o 786 deple ed plasma samples we e ace one p ecipi a ed
and subjec ed o in-solu ion diges ion acco ding o s anda d p o ocol a
he Tu ku P o eomics Facili y, Tu ku, Finland (h ps://bioscience.fi/). A e
diges ion, pep ides we e desal ed wi h a Sep-Pak C18 96-well pla e
(Wa e s), e apo a ed o d yness, and s o ed a −20 °C.
Mass spec ome y analysis
Diges ed pep ide samples we e dissol ed in 0.1% o mic acid, and he
pep ide concen a ion was de e mined wi h a NanoD op de ice. Fo da a-
independen acquisi ion (DIA) analysis, 500 ng o pep ides we e injec ed
and analyzed in a andom o de , de e mined wi h he Excel and() unc ion.
Wash uns we e submi ed be ween each sample o educe po en ial ca y-
o e o pep ides. The Liquid Ch oma og aphy-Elec osp ay Ioniza ion-Mass
Spec ome y (LC-ESI-MS/MS) analysis was pe o med on a nanoflow HPLC
sys em (Easy-nLC1000, The mo Fishe Scien ific) coupled o a Q Exac i e HF
mass spec ome e (The mo Fishe Scien ific, B emen, Ge many) equipped
wi h a nano-elec osp ay ioniza ion sou ce. Pep ides we e fi s loaded on a
A.M. A onin e al.
2
T ansla ional Psychia y (2024) 14:55
apping column and subsequen ly sepa a ed inline on a 15 cm C18
column (75 μm x 15 cm, Rep oSilPu 3 μm 120 Å C18-AQ, D . Maisch HPLC
GmbH, Amme buch-En ingen, Ge many). The mobile phase consis ed o
wa e wi h 0.1% o mic acid (sol en A) o ace oni ile/wa e (80:20 ( / ))
wi h 0.1% o mic acid (sol en B). A 50 min om 5% o 35% sol en B
g adien was used o elu e pep ides. Samples we e analyzed by a DIA LC-
MS/MS me hod. MS da a was acqui ed au oma ically by using The mo
Xcalibu 4.1 so wa e (The mo Fishe Scien ific). In he DIA me hod, a du y
cycle con ained one ull scan (400–1000 m/z) and 25 DIA MS/MS scans
co e ing he mass ange 400–1000 wi h a iable wid h isola ion windows.
P o ein iden ifica ion and quan ifica ion analysis
Da a analysis consis ed o p o ein iden ifica ion and label- ee quan ifica-
ions o p o ein abundances. Da a was analyzed using Spec onau
so wa e (Biognosys; e sion 17.0.2). The di ec DIA app oach was used
o iden i y p o eins. The main da a analysis pa ame e s in Spec onau
we e: (i) Enzyme: T ypsin/P; (ii) up o 2 missed clea ages; (iii) Fixed
modifica ions: Ca bamidome hyl (cys eine); (i ) Va iable modifica ions:
Ace yl (p o ein N- e minus) and oxida ion (me hionine); ( ) P ecu so FDR
Cu o : 0.01; ( i) P o ein FDR Cu o : 0.01; ( ii) Quan ifica ion MS le el: MS2;
( iii) Quan ifica ion ype: A ea unde he cu e wi hin in eg a ion
bounda ies o each a ge ed ion; (ix) P o ein da abase: Homo sapiens
Swiss-P o e e ence p o eome (Unip o elease 2022_01_07_HUMAN) [32],
Uni e sal P o ein Con aminan da abase [33].
Raw da a d i and ba ch co ec ion
P o ein abundances we e analyzed by LC-MS/MS in h ee sepa a e
expe imen al uns o ba ches. Since he numbe o samples in each ba ch
was ela i ely la ge, he da a was no malized be o e u he analysis, and
ba ch e ec s we e emo ed. Fo he ease o compa ing he LC-MS/MS
uns, 10 o he samples we e analyzed in 2 ou o he 3 uns. Fo he aw
da a analysis, we ex ac ed he da a om he .sne file using he iq expo
scheme [34]. The da a used o no maliza ion was he aw peak a ea o he
pep ide g oups. These alues we e used in he u he analyses.
The aw da a in es iga ion p e-p ocessing and s a is ical analyses we e
pe o med in he R ( e sion 4.2.1.) en i onmen (R Co e Team, 2022). The
signal d i and he obse ed ba ch e ec we e co ec ed using he
p oBa ch ( . 1.13.0) [35] package. The median abundance plo s showed he
samples o ming ou dis inc g oups, iden ical o he ba ches o
ins umen uns (Supplemen a y Fig. 1A). The figu e also shows
p onounced signal d i in he hi d and ou h ba ches. These e ec s
we e co ec ed o using he p oBa ch pipeline. A e he ba ch e ec
co ec ion, no significan d i o ba ch e ec could be seen (Supplemen-
a y Fig. 1B).
Bioin o ma ic analysis
A e d i and ba ch co ec ion, he as MaxLFQ me hod om he iq
package ( . 1.9.10) [34] was used o ans o m he pep ide abundancies
in o p o ein abundance alues. The con aminan p o eins and he p o eins
deple ed in he sample p e-p ocessing s ep we e emo ed om he
analysis. Only he iden ified p o eins wi h quan ified abundance le els in a
leas 80% o he samples we e used in u he analyses. Missing alues
emaining in he da ase we e impu ed using he Sample Minimum
me hod [36]. As an addi ional sensi i i y es , he same modeling was
pe o med using he p o eins p esen in 20, 40, 60, 80, and 98% o he
samples, o ensu e ha he modeling was obus , and ha he exclusion o
a e p o eins did no skew he analysis.
The connec ion be ween he p- ac o and he p o ein abundances was
analysed using he limma [37] package ( . 3.54.2). Sex and age we e
included in o linea models as co a ia es o ensu e epo ed associa ions
we e no due o sex o age e ec s. Limma modeling was used o
in es iga e he associa ion o p o ein abundance wi h he p- ac o using
linea and non-linea modeling. The possible non-linea ela ionship
be ween he p- ac o and he p o ein abundance was in es iga ed by
using splines in limma [38]. A basis ma ix o ep esen ing he amily o
piecewise-cubic splines wi h 5 nodes we e gene a ed using he ns unc ion
om he p- ac o a iable (Splines package 3.6.2), and was used in limma
modeling, also including sex and age as co a ia es.
Fig. 1 Dis ibu ion o p- ac o alues in he FT12 coho . The densi y dis ibu ion o he s anda dized p- ac o alues o he pa icipan s.
A.M. A onin e al.
3
T ansla ional Psychia y (2024) 14:55
Mode a e F es on he p- ac o was ca ied ou o assess he significance
o non-linea associa ions o he p o ein abundance wi h he p- ac o using
he unc ion lmFi and eBayes om he R limma package. P alues o
linea and non-linea modeling we e co ec ed o mul iple es ing and he
alse disco e y a e (FDR) was compu ed by using he Benjamini &
Hochbe g me hod [39], which we e epo ed as q- alues. The significance
le el conside ed in all analyses was 0.05. The linea e ec size is epo ed
as he log2- old-change in exp ession ha esul s om a uni (one
s anda d de ia ion) change in p- ac o .
The p o ein–p o ein in e ac ion in o ma ion o he significan ly
di e en ially abundan p o eins was analysed using STRING da abase ( .
12.0) [40]. The en ichmen analysis wi h Gene On ology (P ocess, Func ion,
and Componen ), KEGG and Reac ome pa hways, PubMed publica ions,
UniP o Keywo ds, and PFAM/INTERPRO/SMART domain da abases was
pe o med using he STRINGdb package [41]. Resul isualiza ions we e
pe o med using R and ggplo 2 ( 3.4.0) [42].
RESULTS
Coho cha ac e is ics
The p- ac o was calcula ed based on assessmen s by mul iple
a e s a h ee di e en ages as desc ibed in he Ma e ials and
Me hods. A combined p- ac o alue was a ailable o 775
indi iduals (318 males and 457 emales). The z-sco e-based
p- ac o dis ibu ion is p esen ed in Fig. 1.
P o ein iden ifica ion
MS-based p o eomics success ully iden ified 1494 p o eins (DIA
spec ome y in ensi y alues) in he FT12 coho (N=775) he lis
o ound p o eins is p esen ed in Supplemen a y File 1. A e he
emo al o alues o p o eins deple ed in he sample p e-
p ocessing s ep, 1415 p o eins we e le , wi h a mean numbe o
iden ified p o eins o 835 pe sample (SD =48). P o eins p esen
in a leas 80% o he samples we e used, lea ing 571 p o eins.
Associa ion o p o eins wi h p- ac o
The linea modeling showed 5 p o eins in e sely associa ed wi h
he p- ac o (Table 1). As he ela ionship be ween he al e ed
p o eins and p- ac o is no known, he analysis was also
pe o med using splines, which also made i possible o
in es iga e non-linea ela ionships be ween he p o ein
abundance and he p- ac o . These analyses showed 14 p o eins
associa ed wi h he p- ac o (Table 1). The ela ionships be ween
he p- ac o and he p o ein abundance o he significan ly
associa ed p o eins a e p esen ed in Supplemen a y Figu e 2.
The sensi i i y es ing showed ha 13 o 14 p o eins we e
consis en ac oss models, he S100 calcium binding p o ein A4
was significan ly associa ed wi h he p- ac o only when p o eins
missing in o e 20% o samples we e excluded. The esul s o
addi ional analyses a e p esen ed in Supplemen a y Table 1.
Func ional en ichmen and anno a ion
The STRING p o ein–p o ein in e ac ion ne wo ks unc ional
en ichmen analysis showed wo connec ed clus e s o p o eins
wi h: he fi s being cys a in-M (CST6) and ca hepsin B (CTSB), he
second con aining laminin subuni be a-1 (LAMB1), basemen
memb ane-specific hepa an sul a e p o eoglycan co e p o ein
(HSPG2), and fibulin-1 (FBLN1) (Fig. 2). In es iga ion o he fi s
laye o he s ing ne wo k showed ha nine o he significan
p o eins we e linked specifically h ough he epide mal g ow h
ac o ecep o (EGFR) and ans hy e in (TTR) (Fig. 2). Bo h
p o eins we e among he 636 p o eins we in es iga ed, hough
he q- alues we e abo e he significance h eshold (q alues o
bo h EGFR and TTR we e 0.066).
En ichmen analysis o unc ion ca ego ies showed only he
ex acellula ma ix s uc u al cons i uen o be significan ly
en iched. Compa men s, componen , unc ion, and issue ana-
lyses showed significan ly en iched e ms, mos ly connec ed o
ex acellula space and ma ix, and cell–cell adhesion (Supple-
men a y Table 2).
A connec ion o a disease o he CNS o o he neu odegene a-
i e diseases acco ding o he Disease On ology da abase was
ound o 6 o he 13 significan p o eins [43], shown in Table 2.
DISCUSSION
The field o plasma p o eomics is apidly gaining ac ion in he
ealm o biomedical esea ch, pa icula ly in s udies ela ing o
men al heal h. The e is inc easing e idence ha al e a ions in
plasma p o ein p ofiles a e associa ed wi h majo psychia ic
Table 1. The plasma p o eins significan ly associa ed wi h he p- ac o .
P o ein ID Gene name P o ein name Linea e ec
size
Linea p
alue
Linea q
alue
Non-linea p
alue
Non-linea q
alue
P o eins wi h linea ela ionship wi h p- ac o
Q15828* CST6 Cys a in E/M −0.086 1.76E-04 0.024 8.43E-04 0.047
P98160 HSPG2 Hepa an sul a e
p o eoglycan 2
−0.061 3.86E-05 0.006 1.27E-03 0.066
P23142 FBLN1 Fibulin-1 −0.065 2.49E-05 0.006 1.74E-03 0.075
P07911* UMOD U omodulin −0.145 1.19E-05 0.006 8.89E-05 0.013
Q9Y6R7* FCGBP Fc gamma binding
p o ein
−0.082 8.11E-06 0.005 3.05E-05 0.007
P o eins wi h non-linea ela ionship wi h p- ac o
P04179 SOD2 Supe oxide dismu ase 2 –3.90E-01 0.701 1.86E-06 0.001
Q9BY67 CADM1 Cell adhesion molecule 1 –3.87E-02 0.329 4.24E-06 0.002
Q14126 DSG2 Desmoglein 2 –8.53E-04 0.072 8.80E-05 0.010
Q8NBJ4 GOLM1 Golgi memb ane p o ein 1 –7.93E-01 0.866 2.68E-04 0.010
P07858 CTSB Ca hepsin B –1.22E-01 0.496 6.74E-05 0.010
Q86UN3 RTN4RL2 Re iculon-4 ecep o -like 2 –3.66E-01 0.675 8.59E-05 0.012
O75636 FCN3 Ficolin 3 –9.16E-03 0.183 3.42E-04 0.026
P07942 LAMB1 Laminin subuni be a-1 –9.11E-03 0.183 5.13E-04 0.035
*
indica e p o eins wi h bo h linea and non-linea ela ionship.
A.M. A onin e al.
4
T ansla ional Psychia y (2024) 14:55
condi ions, including majo dep essi e diso de (MDD), schizo-
ph enia, psycho ic diso de s (PSD), and bipola diso de s (BD)
[44–46]. This s udy p esen s he fi s epo o di e ences in
plasma p o ein le els associa ed wi h he p- ac o in a popula ion
sample o young adul s.
We ound 13 plasma p o eins associa ed wi h p- ac o sco es in
young adul s. All bu he FCGBP p o ein we e p esen in he
Human Plasma P o eome Da abase [47,48], FCGBP, howe e , was
p e iously epo ed in se um samples [49]. O hese p o eins, en
belonged o a p o ein ne wo k connec ed o EGFR, eigh being
di ec ly connec ed o EGFR. The EGF- ela ed signaling pa hways
ha e been p e iously linked o neu ode elopmen [50], synap ic
plas ici y [51,52], ch onic pain [53], ea [54], as well as men al
heal h diseases [44,52,55–58]. Fo example, al e ed EGFR
signaling has been epo ed in MDD and BD pa ien s in blood
p o eomics s udies [44].
In addi ion o EGFR signaling, we obse ed he p- ac o o be
nega i ely associa ed wi h hepa an sul a e p o eoglycan 2
(HSPG2). Hepa an sul a e p o eoglycans (HSPG) a e memb ane
p o eins and a majo componen o ex acellula ma ices in ol ed
in many cellula p ocesses, as hey unc ion as co- ecep o s o
g ow h ac o s [59]. HSPG2, combined wi h CEP350 and SMAD5,
was ecen ly p esen ed as a po en ial diagnos ic bioma ke o
MDD [60]. Fu he mo e, he HSPG2 gene was p e iously connec ed
o an ipsycho ic-induced ad e se e ec s such as a di e dyskine-
sia [61,62], specifically in SCZ pa ien s [63], and he main enance
and epai o he blood-b ain ba ie in mice [64]. Mo eo e ,
down egula ion o HSPG2 and a dep essi e-like pheno ype we e
e ealed in mouse models o ch onic mild s ess and impai ed
glu ama e unc ion [65].
We also epo a nega i e associa ion wi h fibulin-1 (FBLN1) and
he p- ac o . The FBLN1 gene is connec ed o cen al ne ous
sys em de elopmen [66,67] and modula ion o neu o ophic
ac i i ies o amyloid p ecu so p o ein in cul u ed oden neu al
s em cells [68]. So a , li le is known abou he possible
connec ion o FBLN1 o men al heal h. Shin [69]. epo ed
dec eased FBLN1 plasma p o ein le els in MDD pa ien s compa ed
o BD pa ien s and heal hy con ols. The model p oposed in ha
s udy also con ained Fc gamma binding p o ein (FCGBP), which
was epo ed o be significan ly highe in BD pa ien s compa ed o
MDD pa ien s bu no in heal hy con ols. In ou s udy, FCGBP was
nega i ely associa ed wi h he p- ac o . Addi ionally, inc eased
plasma p o ein abundance o desmoglein 3 (DSG3) was epo ed
in MDD pa ien s and educed abundance in BD pa ien s compa ed
o heal hy con ols [69]. DSG3 is a p o ein belonging o he same
desmosomal cadhe in amily as he DSG2 epo ed in his s udy,
which had a non-linea associa ion wi h he p- ac o wi h
inc eased abundancies in he middle pa o he p- ac o scale.
DSG2 was p e iously shown o ha e a simila unc ion as DSG3
and was also shown o compensa e o DSG3 in DSG3
−
mouse
models [70]. The Shin e al. pape in es iga ed BD, which is
classified as a Though Diso de ac o , and MDD, which is
classified as an In e nalizing ac o [5], so he di e ences in he
abundance changes obse ed compa ed o ou wo k, whe e we
used he combined p- ac o , a e o be expec ed. Laminin subuni
be a-1 (LAMB1) was associa ed wi h he p- ac o in his s udy. A
polymo phism in LAMB1 gene has been ea lie associa ed wi h
au ism se e i y [71], neu al de elopmen o emb yonic s em cells
[72] and pain sensi i i y in mice [73]. LAMB1 is exp essed du ing
he ea ly de elopmen o ne ous sys em [71] and in he
hippocampus in he ma u e b ain [74]. In a s, LAMB1 showed
nega i e egula ion o spa ial lea ning h ough he inhibi ion o
he ERK/MAPK-SGK1 signaling pa hway in he hippocampus [74].
Fu he mo e, loss o LAMB1 in he an e io cingula e co ex was
ound o inc ease pain sensi i i y and be associa ed wi h anxie y-
and dep essi e-like beha io in mice [73].
Ca hepsin B (CTSB) was iden ified he e wi h a non-linea
ela ionship o he p- ac o . Moon e al. sugges ed CTSB as a
media o o exe cise-induced e ec s on b ain heal h by enhancing
he exp ession o neu o ophins [75]. Exe cise was ound o
inc ease plasma CTSB le els in monkeys and humans [75], bu a
20-week exe cise in e en ion in child en did no find any
significan connec ion be ween CTSB and b ain heal h ou comes
[76]. Addi ionally, CTSB has been connec ed o b ain- ela ed
unc ions in se e al mice s udies [77–79]. Fo example, a mouse
in e ac s wi h
in e ac s wi h
in e ac s wi h
in e ac s wi h
in e ac s wi h
in e ac s wi h
in e ac s wi h
in e ac s wi h
in e ac s wi h
in e ac s wi h
in e ac s wi h
in e ac s wi h
in e ac s wi h
in e ac s wi h
in e ac s wi h
Fig. 2 The esul o STRING analysis o he p o eins significan ly associa ed wi h he p- ac o . Line hickness indica es he s eng h o da a
suppo . G een ci cles deno e p o eins wi h a linea ela ionship o he p- ac o , ed ci cles wi h non-linea ela ionships, and blue ci cles
ep esen ing p o eins wi h epo ed linea and non-linea ela ionships.
Table 2. The disease on ology classifica ion (STRINGdb).
Gene name Disease on ology
LAMB1, FCN3, CTSB, HSPG2 Ne ous sys em disease
FCN3, CTSB, HSPG2, SOD2 Neu odegene a i e disease
FCN3, CTSB, HSPG2 Cen al ne ous sys em disease
A.M. A onin e al.
5
T ansla ional Psychia y (2024) 14:55
model o ch onic social s ess e ealed inc eased ac i i y o
ca hepsin Вin he hypo halamus and nucleus cauda us wi h
dep essi e-like beha io [79]. Con a ily, dec eased ca hepsin B
ac i i y was ound a e acu e emo ional s ess in mice [77]. CTSB
shows a po en ial media o ole in he b ain induced by physical
and men al s esso s, which should be u he in es iga ed.
O he p o eins significan ly associa ed wi h he p- ac o and
di ec ly connec ed o EGFR in ou s udy we e golgi memb ane
p o ein 1 (GOLM1), supe oxide dismu ase 2 (SOD2), and u omodu-
line UMOD. Inc eased GOLM1 gene exp ession was ound in
soldie s wi h PTSD [80]. This e ec occu s h ough he ac i a ion
o E bB4-BDNF signaling pa hway [81,82]. Pa icula ly s ong
e idence suppo s he ole o he Neu egulin-1 (NRG1)-
E bB4 signaling on synap ic plas ici y [51,52]. Neu egulins a e a
amily o epide mal g ow h ac o - ela ed p o eins ac ing on he
E bB y osine kinase ecep o s [51,52]. SOD2 was ound o play a
ole in neu odegene a i e disease acco ding o he Disease
On ology da abase, a polymo phism in he sod2 gene was
associa ed wi h di e ences in whi e ma e mic os uc u e and
subop imal b ain aging [83]. Fo he u omodulin (UMOD) p o eins
and CST6 gene, no p e ious connec ion o men al heal h
p oblems was epo ed.
We obse ed associa ions o plasma e iculon-4 ecep o -like 2
(RTN4L2), and ficolin 3 (FCN3) wi h he p- ac o . Re iculon-4
ecep o s (RTN4R), also known as NogoRs, a e su ace p o eins
exp essed in neu ons [84]. RTN4Rs a e in ol ed in synap ogenesis
and inhibi ion o axonal and dend i e g ow h, and, hus neu onal
plas ici y [84,85]. Human gene ics s udies ha e e ealed he
linkage be ween Nogo ecep o s and SCZ [85–87]. Fo example, a
a e a ian in RTN4R, a ec ing he o ma ion o g ow h cones
in i o, was associa ed wi h SCZ [87]. The ole o RTN4Rs in SCZ
seems o be media ed by neu ode elopmen al and myelin- ela ed
abno mali ies [85]. Howe e , u he s udies a e needed o cla i y
he exac ole o RTN4Rs in men al heal h. In e es ingly, ficolin
ac i a ion was nega i ely associa ed wi h se e i y o SCZ [88], and
in ou ecen s udy, he plasma abundance o ficolin 2, a simila
p o ein, was ound o be posi i ely co ela ed wi h he S eng h
and Di ficul ies Ques ionnai e (SDQ) sco e in adolescen s.
Hal o he p o eins ound o be significan in his s udy we e
connec ed o he ex acellula ma ix. HSPG2, FBLN1, and LAMB1
we e also s ongly connec ed o each o he , acco ding o he
STRING da abase, being s uc u al componen s o he basal
memb ane, specifically in he b ain. Coupled wi h p o eins ela ed
o neu onal plas ici y, p o eins iden ified in his s udy may be
po en ially connec ed o he p e iously no ed in e se ela ionship
be ween he p- ac o and he mic os uc u al in eg i y o whi e
ma e as obse ed h ough neu oimaging [89]. Fu he s udies
a e needed o in es iga e he possible connec ions o he ound
p o eins wi h he b ain mic os uc u e and unc ioning.
La ge-scale p o eomic s udies wi h plasma samples can p esen
mul iple challenges ha need o be add essed o gene a e obus
and meaning ul esul s. Fo ins ance, p o ein exp ession in plasma
is dynamic, and bo h in e indi idual and sample a iabili y can be
no able. Fu he mo e, plasma p o eomic s udies di e in he
pipelines and me hods used due o a lack o s anda d p o ocols
[19]. Addi ional challenges include ensu ing consis en sample
handling and p ocessing [90], no malizing da a, co ec ing signal
d i and ba ch e ec s [35,91], accoun ing o biological a iabili y
[92], imp o ing ep oducibili y [93], and managing he esou ce-
in ensi e na u e o such s udies [94]. Despi e hese limi a ions,
p o eomics emains a powe ul ool ha can con ibu e o be e
diagnos ics o men al heal h [95,96]. The majo cons ain in his
s udy is ha he p o eomic da a was only ob ained once o each
pa icipan . This one- ime snapsho o a dynamically e ol ing
o ganism makes i challenging o conclusi ely link he iden ified
bioma ke s o he in es iga ed p- ac o . The ue na u e o hese
associa ions is also ha d o de e mine based solely on hese da a.
These co ela ions could be he ou come o unde lying biological
p ocesses o inhe en biological ai s o he pa icipan s, which
migh simul aneously influence bo h p o ein abundance and he
p- ac o ( he obse ed beha io ). Al e na i ely, he changes in
p o ein abundance and he p- ac o could be causally ela ed,
ei he as a cause o as an e ec . Men al condi ions may cause
di e gen e ec s on he abundance o plasma p o eins, as
demons a ed in he s udy by Shin and colleagues [69]. Fu he
in es iga ions will benefi om he inclusion o he diso de
symp oms in o he p- ac o , which is missing om he sco e used
in he p esen manusc ip . These limi a ions sugges ha a mo e
de ailed in es iga ion in o he a ious componen s o he p- ac o
may be needed o iden i y mo e specific bioma ke s.
The s eng h o his s udy lies in i s la ge coho size, and he use
o mode n p o eomics me hods, which made i possible o ob ain
p o eome p ofiles o hund eds o indi iduals, each comp ising
hund eds o plasma p o ein abundancies. This la ge scale allows us
o iden i y common pa e ns in he p o eomes o indi iduals wi h
high and low p- ac o alues. While he changes in plasma
abundancies o some o he p o eins we e p e iously epo ed,
o he p o eins we e linked o a ulne abili y o he de elopmen o
gene al psychopa hology o he fi s ime. Ou esea ch u ilized
he FT12 coho , a la ge and ho oughly cha ac e ized popula ion-
based coho wi h a b oad ange o measu ed cha ac e is ics,
making he p o eomic da a ga he ed in his s udy an in aluable
esou ce o u u e explo a ion and analysis.
CONCLUSIONS
The s udy sugges s ha examining plasma p o eomic p ofiles
makes i possible o elucida e he biological p ocesses ela ed o
he p- ac o , which may in o m he u u e de elopmen o no el
sc eening, diagnos ic, o he apeu ic s a egies o men al
diso de s. The esul s e ealed p o eins wi h common cellula
unc ions connec ed o he p- ac o , eflec ing he gene al
psychopa hology. Howe e , u he s udies a e needed o examine
he iden ified p o eins and hei po en ial as bioma ke s o
men al heal h dys unc ion. In he u u e, u iliza ion o he p- ac o
may also ha e implica ions o he de elopmen o in e en ions
a ge ing common unde lying ac o s ha con ibu e o mul iple
o ms o men al diso de s. By add essing hese sha ed ac o s,
in e en ions could po en ially be mo e e ec i e in imp o ing
men al heal h ou comes ac oss a ange o diso de s.
DATA AVAILABILITY
The da a analyzed in his s udy is subjec o he ollowing licenses/ es ic ions: The
FT12 da a is no publicly a ailable due o he es ic ions o in o med consen .
Reques s o access hese da ase s should be di ec ed o he Ins i u e o Molecula
Medicine Finland (FIMM) Da a Access Commi ee (DAC) (fimmdac@helsinki.fi) o
au ho ized esea che s who ha e IRB/e hics app o al and an ins i u ionally app o ed
s udy plan. To ensu e he p o ec ion o p i acy and compliance wi h na ional da a
p o ec ion legisla ion, a da a use/ ans e ag eemen is needed, he con en and
specific clauses o which will depend on he na u e o he eques ed da a.
REFERENCES
1. O ganiza ion WH. Wo ld men al heal h epo : ans o ming men al heal h o all.
(2022).
2. Wo ld Heal h O ganiza ion. Adolescen men al heal h. 2021. h ps://
www.who.in /news- oom/ ac -shee s/de ail/adolescen -men al-heal h. Accessed
1 Sep embe 2022.
3. Heal h a a Glance: Eu ope 2022. OECD; 2022.
4. Smi h GT, A kinson EA, Da is HA, Riley EN, Ol manns JR. The gene al ac o o
psychopa hology. Annu Re Clin Psychol. 2020;16:75–98.
5. Caspi A, Hou s RM, Belsky DW, Goldman-Mello SJ, Ha ing on H, Is ael S, e al.
The p ac o : one gene al psychopa hology ac o in he s uc u e o psychia ic
diso de s? Clin Psychol Sci. 2014;2:119–37.
6. Lahey BB, Applega e B, Hakes JK, Zald DH, Ha i i AR, Ra houz PJ. Is he e a gene al
ac o o p e alen psychopa hology du ing adul hood? J Abno m Psychol.
2012;121:971–7.
A.M. A onin e al.
6
T ansla ional Psychia y (2024) 14:55
7. Ronald A. Edi o ial: he psychopa hology p ac o : will i e olu ionise he science
and p ac ice o child and adolescen psychia y? J Child Psychol Psychia y.
2019;60:497–9.
8. Jensen AR. The g ac o : he science o men al abili y. Psycoloquy.
1999;10:36–2443.
9. Ol manns JR, Smi h GT, Ol manns TF, Widige TA. Gene al ac o s o psycho-
pa hology, pe sonali y, and pe sonali y diso de : ac oss domain compa isons.
Clin Psychol Sci. 2018;6:581–9.
10. Laceulle OM, Vollebe gh WAM, O mel J. The s uc u e o psychopa hology in
adolescence. Clin Psychol Sci. 2015;3:850–60.
11. Shanmugan S, Wol DH, Calkins ME, Moo e TM, Rupa el K, Hopson RD, e al.
Common and dissociable mechanisms o execu i e sys em dys unc ion ac oss
psychia ic diso de s in you h. Am J Psychia y. 2016;173:517–26.
12. Ha wig FP, Bo ges MC, Ho a BL, Bowden J, Da ey Smi h G. Inflamma o y bio-
ma ke s and isk o schizoph enia: a 2-sample mendelian andomiza ion s udy.
JAMA Psychia y. 2017;74:1226–33.
13. Haywood D, Baughman FD, Mullan BA, Heslop KR. Wha accoun s o he ac o s
o psychopa hology? An in es iga ion o he neu ocogni i e co ela es o in e -
nalising, ex e nalising, and he p- ac o . B ain Sci. 2022;12:421.
14. Pulkkinen L. Human de elopmen om middle childhood o middle adul hood.
London: Rou ledge; 2017.
15. Wal e s RK, Poliman i R, Johnson EC, McClin ick JN, Adams MJ, Adkins AE, e al.
T ansances al GWAS o alcohol dependence e eals common gene ic unde -
pinnings wi h psychia ic diso de s. Na Neu osci. 2018;21:1656–69.
16. Munn‐Che no MA, Johnson EC, Chou Y, Coleman JRI, Tho n on LM, Wal e s RK,
e al. Sha ed gene ic isk be ween ea ing diso de ‐and subs ance‐use‐ ela ed
pheno ypes: E idence om genome‐wide associa ion s udies. Addic Biol.
2021;26:e12880.
17. O lando E, Aebe sold R. On he con ibu ion o mass spec ome y-based pla o ms
o he field o pe sonalized oncology. T AC T ends Anal Chem. 2019;110:129–42.
18. Zhou B, Zhou Z, Chen Y, Deng H, Cai Y, Rao X, e al. Plasma p o eomics-based
iden ifica ion o no el bioma ke s in ea ly gas ic cance . Clin Biochem. 2020;76:5–10.
19. Ignja o ic V, Geye PE, Palaniappan KK, Chaaban JE, Omenn GS, Bake MS, e al.
Mass spec ome y-based plasma p o eomics: conside a ions om sample col-
lec ion o achie ing ansla ional da a. J P o eome Res. 2019;18:4085–97.
20. Comes AL, Papiol S, Muelle T, Geye PE, Mann M, Schulze TG. P o eomics o
blood bioma ke explo a ion o se e e men al illness: pi alls o he pas and
po en ial o he u u e. T ansl Psychia y. 2018;8:160.
21. Domenici E, Willé DR, Tozzi F, P okopenko I, Mille S, McKeown A, e al. Plasma
p o ein bioma ke s o dep ession and schizoph enia by mul i analy e p ofiling o
case-con ol collec ions. PLoS One. 2010;5:e9166.
22. Ziani PR, Fei en JG, Goula e JF, Colombo R, An que iezc B, Géa LP, e al. Po en ial
candida es o bioma ke s in bipola diso de : a p o eomic app oach h ough
sys ems biology. Clin Psychopha macol Neu osci. 2022;20:211–27.
23. Malik S, Singh R, A o a G, Dangol A, Goyal S. Bioma ke s o majo dep essi e
diso de : knowing is hal he ba le. Clin Psychopha macol Neu osci. 2021;19:12–25.
24. Campeau A, Mills RH, S e ens T, Rossi o L-A, Meehan M, Do es ein P, e al. Mul i-
omics o human plasma e eals molecula ea u es o dys egula ed inflamma ion
and accele a ed aging in schizoph enia. Mol Psychia y. 2022;27:1217–25.
25. Kap io J. Twin s udies in Finland 2006. Twin Res Hum Gene . 2006;9:772–7.
26. Rose RJ, Sal a o e JE, Aal onen S, Ba PB, Bogl LH, Bye s HA, e al. FinnTwin12
coho : an upda ed e iew. Twin Res Hum Gene . 2019;22:302–11.
27. Whipp AM, Heinonen-Guzeje M, Pie iläinen KH, an Kamp I, Kap io J. B anched-chain
amino acids linked o dep ession in young adul s. F on Neu osci. 2022;16:935858.
28. Pulkkinen L, Kap io J, Rose RJ. Pee s, eache s and pa en s as assesso s o he
beha iou al and emo ional p oblems o wins and hei adjus men : he Mul i-
dimensional Pee Nomina ion In en o y. Twin Res. 1999;2:274–85.
29. Achenbach TM, McConaughy SH, Howell CT. Child/adolescen beha io al and
emo ional p oblems: implica ions o c oss-in o man co ela ions o si ua ional
specifici y. Psychol Bull. 1987;101:213–32.
30. Whipp AM, Ko honen T, Rae uo i A, Heikkilä K, Pulkkinen L, Rose RJ, e al. Ea ly
adolescen agg ession p edic s an isocial pe sonali y diso de in young adul s: a
popula ion-based s udy. Eu Child Adolesc Psychia y. 2019;28:341–50.
31. Whipp AM, Vuoksimaa E, Bolhuis K, de Zeeuw EL, Ko honen T, Mau i M, e al.
Teache - a ed agg ession and co-occu ing beha io s and emo ional p oblems
among schoolchild en in ou popula ion-based Eu opean coho s. PLoS One.
2021;16:e0238667.
32. Ba eman A, Ma in M-J, O cha d S, Mag ane M, Ahmad S, Alpi E, e al. UniP o : he
uni e sal p o ein knowledgebase in 2023. Nucleic Acids Res. 2023;51:D523–D531.
33. F ankenfield AM, Ni J, Ahmed M, Hao L. P o ein con aminan s ma e : building
uni e sal p o ein con aminan lib a ies o DDA and DIA p o eomics. J P o eome
Res. 2022;21:2104–13.
34. Pham TV, Henneman AA, Jimenez CR. iq: an R package o es ima e ela i e
p o ein abundances om ion quan ifica ion in DIA-MS-based p o eomics.
Bioin o ma ics. 2020;36:2611–3.
35. Čuklina J, Lee CH, Williams EG, Sajic T, Collins BC, Rod íguez Ma ínez M, e al.
Diagnos ics and co ec ion o ba ch e ec s in la ge‐scale p o eomic s udies: a
u o ial. Mol Sys Biol. 2021;17:e10240.
36. Liu M, Dong e A. P ope impu a ion o missing alues in p o eomics da ase s o
di e en ial exp ession analysis. B ie Bioin o m. 2021;22:bbaa112.
37. Phipson B, Lee S, Majewski IJ, Alexande WS, Smy h GK. Robus hype pa ame e
es ima ion p o ec s agains hype a iable genes and imp o es powe o de ec
di e en ial exp ession. Ann Appl S a . 2016;10:946–63.
38. Ri chie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, e al. limma powe s di e en ial
exp ession analyses o RNA-sequencing and mic oa ay s udies. Nucleic Acids
Res. 2015;43:e47.
39. Benjamini Y, Hochbe g Y. Con olling he alse disco e y a e: a p ac ical and
powe ul app oach o mul iple es ing. J R S a Soc Se B. 1995;57:289–300.
40. Szkla czyk D, Gable AL, Nas ou KC, Lyon D, Ki sch R, Pyysalo S, e al. The STRING
da abase in 2021: cus omizable p o ein–p o ein ne wo ks, and unc ional cha -
ac e iza ion o use -uploaded gene/measu emen se s. Nucleic Acids Res.
2021;49:D605–D612.
41. Szkla czyk D, Gable AL, Lyon D, Junge A, Wyde S, Hue a-Cepas J, e al. STRING
11: p o ein–p o ein associa ion ne wo ks wi h inc eased co e age, suppo ing
unc ional disco e y in genome-wide expe imen al da ase s. Nucleic Acids Res.
2019;47:D607–D613.
42. Wickham H ggplo 2. New Yo k, NY: Sp inge New Yo k; 2009.
43. Sch iml LM, Mun o JB, Scho M, Olley D, McC acken C, Felix V, e al. The human
disease on ology 2022 upda e. Nucleic Acids Res. 2022;50:D1255–D1261.
44. Fe nandes BS, Dai Y, Jia P, Zhao Z. Cha ing he p o eome landscape in majo
psychia ic diso de s: om bioma ke s o biological pa hways owa ds d ug
disco e y. Eu Neu opsychopha macol. 2022;61:43–59.
45. Ga cía-Gu ié ez MS, Na a e e F, Sala F, Gaspa yan A, Aus ich-Oli a es A, Man-
zana es J. Bioma ke s in psychia y: concep , defini ion, ypes and ele ance o
he clinical eali y. F on Psychia y. 2020;11:432.
46. Rod íguez Ce dei a C, Sánchez-Blanco E, Sánchez-Blanco B, González-Cespón JL.
P o ein bioma ke s o mood diso de s. In J Immunopa hol Pha m. 2017;30:7–12.
47. Human P o ein A las. p o eina las.o g. 2022.
48. Uhlén M, Ka lsson MJ, Hobe A, S ensson A-S, Sche el J, Ko ol D, e al. The human
sec e ome. Sci Signal. 2019;12:eaaz0274.
49. Ji E, Boe ig e D, Cai HQ, Lloyd D, B uggemann J, O’Donnell M, e al. Pe iphe al
complemen is inc eased in schizoph enia and in e sely ela ed o co ical
hickness. B ain Beha Immun. 2022;101:423–34.
50. Bi chmeie C. E bB ecep o s and he de elopmen o he ne ous sys em. Exp
Cell Res. 2009;315:611–8.
51. Ledonne A, Me cu i NB. On he modula o y oles o neu egulins/E bB signaling
on synap ic plas ici y. In J Mol Sci. 2019;21:275.
52. Mei L, Na e K-A. Neu egulin-ERBB signaling in he ne ous sys em and neu-
opsychia ic diseases. Neu on. 2014;83:27–49.
53. Bo ges JP, Mekhail K, Fai n GD, An onescu CN, S einbe g BE. Modula ion o
pa hological pain by epide mal g ow h ac o ecep o . F on Pha m.
2021;12:642820.
54. Chen Y-H, Hu N-Y, Wu D-Y, Bi L-L, Luo Z-Y, Huang L, e al. PV ne wo k plas ici y
media ed by neu egulin1-E bB4 signalling con ols ea ex inc ion. Mol Psy-
chia y. 2022;27:896–906.
55. Fio i LM, Kos A, Lin R, Thé oux J-F, Lopez JP, Kühne C, e al. miR-323a egula es
ERBB4 and is in ol ed in dep ession. Mol Psychia y. 2021;26:4191–204.
56. Mei L, Xiong W-C. Neu egulin 1 in neu al de elopmen , synap ic plas ici y and
schizoph enia. Na Re Neu osci. 2008;9:437–52.
57. Nawwa DA, Zaki HF, Sayed RH. Role o he NRG1/E bB4 and PI3K/AKT/mTOR
signaling pa hways in he an i-psycho ic e ec s o a ipip azole and se indole in
ke amine-induced schizoph enia-like beha io s in a s. Inflammopha macology.
2022;30:1891–907.
58. Shi L, Be gson CM. Neu egulin 1: an in iguing he apeu ic a ge o neu ode-
elopmen al diso de s. T ansl Psychia y. 2020;10:190.
59. Bishop JR, Schuksz M, Esko JD. Hepa an sulpha e p o eoglycans fine- une
mammalian physiology. Na u e. 2007;446:1030–7.
60. Long Q, Wang R, Feng M, Zhao X, Liu Y, Ma X, e al. Cons uc ion and analysis o a
diagnos ic model based on di e en ial exp ession genes in pa ien s wi h majo
dep essi e diso de . F on Psychia y. 2021;12:762683.
61. MacNeil RR, Mülle DJ. Gene ics o common an ipsycho ic-induced ad e se
e ec s. Complex Psychia y. 2016;2:61–78.
62. Zai CC, Maes MS, Tiwa i AK, Zai GC, Reming on G, Kennedy JL. Gene ics o a di e
dyskinesia: p omising leads and ways o wa d. J Neu ol Sci. 2018;389:28–34.
63. Zai CC, Lee FH, Tiwa i AK, Lu JY, Luca Vde, Maes MS, e al. In es iga ion o he
HSPG2 gene in a di e dyskinesia –new da a and me a-analysis. F on Pha m.
2018;9:974.
64. Nakamu a K, Ikeuchi T, Na a K, Rhodes CS, Zhang P, Chiba Y, e al. Pe lecan
egula es pe icy e dynamics in he main enance and epai o he blood–b ain
ba ie . J Cell Biol. 2019;218:3506–25.
A.M. A onin e al.
7
T ansla ional Psychia y (2024) 14:55
65. To de a RM, Ga cia-Ga cía AL, Elizalde N, Segu a V, Aso E, Venzala E, e al. Ch onic
s ess and impai ed glu ama e unc ion elici a dep essi e-like pheno ype and
common changes in gene exp ession in he mouse on al co ex. Eu Neu-
opsychopha macol. 2011;21:23–32.
66. Bohlega S, Al-Ajlan H, Al-Sai A. Mu a ion o fibulin-1 causes a no el synd ome
in ol ing he cen al ne ous sys em and connec i e issues. Eu J Hum Gene .
2014;22:640–3.
67. Cooley MA, Ke n CB, F esco VM, Wessels A, Thompson RP, McQuinn TC, e al.
Fibulin-1 is equi ed o mo phogenesis o neu al c es -de i ed s uc u es. De
Biol. 2008;319:336–45.
68. Ohsawa I, Takamu a C, Kohsaka S. Fibulin-1 binds he amino- e minal head o
β-amyloid p ecu so p o ein and modula es i s physiological unc ion. J Neu-
ochem. 2001;76:1411–20.
69. Shin D, Rhee SJ, Lee J, Yeo I, Do M, Joo E-J, e al. Quan i a i e p o eomic app oach
o disc imina ing majo dep essi e diso de and bipola diso de by mul iple
eac ion moni o ing-mass spec ome y. J P o eome Res. 2021;20:3188–203.
70. Ha lieb E, Rö ze V, Rade a M, Spindle V, Waschke J. Desmoglein 2 compensa es
o desmoglein 3 bu does no con ol cell adhesion ia egula ion o p38
mi ogen-ac i a ed p o ein kinase in ke a inocy es. J Biol Chem.
2014;289:17043–53.
71. Kim YJ, Pa k JK, Kang WS, Kim SK, Pa k HJ, Nam M, e al. LAMB1 polymo phism is
associa ed wi h au ism symp om se e i y in Ko ean au ism spec um diso de
pa ien s. No d J Psychia y. 2015;69:594–8.
72. Sun Y-M, Coope M, Finch S, Lin H-H, Chen Z-F, Williams BP, e al. Res -media ed
egula ion o ex acellula ma ix is c ucial o neu al de elopmen . PLoS One.
2008;3:e3656.
73. Li Z-Z, Han W-J, Sun Z-C, Chen Y, Sun J-Y, Cai G-H, e al. Ex acellula ma ix
p o ein laminin β1 egula es pain sensi i i y and anxiodep ession-like beha io s
in mice. J Clin In es . 2021;131:e146323.
74. Yang YC, Ma YL, Liu WT, Lee EH. Laminin-β1 impai s spa ial lea ning h ough
inhibi ion o ERK/MAPK and SGK1 signaling. Neu opsychopha macology.
2011;36:2571–86.
75. Moon HY, Becke A, Be on D, Becke B, Sah N, Benoni G, e al. Running-induced
sys emic ca hepsin B sec e ion is associa ed wi h memo y unc ion. Cell Me ab.
2016;24:332–40.
76. Rod iguez-Ayllon M, Plaza-Flo ido A, Mendez-Gu ie ez A, Al mäe S, Solis-U a P,
Aguile a CM, e al. The e ec s o a 20-week exe cise p og am on blood-
ci cula ing bioma ke s ela ed o b ain heal h in o e weigh o obese child en:
he Ac i eB ains p ojec . J Spo Heal h Sci. 2023;12:175–85.
77. Sha ano a NE, Ki bae a NV, To opygin IY, Kh yapo a EV, Koplik EV, So o CK, e al.
E ec o acu e emo ional s ess on p o eomic p ofile o selec ed b ain a eas and
lysosomal p o eolysis in a s wi h di e en beha io al ac i i y. Bull Exp Biol Med.
2016;161:355–8.
78. Wang Z, Li P, Wu T, Zhu S, Deng L, Cui G. Axon guidance pa hway genes a e
associa ed wi h schizoph enia isk. Exp The Med. 2018;16:4519–26.
79. Zhanae a SY, Rogozhniko a AA, Alpe ina EL, Ge o gyan MM, Ido GV. Changes in
ac i i y o cys eine ca hepsins b and l in b ain s uc u es o mice wi h agg essi e
and dep essi e-like beha io o med unde condi ions o social s ess. Bull Exp
Biol Med. 2018;164:425–9.
80. Bosca ino C, Nalpa hamkalam T, Pellecchia G, Li W, Thi u ahind apu am B, Me ico
D. Using nex -gene a ion sequencing ansc ip omics o de e mine ma ke s o
pos - auma ic symp oms: p elimina y findings om a pos -deploymen coho
o soldie s. G3. 2019;9:463–71.
81. Han Q-Q, Wu P-F, Li Y-H, Cao Y, Chen J-G, Wang F. SVCT2–media ed asco bic acid
up ake bu e s s ess esponses ia DNA hyd oxyme hyla ion ep og amming o
S100 calcium-binding p o ein A4 gene. Redox Biol. 2022;58:102543.
82. Pank a o a S, Klingelho e J, Dmy iye a O, Owcza ek S, Renziehausen A, Syed N,
e al. The S100A4 p o ein signals h ough he E bB4 ecep o o p omo e neu-
onal su i al. The anos ics. 2018;8:3977–90.
83. Salminen LE, Schofield PR, Pie ce KD, B uce SE, G i fin MG, Ta e DF, e al. Vul-
ne abili y o whi e ma e ac s and cogni ion o he SOD2 polymo phism: a
p elimina y s udy o an ioxidan de ense genes in b ain aging. Beha B ain Res.
2017;329:111–9.
84. Wang J, Miao Y, Wicklein R, Sun Z, Wang J, Jude KM, e al. RTN4/NoGo- ecep o
binding o BAI adhesion-GPCRs egula es neu onal de elopmen . Cell.
2021;184:5869–.e25.
85. Willi R, Schwab ME. Nogo and Nogo ecep o : ele ance o schizoph enia?
Neu obiol Dis. 2013;54:150–7.
86. Ji oku D, Ha o i E, Iwayama Y, Yamada K, Toyo a T, Kikuchi M, e al. Associa ion
s udy o Nogo- ela ed genes wi h schizoph enia in a Japanese case-con ol
sample. Am J Med Gene Pa B Neu opsychia Gene . 2011;156:581–92.
87. Kimu a H, Fuji a Y, Kawaba a T, Ishizuka K, Wang C, Iwayama Y, e al. A no el a e
a ian R292H in RTN4R a ec s g ow h cone o ma ion and possibly con ibu es
o schizoph enia suscep ibili y. T ansl Psychia y. 2017;7:e1214.
88. G acia DFK, Gomes EMP, Coelho TA, Ca iello M, de And ade FA, Ba ia L, e al.
Ficolin ac i a ion as a po en ial bioma ke o he se e i y o schizoph enia. Psy-
chia y Res. 2021;304:114122.
89. Rome AL, Knod AR, Sison ML, I eland D, Hou s R, Ram akha S, e al. Replicabili y
o s uc u al b ain al e a ions associa ed wi h gene al psychopa hology: e idence
om a popula ion- ep esen a i e bi h coho . Mol Psychia y. 2021;26:3839–46.
90. Bell AW, Deu sch EW, Au CE, Kea ney RE, Bea is R, Sechi S, e al. A HUPO es
sample s udy e eals common p oblems in mass spec ome y–based p o-
eomics. Na Me hods. 2009;6:423–30.
91. Laza C, Ga o L, Fe o M, B uley C, Bu ge T. Accoun ing o he mul iple na u es
o missing alues in label- ee quan i a i e p o eomics da a se s o compa e
impu a ion s a egies. J P o eome Res. 2016;15:1116–25.
92. Paul D, Kuma A, Gajbhiye A, San a MK, S ikan h R. Mass spec ome y-based
p o eomics in molecula diagnos ics: disco e y o cance bioma ke s using issue
cul u e. Biomed Res In . 2013;2013:1–16.
93. Ioannidis JPA. Compa ison o e ec sizes associa ed wi h bioma ke s epo ed in
highly ci ed indi idual a icles and in subsequen me a-analyses. JAMA.
2011;305:2200.
94. Nes izhskii AI. P o eogenomics: concep s, applica ions and compu a ional s a-
egies. Na Me hods. 2014;11:1114–25.
95. Da alie a K, Kos o ska IM, Dwo k AJ. P o eomics esea ch in schizoph enia. F on
Cell Neu osci. 2016;10:18.
96. Rod igues-Amo im D, Ri e a-Bal anás T, Vallejo-Cu o MdelC, Rod iguez-Jama do
C, de las He as E, Ba ei o-Villa C, e al. P o eomics in schizoph enia: a ga eway o
disco e po en ial bioma ke s o psychoneu oimmune pa hways. F on Psy-
chia y. 2019;10:885.
ACKNOWLEDGEMENTS
We g a e ully acknowledge he con ibu ion o he Ea ly En i onmen al Quali y and
li e-cou se men al heal h e ec s (Equal-Li e) p ojec eam, he Tu ku P o eomics
Facili y eam suppo ed by Biocen e Finland o mass spec ome y, and he
labo a o y assis ance o Ms. Mi ka Tikkanen. We also hank Teemu Pal iainen and Mia
U jansson o da a and sample managemen , as well as Ma ja Heinonen-Guzeje and
Gabin D oua d o hei eedback on he manusc ip . This p ojec has ecei ed
unding om he Eu opean Union’s Ho izon 2020 esea ch and inno a ion p og am
unde g an ag eemen No 874724. Equal-Li e is pa o he Eu opean Human
Exposome Ne wo k. Pheno ype and omics da a collec ion in FinnTwin12 coho has
been suppo ed by FP7-HEALTH-F4-2007, g an ag eemen numbe 201413, Na ional
Ins i u e o Alcohol Abuse and Alcoholism (g an s AA-12502, AA-00145, and AA-
09203 o R J Rose; AA15416 and K02AA018755 o D M Dick; R01AA015416 o Jessica
Sal a o e) and he Academy o Finland (g an s 100499, 205585, 118555, 141054,
264146, 308248 o JK, and he Cen e o Excellence in Complex Disease Gene ics
(g an s 312073, 336823, and 352792 o J Kap io). J Kap io acknowledges suppo om
he Academy o Finland (g an s 265240, 263278) and he Sig id Juselius Founda ion.
AUTHOR CONTRIBUTIONS
KMK, ISM, JK, and I K designed he s udy. JK, AW LP, and RJR guided he p ocess and
p o ided he samples. ISM, MI, and AA p e-p ocessed he samples. AMA pe o med
s a is ical and bioin o ma ics analyses. A-KP, AMA, ISM, and MI pa icipa ed in
planning and li e a u e analyses. AMA, A-KP, AW, and KMK d a ed he manusc ip .
AW, JK, LP, and RJR p o ided c i ical inpu o he d a manusc ip . All au ho s ead
and app o ed he final e sion o he manusc ip .
CONFLICT OF INTEREST
The au ho s decla e no compe ing in e es s.
ADDITIONAL INFORMATION
Supplemen a y in o ma ion The online e sion con ains supplemen a y ma e ial
a ailable a h ps://doi.o g/10.1038/s41398-024-02751-z.
Co espondence and eques s o ma e ials should be add essed o Ka ja M.
Kanninen.
Rep in s and pe mission in o ma ion is a ailable a h p://www.na u e.com/
ep in s
Publishe ’s no e Sp inge Na u e emains neu al wi h ega d o ju isdic ional claims
in published maps and ins i u ional a filia ions.
A.M. A onin e al.
8
T ansla ional Psychia y (2024) 14:55
Open Access This a icle is licensed unde a C ea i e Commons
A ibu ion 4.0 In e na ional License, which pe mi s use, sha ing,
adap a ion, dis ibu ion and ep oduc ion in any medium o o ma , as long as you gi e
app op ia e c edi o he o iginal au ho (s) and he sou ce, p o ide a link o he C ea i e
Commons license, and indica e i changes we e made. The images o o he hi d pa y
ma e ial in his a icle a e included in he a icle’s C ea i e Commons license, unless
indica ed o he wise in a c edi line o he ma e ial. I ma e ial is no included in he
a icle’s C ea i e Commons license and you in ended use is no pe mi ed by s a u o y
egula ion o exceeds he pe mi ed use, you will need o ob ain pe mission di ec ly
om he copy igh holde . To iew a copy o his license, isi h p://
c ea i ecommons.o g/licenses/by/4.0/.
© The Au ho (s) 2024
A.M. A onin e al.
9
T ansla ional Psychia y (2024) 14:55
