Translational Developmental Psychiatry

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Neurological soft signs in patients with

schizophrenia: current knowledge and future
perspectives in the post-genomics era

Sergi Papiol, Mar Fatj-Vilas & Thomas G Schulze

To cite this article: Sergi Papiol, Mar Fatj-Vilas & Thomas G Schulze (2016) Neurological
soft signs in patients with schizophrenia: current knowledge and future perspectives in the post-
genomics era, Translational Developmental Psychiatry, 4:1, 30071, DOI: 10.3402/tdp.v4.30071

To link to this article: http://dx.doi.org/10.3402/tdp.v4.30071

2016 Sergi Papiol et al.

Published online: 08 Jul 2016.

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 Translational
Developmental
Psychiatry

REVIEW ARTICLE

Neurological soft signs in patients with schizophrenia:

current knowledge and future perspectives in the
post-genomics era
Sergi Papiol1,2,3*, Mar Fatjo-Vilas3,4,5 and Thomas G Schulze1
1
Institute of Psychiatric Phenomics and Genomics (IPPG), Ludwig Maximilian University, Munich, Germany;
2
Molecular and Behavioural Neurobiology, Department of Psychiatry, Ludwig Maximillian University, Munich,
Germany; 3Centro de Investigacion Biomedica en Red de Salud Mental (CIBERSAM), Instituto de Salud
Carlos III, Madrid, Spain; 4Departament de Biologia Animal, Facultat de Biologia, Institut de Biomedicina
de la Universitat de Barcelona (IBUB), Universitat de Barcelona, Barcelona, Spain; 5FIDMAG Hermanas
Hospitalarias Research Foundation, Barcelona, Spain

Neurological soft signs (NSS), minor and subtle neurological abnormalities in sensory integration and motor
performance that are not part of a properly defined neurological syndrome, have been consistently observed in
patients with schizophrenia. The prevalence estimates of NSS in patients with schizophrenia have been reported
to be higher than in healthy subjects. Current evidence suggests that NSS are an integral part of the disease and
cannot be fully explained by the exposure to antipsychotic medication, as they are already present in treatment-
nave patients. NSS have been associated with cardinal features of the disorder such as cognitive impairment,
psychopathological severity, or functional outcome. The increased prevalence of NSS and/or related motor
precursors has been described at different stages of development (infancy, childhood, adolescence) in those
subjects who later developed schizophrenia. Evidence from family and twin studies indicates that genetic
factors play an important role in the emergence of NSS, and some authors have already suggested that such
neurological anomalies are suitable endophenotypes for schizophrenia. Some genetic association studies based
on a candidate gene approach have already reported the association of genetic variants with the severity of NSS.
This non-systematic review describes the potential relevance of NSS 1) in the understanding of schizophrenia as
a neurodevelopmental disorder, 2) as outcome predictors, 3) as biological markers during several stages of
development, and 4) as a candidate (endo)phenotype for genetic analyses. Likewise, the possibilities afforded by
the advances in high-throughput techniques in genomic analysis are also discussed.
Keywords: genome-wide association studies; motor function; sensory integration; endophenotype

Received: 18 October 2015; Revised: 28 April 2016; Accepted: 29 April 2016; Published: 8 July 2016

chizophrenia is an extremely severe and disabling Regarding the aetiology of the disorder, compelling

S neuropsychiatric disorder which usually emerges

during adolescence or early adulthood. It is char-
acterised by a set of symptoms and signs that include
evidence supports the notion that schizophrenia is a
neurodevelopmental disorder (3, 4). This model suggests
that schizophrenia is the final behavioural consequence of
delusions, hallucinations, paranoid ideation, disordered neurodevelopmental disturbances that start long before
thought, and cognitive impairment. Alterations in drive the onset of behavioural/clinical symptoms. Such distur-
and volition, blunted emotions, difficulties in commu- bances would be the result of certain combinations of
nication, and motor abnormalities are also commonly genetic and environmental risk factors. As regards genetic
observed in these patients. These symptoms and signs are risk factors, recent genome-wide association studies
generally clustered into positive, negative, cognitive, (GWAS) have just started to shed light on the polygenic
disorganisation, mood, and motor symptom dimensions architecture of this and other neuropsychiatric disorders
(1, 2). At least some of these dimensions (e.g. positive, (5, 6). However, the role of this genetic risk component in
negative, disorganisation) have different levels of pro- a developmental framework still needs to be ascertained.
minence across time and across individuals, making the Among environmental insults potentially related with
course and outcome of schizophrenia heterogeneous and alterations in neurodevelopment, obstetric/perinatal com-
clinically diverse (2). plications and prenatal infections are perhaps the most
Translational Developmental Psychiatry 2016. # 2016 Sergi Papiol et al. This is an Open Access article distributed under the terms of the Creative Commons 1
Attribution-Noncommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), permitting all non-commercial use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Citation: Translational Developmental Psychiatry 2016, 4: 30071 - http://dx.doi.org/10.3402/tdp.v4.30071
(page number not for citation purpose)
Sergi Papiol et al.

Fig. 1. Schematic summary of the current evidences of the presence of NSS or potentially related psychomotor precursors in
those subjects at high risk or who eventually developed schizophrenia across the developmental span. The developmental
periods in which environmental or genetic risk factors are relevant are also depicted. The period in which schizophrenia onset is
more likely is also represented. CNS: central nervous system; NSS: neurological soft signs.

commonly reported and replicated factors increasing the
risk of schizophrenia (7
10).
Several indicators of an abnormal development already
present in early childhood also support a neurodevelop-
mental model. Significant neuromotor impairments are
frequently observed in an important proportion of
schizophrenia patients many years before the full-blown
clinical symptomatology appears (11). Developmental
delays in the areas of motor/language development are
more frequently found in patients with schizophrenia than
in the general population (12
14). Likewise, lower general
cognitive abilities and impaired social development have
been observed in children who will later develop this
disorder with respect to those who will not (11, 13, 15
19).
Brain imaging has also provided evidence of structural
brain disturbances present before the onset of the disease
or in first-episode schizophrenia patients (20
22).
Congenital abnormalities are perhaps the features that
better illustrate the effect of early developmental insults
on the overall phenotype of this disorder. In this sense,
minor physical anomalies (23, 24) or dermatoglyphic
deviances (25, 26) have been found in these patients in a
higher frequency than in the general population. Besides
these features, neurological soft signs (NSS) are another
marker of especial interest (27). The present non-systematic
review will focus on the potential relevance of NSS 1) in
the understanding of schizophrenia as a neurodevelop-
mental disorder, 2) as outcome predictors, 3) as biological
markers during several stages of development, and 4) as a
suitable phenotype for genetic analyses.
NSS in schizophrenia patients
An interesting observation in an important percentage
of patients with schizophrenia after a careful clinical
evaluation is the presence of NSS, minor and subtle
neurological abnormalities in sensory integration and
motor performance (Fig. 1). NSS have been defined as
neurological abnormalities that, in principle, are not part
of a properly defined neurological syndrome (27). The
Neurological Evaluation Scale (28) and the Cambridge
Neurological Inventory (29) are the most commonly used
scales to measure NSS. Clustering analyses considering
the items contained in these or similar scales have shown
that NSS can be grouped into several categories: integra-
tive sensory function, motor coordination, sequencing of
complex motor acts, and primitive reflexes (30). These
categories should not be considered as definitive since
different authors have proposed different groupings of
signs depending on the analytical approaches/principles
applied (31
33).
The original definition of NSS considered the fact that
they cannot be easily linked to abnormalities in specific
brain regions. However, advances in structural and
functional neuroimaging techniques have already pro-
vided some clues regarding the neuroanatomical sub-
strate of, at least, some of these NSS (34
39). In a recent
meta-analysis, NSS have been associated with atrophy in
precentral gyrus, cerebellum, inferior frontal gyrus, and
thalamus (40). The same study also showed that NSS-
related tasks resulted in abnormal brain activation in

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inferior frontal gyrus, bilateral putamen, cerebellum, and
superior temporal gyrus (40).
Despite the differences in the scales and cluster
definitions, both descriptive reviews and meta-analytic
approaches have consistently shown that NSS are more
commonly observed in patients with schizophrenia com-
pared with healthy controls (27, 30, 41
43). Likewise, a
very important fraction of these patients (73%) has been
reported to show NSS aggregate scores outside the range
observed in the healthy population (42). According to
these studies, NSS represent one of the traits that better
differentiates schizophrenia patients from healthy sub-
jects. However, it has to be mentioned that it is not
a specific feature of this disorder since NSS have also
been observed in other neuropsychiatric disorders (30),
although discussion exists about the specificity of some
NSS clusters (32, 39).
An important confounding factor that may have
influenced the aforementioned studies is antipsychotic
medication. Motor side effects induced by this treatment
such as tardive dyskinesia may easily be rated as NSS.
As regards this issue, studies based on neuroleptic-nave
patients have shown that NSS are, to a large extent, not
dependent on the exposure to antipsychotic treatment
(39, 44, 45). Moreover, no associations have been found
between antipsychotic medication dosage and NSS (30, 42).
However, some studies have observed associations be-
tween extrapyramidal symptoms or tardive dyskinesia
and NSS (44, 46). Taken together, these results indicate
that NSS are an integral part of the disease rather than
the result of the exposure to antipsychotic medication.
NSS and the clinical phenotype of
schizophrenia
Besides the intrinsic interest of NSS as indicators of an
altered neurodevelopment in patients with schizophrenia,
an increasing body of evidence suggests that NSS might
be an important predictor of psychopathological severity,
neurocognitive impairment, and overall functional out-
come in this disorder (30, 42, 43).
Specifically, studies ascertaining the relationship be-
tween psychopathology and NSS have reported that
neurological signs have an important correlation with the
severity of negative symptoms and the degree of disorga-
nised behaviour (47
51). On the contrary, evidence of an
influence on positive symptomatology is less conclusive
(52, 53).
Cognitive impairment is increasingly being recognised
as a core feature of schizophrenia. It affects several
domains: working memory, executive function, verbal/
visual learning, attention or speed of processing, among
others (54, 55). The literature regarding the relationship
between NSS and cognition suggests that specific NSS
clusters are associated with specific cognitive domains
(30, 42, 43). Regarding functional outcome, several
Citation: Translational Developmental Psychiatry 2016, 4: 30071 - http://dx.doi.org/10.3402/tdp.v4.30071
Neurological soft signs in patients with schizophrenia
studies have reported that NSS are associated with worse
pre-morbid functioning, longer hospitalisation length, or
a worse social functioning (56
59).
An important consideration while assuming that
NSS are a schizophrenia trait is their stability over the
course of the disorder. The static/dynamic status of NSS
has important implications not only for their potential
predictive value regarding clinical course but also for
their definition as a candidate endophenotype for genetic
analyses (41). Several studies have reported that some
motor anomalies, which could be understood as pre-
cursors of NSS, are already present long before the onset
of the disease (12, 60, 61). Along the same lines, studies
in high-risk individuals and in first-episode medication-
nave patients have also reported the higher prevalence of
NSS with respect to healthy controls (62
66). These and
other studies provide evidence for the pre-existence of
neurological disturbances in subjects at risk to develop
schizophrenia and reinforce the hypothesis of schizo-
phrenia as a neurodevelopmental disorder (see the next
section for further details). These studies, however, lack
the capacity to explain if once NSS are established, they
remain with or without fluctuations over the course
of the disorder. As regards the NSS stability over time,
some studies have shown that the decrease of NSS scores
across adolescence is a normal brain maturation process
in healthy subjects that is to a certain degree impaired
in patients with schizophrenia. However, it is not clear
which NSS domains are affected as a result of a deviation
from this maturation process (67, 68).
Some individual longitudinal studies (69) and a recent
meta-analysis (70) have provided interesting evidence
of NSS scores decreasing in parallel with remission of
psychopathological symptoms, although not reaching the
scores typically observed in healthy subjects, suggesting
the putative role of NSS as disease progression markers.
It should be noted, however, that some follow-up studies
have observed an important degree of stability in NSS
over the course of schizophrenia (71).
Neurological abnormalities in childhood and
adolescence
As already mentioned in the previous section, a signifi-
cant amount of evidence indicates that 1) NSS are present
before the onset of the disease and 2) a decrease in NSS
scores during adolescence is a normal process that may
be altered in schizophrenia patients (Fig. 1). From a
neurodevelopmental perspective, the close relationship
between an altered development and NSS has been
shown by several studies reporting that very early
developmental insults are associated with increased NSS
scores in the postnatal period (59, 72
75).
Prospective studies spanning infancy through adoles-
cence have reported compelling evidence of the associa-
tion of neurodevelopmental abnormalities/delays with
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Sergi Papiol et al.
schizophrenia (76). In a prospective study based on the
British 1946 Birth Cohort, patients with schizophrenia
achieved motor development milestones later than con-
trols (13). The milestone with the most striking differences
between cases and controls was walking (13). Data from
the Northern Finland 1966 Birth Cohort pointed in a
similar direction, showing that a later attainment of motor
development milestones such as standing or walking was
associated with a higher risk of schizophrenia in adult-
hood (77). The analysis of the 1972
1973 Cohort from
Dunedin, New Zealand, reported that children who
eventually developed a schizophreniform disorder showed
a poorer motor function over the several assessments they
underwent during childhood (11). Rosso et al., also in a
prospective approach based on the 1959
1966 Boston
NCPP Cohort, observed anomalies in motor coordina-
tion at 7 years of age and unusual movements at ages
4 and 7 in children who later developed schizophrenia (78).
Cannon et al., by using a case-control design nested
within the 1951
1960 Helsinki Cohort, observed a motor
coordination deficit in those children who developed
schizophrenia in adulthood (79).
In this context, studies based on the analysis of home
movies of children who later developed schizophrenia are
also of special interest. Walker et al. showed that during
the first 2 years of life, motor skills and neuromotor
functioning had important differences between children
who later developed schizophrenia and those who did
not (12). Subsequent studies, based on a similar design
(videotaped behaviours), also reported these deficits on
general neuromotor functioning at older ages in children
who later suffered the disorder (80).
Another methodological approach that has reported
interesting results is the assessment of neuromotor im-
pairments in high-risk children (81, 82). High-risk children
are defined as those with relatives (mainly parents) with
schizophrenia/psychosis diagnoses. Taking into account
the outstanding heritability estimates of the disorder (83)
and the evidence from previous family studies (84), these
children are potential carriers of a substantial genetic risk
to develop schizophrenia. According to the results of the
Swedish high-risk study, already on the third or fourth day
of life, neurological deviations can be observed in the
offspring of mothers diagnosed with schizophrenia (85).
The combination of a sample characterised by a high
genetic risk burden together with a prospective design is
theoretically optimal to understand how high-risk subjects
behave regarding neuromotor function, cognition, social
adjustment during childhood
adolescence, or their re-
sponse upon exposure to environmental risk factors such
as obstetric complications or drug use. Likewise, such a
design has the potential to identify indicators/markers
of risk long before the onset of the disorder. The first
notable approach using this design was carried out
in the context of the New York Infant Study (86).
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The author showed that 7 out of 12 high-risk children had
a neurointegrative defect characterised by a delay of
motor development (together with other developmental
features). These seven infants received a diagnosis of
schizophrenia, or schizotypal or paranoid personality
disorder (1:5:1) in adulthood. Several of these types of
studies indicated the existence of an altered psychomotor
development during the first 2 years of life (86
90). It
should be noted, however, that two of the studies observed
a reduction of these abnormalities with age (90, 91). Such a
resolution with age during infancy is difficult to interpret
taking into account the disturbances in coordination
and fine motor control commonly observed in high-risk
individuals during childhood and adolescence (63, 86, 88,
92). For example, the New York High-Risk Project
reported, after neurobehavioural measuring, deficits in
gross motor skills in 75% of the children between 7 and
12 years of age who were diagnosed with schizophrenia-
related psychosis in adulthood (63). Very similar results
were obtained by the Swedish high-risk study after
analysing 6-year-old children as regards gross and fine
neuromotor deviations (93). Mild incoordination and
awkwardness while performing rapidly alternating move-
ments at age 7 were especially frequent in the offspring of
patients with schizophrenia in the Boston NCPP Study
(94). With regards to school age and adolescence periods,
the Jerusalem Infant Development Study reported poor
motor coordination, poor right
left orientation, poor
balance, and motor overflow in the offspring of patients
with a schizophrenia diagnosis (95). The same study
reported that poor neurobehavioural functioning was
two times more frequent in the adolescent offspring
of patients with this disorder than in the offspring of
control parents, with male offsprings showing a poorer
functioning (96).
Taken together, these results indicate that slow neuro-
motor development is one of the main known risk factors
in the development of schizophrenia (97). Although some
of the motor abnormalities described in these studies are
not strictly NSS according to standard definitions, they
could be understood as the first indicators of a neurolo-
gical disturbance in these children.
Overlap between general neurological
abnormalities and NSS
Although evidence suggests a certain continuum of
anomalies starting with a very early neuromotor dysfunc-
tion eventually leading to subtle neurological anomalies in
adult patients with schizophrenia, it has not been firmly
proved. Moreover, a considerable fraction of patients with
schizophrenia show motor signs not considered as NSS
such as abnormal involuntary movements, parkinsonism,
catatonia, or psychomotor slowing (98, 99). These reports
suggest that, at least regarding motor functions, NSS
would represent one of the expressions of an aberrant

motor system rather than a final developmental stage of a
generalised motor dysfunction.
Among those studies measuring NSS with suitable
instruments, the Jerusalem Infant Development Study
explored the stability of NSS over time, showing a long-
term stability from the childhood to adolescent assess-
ments regarding motor coordination, motor overflow,
and sensory-perceptual signs (95). In the context of the
same prospective study, Hans et al. observed that 40% of
the high-risk adolescents with a poor neurobehavioural
functioning already had a poor functioning in infancy
and school age (96). Interestingly, a cohort study from
Sweden reported that the total score for neurological
abnormalities at 22 years in high-risk subjects correlated
positively with the score at 6 years of age (100). However,
the same study failed to find such a correlation between
the score at 22 years and the score registered during early
infancy (100).
Data provided by these studies suggest that 1) NSS in
high-risk subjects present a certain degree of stability
during childhood
adolescence and 2) the link between
very early neuromotor abnormalities and NSS in adult
patients is not straightforward, especially considering that
fluctuations in these neurological functions are expected
to happen as brain maturation progresses. Understanding
whether this heterogeneous group of neurological distur-
bances across the developmental span have a similar origin
or, on the contrary, represent different biological processes
with phenotypical resemblance might help elucidate their
interest as predictors of disease onset/course at different
stages of development. Likewise, it might lead to the
definition of suitable phenotypes for genetic analysis.
Evidence for a genetic component in NSS
The first family studies taking into consideration NSS
already described their increased frequency in non-
affected relatives of patients with schizophrenia compared
with healthy controls (101, 102). Most of the subsequent
family studies have reported that healthy relatives of
patients with schizophrenia diagnosis have higher NSS
scores than healthy independent controls and lower NSS
scores than their relatives with schizophrenia (31, 100,
103
115). In the review by Bombin et al., motor signs are
suggested to be the cluster of signs with a larger overlap
with schizophrenia genetic vulnerability (30). These
results have been confirmed using meta-analytic techni-
ques (116, 117). These findings suggest that NSS are, to a
certain extent, genetically determined.
In this context, NSS heritability (h2) studies are of
special interest in order to ascertain the amount of phe-
notypic variance of NSS that can be explained by genetic
factors (118). Few studies have attempted to estimate the
heritability of NSS (31, 119, 120). One of them reported
important h2 values (between 0.53 and 0.99) for measures
of neurological motor signs while the other NSS clusters
Citation: Translational Developmental Psychiatry 2016, 4: 30071 - http://dx.doi.org/10.3402/tdp.v4.30071
Neurological soft signs in patients with schizophrenia
barely provided any outstanding heritability estimate
(120). Convergent evidence from family-based and herit-
ability studies, therefore, suggest that NSS clusters closely
related to motor function would be the ones better suited
for genetic analyses. However, further heritability studies
are warranted in order to obtain better estimates of the
heritability of not only the total NSS but also the
different clusters of signs.
According to the evidence mentioned in the previous
sections, NSS 1) behave as a trait marker within the
schizophrenia phenotype, 2) have a close relationship
with some of the cardinal features of the disorder, 3) may
have an important predictive value regarding functional
outcomes, and 4) are closely related to developmental
events leading to the disease onset. Therefore, under-
standing how genetic factors determine the emergence of
NSS might provide clues to specific genetic factors that
contribute to the risk of schizophrenia in the context of
an altered neurodevelopment. In this sense, the potential
interest of NSS as candidate endophenotypes in schizo-
phrenia has been thoroughly discussed in a review by
Chan and Gottesman (41). These authors concluded that
NSS meet most of the criteria required for an endophe-
notype to be useful, although they acknowledged that
further research is required in order to confirm their
potential as suitable phenotypes for genetic analyses.
Molecular genetics and NSS
Despite the interest of NSS in a genetic context, few
studies have attempted to associate them with specific
genetic variants in genes of interest. The scarce literature
based on candidate-gene approaches, however, has re-
ported some results of interest. The first of these studies
analysed a single nucleotide polymorphism (SNP) in the
serotonin 2-A receptor gene (HTR2A, chr13q14.2) in a
sample of Han Chinese population (121). This study found
a trend for association between this genetic variant
(T102C) and lower NSS scores related to motor coordina-
tion in schizophrenia. Interestingly, very similar results
have been obtained in a more recent study based on a
Caucasian sample (122). In this study, the T102C poly-
morphism of the HTR2A gene was also associated with
a lower degree of NSS related to motor coordination
in a sample of schizophrenia patients. Another study
based on the catechol-O-methyltransferase gene (COMT,
chr22q11.21) analysed the influence on NSS of another
SNP which modifies the structure and function of the
resulting protein (Val158Met) (123). This study, based on a
Caucasian population, found an association of Val158Met
polymorphism with cognitive and motor deficits in
patients with schizophrenia. Another study based on
general healthy population reported the effect apolipo-
protein E gene (APOE, chr19q13.32) variants have on
NSS (124). This study showed the association of APOE4
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Sergi Papiol et al.
variant with NSS and its interest to identify subjects at risk
of cognitive decline in later life.
NSS in the post-genomics era: current and
future challenges
Genetic studies of complex traits like psychiatric pheno-
types have experienced a revolution in the past few years
as a result of the technological advance in high-throughput
techniques for genomic analysis (5). In this regard GWAS
have significantly contributed to the understanding of the
genetic architecture of many complex traits (see GWAS
Catalog www.ebi.ac.uk/gwas/).
Neuropsychiatric disorders are not an exception, and
GWAS have currently identified more than 100 loci
associated with an increased risk of schizophrenia (6).
Moreover, these studies have shed light on the polygenic
nature of this disorder in which, as in many other
complex traits such as height (125), body mass index
(126), or multiple sclerosis (127), the contribution of each
common genetic variant to the phenotype is small but the
global effect of many of these variants accounts for an
important fraction of the phenotype.
To our knowledge, only one study has analysed the role
of specific genetic variants identified by GWAS on NSS. In
this study, a genetic variant (rs1344706) in the ZNF804A
gene (chr2q32.1) has been found to be associated with
NSS, although results are difficult to interpret since the
schizophrenia risk allele was associated with the presence
of fewer NSS (128). Such an approach can be useful to
unmask the role of common genetic variants in both the
risk of schizophrenia and the emergence of these neuro-
logical anomalies.
The possibility of carrying out genome-wide association
studies with NSS as the target phenotype might pave the
way for a better understanding of the genetic architecture
of NSS. Since small genetic effects are expected despite the
use of such a potential endophenotype, large samples
comprehensively characterised for their neurological pro-
file, ideally using the same instruments for the assessment,
would be needed in order to gain enough statistical power.
Likewise, this approach should include not only patients
with schizophrenia but also healthy relatives and indivi-
duals from the general population in order to determine if
the potential genetic associations are diagnosis specific or,
on the contrary, such genetic effects influence the expres-
sion of NSS regardless of the diagnostic status. Moreover,
equally assessed subjects at genetic risk (high-risk sub-
jects) at different developmental times should also be
included in order to ascertain the role of genetic variants in
premorbid stages of the disease. Last but not least, the
potential interactions between a genetic risk background
with environmental factors acting in early developmental
stages such as, for example, obstetric complications or
prenatal infections should also be considered.
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Citation: Translational Developmental Psychiatry 2016, 4: 30071 - http://dx.doi.org/10.3402/tdp.v4.30071
If the difficulties of collecting a sample with these
characteristics could be overcome, GWAS analyses using
NSS as the target phenotype might help elucidating the
role of genetic factors intimately related to the processes
leading to an altered neurodevelopment in patients with
schizophrenia. This could consequently provide a better
understanding of the aetiology of schizophrenia in the
context of a neurodevelopmental model, despite the fact
that NSS cannot be considered as predictors of the risk of
schizophrenia due to the lack of specificity. Likewise, it
could enhance the identification of genetic factors closely
related to disease features involving psychopathology,
cognition, or functional outcome, finally finding paths
from genes to the clinical subphenotypes that have been
elusive so far.
Conflict of interest and funding
The authors report no conflict of interest. This research
was funded by the Deutsche Forschungsgemeinschaft
(DFG) grants: Klinische Forschergruppe (KFO) 241:
Genotype-phenotype relationships and neurobiology of
the longitudinal course of psychosis TP1 (SCHU 1603/5-
1) and PsyCourse Project 1: Complex clinical, neurobio-
logical, and molecular signatures of the longitudinal
course of psychosis: leveraging comprehensive phenotyp-
ing, novel machine learning, and (epi)genomic approaches
(SCHU 1603/7-1). Thomas G. Schulze was supported by
the Lisa-Oehler-Foundation. This work was also sup-
ported by the Spanish Ministry of Economy and Com-
petitivity, Instituto de Salud Carlos III (PI15/01420)

co-financed by Fondo Europeo de Desarrollo Regional
(FEDER) Una manera de hacer Europa. Thanks to
CIBERSAM and to Comissionat per a Universitats i
Recerca del DIUE (2014SGR1636).
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*Sergi Papiol
Institute of Psychiatric Phenomics and Genomics (IPPG)
Ludwig Maximilian University
Nussbaumstrasse 7
DE-80336 Munich, Germany
Email: sergi.papiol@med.uni-muenchen.de