Review article 1
Schizophrenia in a genomic era: a review from the
pathogenesis, genetic and environmental etiology to
diagnosis and treatment insights
Mansour Zamanpoora,b
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Schizophrenia is a common multigenic and debilitating
neurological disorder characterized by chronic psychotic
symptoms and psychosocial impairment. Complex
interactions of genetics and environmental factors
have been implicated in etiology of schizophrenia.
There is no central pathophysiology mechanism,
diagnostic neuropathology, or biological markers have
been defined for schizophrenia. However, a number of
different hypotheses including neurodevelopmental and
neurochemical hypotheses have been proposed to explain
the neuropathology of schizophrenia. This review provides
an overview of pathogenesis, genetic and environmental
etiologies to diagnosis and treatment insights in clinical
management of schizophrenia in light of the recent
Introduction
Schizophrenia is a relatively common and debilitating
neurological disorder characterized by chronic psychotic
symptoms and psychosocial impairment (Wong and Van
Tol, 2003). Schizophrenia is a multigenic disorder with
an estimated heritability of 81% and affects about 1% of
the population worldwide (Sullivan et al., 2003; Ross et al.,
2006). There are substantial co-morbidity of social isola-
tion, depression, substance abuse, and suicide in patients
with schizophrenia as a psychiatric illness (Lewis and
Gonzalez-Burgos, 2006).
Schizophrenia is made up of three types of symp-
toms, negative, positive, and cognitive (Birnbaum and
Weinberger, 2017). Negative symptoms have been con-
ceptualized as a core aspect of schizophrenia and consist
of five constructs including affective flattening or blunt-
ing (a decrease in the observed emotional expression and
reactivity), alogia (lack of additional, unprompted content
seen in normal speech), anhedonia (inability to experi-
ence pleasure), asociality (lack of motivation to engage in
social interaction), and avolition (lack of desire or moti-
vation) (Marder and Galderisi, 2017). Positive symptoms
include paranoid delusions, hallucinations, bizarre behav-
ior, and positive formal thought disorder (Birnbaum and
Weinberger, 2017; Bliksted et al., 2017). Cognitive symp-
toms includes poor trouble focusing, deficits in executive
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discoveries of genetic loci associated with susceptibility to
schizophrenia. Psychiatr Genet 30: 1–9 Copyright © 2019
Wolters Kluwer Health, Inc. All rights reserved.
Psychiatric Genetics 2020, 30:1–9
Keywords: schizophrenia, neurogenetics, neuropathology, neuroimmune,
genomics, GWAS
a
Department of Biochemistry, University of Otago, Dunedin, New Zealand
and bWellington Regional Genetics Laboratory, Genetic Health Service New
Zealand, Wellington Regional Hospital, Wellington, New Zealand
Correspondence to Mansour Zamanpoor, Wellington Regional Genetics
Laboratory, Wellington Regional Hospital, Wellington 6021, New Zealand
Tel: +6449185352; fax: +6443855822;
e-mail: mansour.zamanpoor@ccdhb.org.nz
Received 7 March 2019 Accepted 27 September 2019
functioning and impaired working memory (Birnbaum
and Weinberger, 2017).
Pathophysiology of schizophrenia
One of the complexities of schizophrenia is that no
central pathophysiology mechanism, diagnostic neuro-
pathology, or biological markers, has been recognized in
schizophrenia (Wong and Van Tol, 2003). To explain the
neuropathology of schizophrenia, a number of different
hypotheses including neurodevelopmental and neuro-
chemical hypotheses have been proposed (Birnbaum and
Weinberger, 2017). The absence of pathological evidence
of neurodegenerative such as cytopathological inclusion
bodies, dystrophic neuritis, reactive gliosis, dysmyelina-
tion, and overall neuronal loss in schizophrenia, support
the role of the neurodevelopmental process in schiz-
ophrenia neuropathology (Wong and Van Tol, 2003).
However, the proposed neurodevelopmental and neuro-
degenerative models of the pathology are not necessarily
exclusive (Wong and Van Tol, 2003). The incorporation of
the neurodevelopmental and neurodegenerative models
has also been hypothesized in neuropathology of schizo-
phrenia (Kochunov and Hong, 2014).
Postmortem studies investigating the macroscopic and
histological pathology of schizophrenic brain tissue dis-
covered decreased brain weight, increased ventricular
volume, and abnormal neural distribution in the pre-
frontal cortex and hippocampus of schizophrenic brain
tissue (Wong and Van Tol, 2003; Brennand et al., 2011).
Neuropharmacological studies confirmed the involve-
ment of dopaminergic, glutamatergic and GABAergic
DOI: 10.1097/YPG.0000000000000245
 2 Psychiatric Genetics 2020, Vol 30 No 1
activity in schizophrenia (Javitt et al., 2008; Brennand et
al., 2011).
Induced pluripotent stem cells (iPSCs) have been
used as disease-relevant cell types from early brain
development to investigate the molecular and cellular
underpinnings of schizophrenia (Brennand et al., 2011;
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Hoffmann et al., 2018; Liu et al., 2019). The potential of
the iPSCs-based modeling of schizophrenia has been
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supported by the high concordance between transcrip-
tional signatures in iPSCs-derived cells from patients
with childhood-onset schizophrenia and differential
expression results from postmortem brain (reviewed
by Hoffmann et al., 2018).
The two-hit hypothesis, the combination of genetic
and environmental insult during early life, is consistent
with the neurodevelopmental hypothesis (Feigenson
et al., 2014). The neurodevelopmental model of schiz-
ophrenia suggest that abnormal neurodevelopmen-
tal processes start many years before the onset of the
psychotic illness, as a result of an interaction between
multiple susceptibility genes and environmental fac-
tors (Jarskog et al., 2007; Rapoport et al., 2012). This
hypothesis has been widely accepted and supported
in the childhood-onset neuropsychiatric disorders in
which brain abnormalities may pre-date disease onset
(Rapoport et al., 2012).
The neurochemical hypothesis states the involvement of
neurotransmitters such as dopamine, serotonin, and glu-
tamate in the pathophysiology of schizophrenia (Howes
and Kapur, 2009). Discovery of the dopamine receptor’s
role in inducing the schizophrenia-like psychosis led to
the ‘dopamine hypothesis’ of schizophrenia that impli-
cates dopamine hyperactivity in the psychotic symptoms
(Seeman, 1987; Wong and Van Tol, 2003; Howes and
Kapur, 2009). However, there is inconclusive evidence for
the implication of an overactive dopamine system in the
etiology of schizophrenia (Wong and Van Tol, 2003). The
glutamate neurotransmitter system and more arguably,
glutamate receptor genes, have been implicated in schiz-
ophrenia pathophysiology (Harrison and Weinberger,
2005). Furthermore, abnormal glutamate signaling is a
well-established characteristic of schizophrenia patho-
physiology (Feigenson et al., 2014).
There is growing evidence for the involvement of dis-
rupted synaptic connectivity in the pathophysiology of
schizophrenia; this has been supported by several neu-
roimaging, neurocognitive, gene array, and post mortem
neuropathological studies (Jarskog et al., 2007). Clinical
findings consistently suggested the role of molecular
alterations in three neurotransmitter systems includ-
ing glutamate, dopamine, and gamma-aminobutyric
acid neurotransmission in the pathophysiology of work-
ing memory impairments in schizophrenia (Lewis and
Gonzalez-Burgos, 2006).
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Genetic factors that contribute to
schizophrenia
The heritability of schizophrenia was estimated to be
79%–81% by using meta-analysis of twin studies (Sullivan
et al., 2003; Lichtenstein et al., 2009; Hilker et al., 2018).
The high heritability also applies in a broader neuropsy-
chiatric and schizophrenia spectrum disorders (Hilker
et al., 2018). Meta-analyses of linkage studies suggested
that many chromosomal regions may contain schizophre-
nia susceptibility loci (Ng et al., 2009; Henriksen et al.,
2017). Many genes play a role each with small to moder-
ate effect sizes in schizophrenia (Wong and Van Tol, 2003;
Modinos et al., 2013).
Prior to genome-wide association studies (GWAS), only
a few genes had been proposed as schizophrenia candi-
date genes based on their involvement in the nervous
system or their position from findings in linkage analyses
(Gejman et al., 2011). Evidence of association with neu-
rological and neurodevelopmental pathways of schizo-
phrenia has been shown in some genes including ERBB4
(Benzel et al., 2007), dystrobrevin-binding protein 1
(DTNBP1) (Weickert et al., 2004), neuroregulin 1 (NGR-1)
(Stefansson et al., 2002; Munafò et al., 2006), disrupted
in schizophrenia 1 (DISC1) (Kamiya et al., 2005), AKT1
(Tan et al., 2008), regulator of G-protein signaling 4 (RGS-
4) (Mirnics et al., 2001), catechol-O-methyl-transferase
(COMT) (Chen et al., 2004), vesicular monoamine trans-
porter 2 (VMAT2) (Richards et al., 2006), and cardiomyopa-
thy-associated 5 (CMYA5) (Chen et al., 2011). The overview
of gene loci associated with schizophrenia, including their
function and discovery method, are shown in Table 1.
Some of associated loci discovered by linkage and can-
didate gene studies have proved difficult to replicate
in subsequent studies (Henriksen et al., 2017). The low
replication can be due to false discovery, limited knowl-
edge of the candidate genes (believed to be implicated
in the pathophysiology of schizophrenia) that makes it
difficult to select relevant genes for testing, or that the
power of these studies was inadequate (Henriksen et al.,
2017). This low replication provides more support for the
hypotheses indicating that the etiology of schizophre-
nia involves multiple genes with a small contribution in
risk, interacting together or with environmental risk fac-
tors (Purcell et al., 2009; Sun et al., 2010). Furthermore,
this polygenic model of schizophrenia susceptibility
has been supported by the International Schizophrenia
Consortium (Gejman et al., 2011).
The detection of chromosomal rearrangements in patients
with schizophrenia provided evidence that structural var-
iations or copy number variants (CNVs) are implicated in
the genetic etiology of schizophrenia (Walsh et al., 2008;
Marshall et al., 2017; Kushima et al., 2018; Sriretnakumar
et al., 2019). Genome-wide enrichment of rare deletions
and duplications, and a higher rate of de-novo CNVs
have been reported in schizophrenia cases compared to
 Schizophrenia in a genomic era by Zamanpoor 3

Table 1 Overview of associated gene loci with schizophrenia including their method of discovery and function
Gene loci Function Discovery method Reference

DISC1 Neural development, proliferation, differentiation and brain Linkage studies Kamiya et al. (2005); Millar et al. (2005)
maturation, cAMP signaling
NRG1 Neuron development and differentiation. Gliogenesis, NMDAR Linkage studies Stefansson et al. (2002); Munafò et al.
pathway (2006)
AKT1 Neuronal connectivity and modulation Confirmed by GWAS Tan et al. (2008)
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COMT Dopamine metabolism Linkage studies Chen et al. (2004)

DRD2 Dopamine signaling Confirmed by GWAS Arinami et al. (1994); He et al. (2016)
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ERBB4 Receptor tyrosine kinase NRG1, NMDAR pathway Linkage studies Benzel et al. (2007); Chang et al. (2018)
DTNBP1/CMYA5 Regulation of cAMP signal pathway and the BLOC-1 processes Confirmed by GWAS Weickert et al. (2004); Chen et al. (2011)
GABRB2 GABA signaling Linkage studies Liu et al. (2005); Chang et al. (2018)
GRIN2B Glutamate signaling, NMDAR pathway Linkage studies Hong et al. (2001); Ohtsuki et al. (2001);
Chang et al. (2018)
HTR2A Serotonin signaling Confirmed by GWAS Abdolmaleky et al. (2004)
IL1B Immune system Association studies Shirts et al. (2006)
NOTCH4 Neuron development Confirmed by GWAS Wei and Hemmings (2000)
NRXN1 Synapses Linkage studies Tam et al. (2009)
PDE4B Synapses Linkage studies Millar et al. (2005)
RELN Synapses Linkage studies Abdolmaleky et al. (2005)
RGS-4 Regulator of G-protein signaling Linkage studies Mirnics et al. (2001)
VMAT2 Vesicular monoamine transporter Linkage studies Richards et al. (2006)

For schizophrenia-associated loci discovered by GWAS see (Schizophrenia Working Group of the Psychiatric Genomics, 2014) and (Li et al., 2017).

controls (Marshall et al., 2017; Sriretnakumar et al., 2019).
Most CNVs involved in schizophrenia are unique and
rare in the population but confer significant risk for schiz-
ophrenia (Gulsuner and McClellan, 2015; Marshall et al.,
2017; Kushima et al., 2018; Sriretnakumar et al., 2019).
Rare structural variants play a role in schizophrenia by
disrupting multiple genes such as NRXN1, APBA2, NRG1,
and CNTNAP2 that are involved in neurodevelopmental
pathways (e.g. neuregulin and neurexin) related to syn-
aptic development and functions (Walsh et al., 2008; Tam
et al., 2009). Several large-scale whole-genome schiz-
ophrenia association studies reported the detection of
CNVs that uncovered some schizophrenia susceptibility
loci and also highlighted some aspects of schizophrenia
pathophysiology (Tam et al., 2009; Marshall et al., 2017).
GWAS interrogate the genome purely empirically and scan
millions of single nucleotide polymorphisms (SNPs) for
associations with schizophrenia using a case-control study
design (Henriksen et al., 2017). The Molecular Genetics
of Schizophrenia (MGS) research group, namely Genetic
Association Information Network, used two sample sets,
one of European ancestry (1440 cases and 1469 controls)
and the other with African ancestry (1280 cases and 1000
controls) (Manolio et al., 2007). However few markers
reached genome-wide significance for association with
schizophrenia in the schizophrenia GWAS (Ripke et al.,
2011). The combination of SNP data from several large
studies confirmed associations of schizophrenia with sev-
eral markers in the MHC region of chromosome 6, and
in NRGN and TCF4 (Stefansson et al., 2009). MYO18B
and ZNF804A were associated with schizophrenia by
GWAS (Purcell et al., 2009). Research groups of the schiz-
ophrenia Psychiatric GWAS Consortium (PGC) collabo-
rated to create a large schizophrenia sample set (Ripke
et al., 2011). A two-stage analysis of 51 695 individuals
of European ancestry identified five novel schizophre-
nia loci and two previously implicated loci (PCGEM1,
TRIM26, CSMD1, MMP16, CNNM2-NT5C2, STT3A, and
CCDC68-TCF4) at a genome-wide level of significance
(Ripke et al., 2011). Interestingly four of these loci con-
tain MIR137 (microRNA 137) predicted targets that sug-
gest an implication of MIR137-mediated dysregulation
in schizophrenia etiology (Ripke et al., 2011). MIR137
plays a role in neuronal development by regulating neu-
ronal maturation and function (Ripke et al., 2011).
PGC conducted another GWAS with a substantially
larger sample set, combining the Swedish national sam-
ple set of 5001 cases and 6243 controls with the PGC1
GWAS dataset (PGC1 + SWE) (Ripke et al., 2013). The
number of significant schizophrenia loci at genome-
wide significance was increased to 22 by this multi-stage
meta-analyzed GWAS (Ripke et al., 2013). This GWAS
meta-analysis highlighted the importance of larger stud-
ies for discovery of common genetic variants associated
with schizophrenia (Ripke et al., 2013).
Another large multi-stage GWAS of schizophrenia was
conducted by PGC. A total of 36 989 cases and 113 075
controls, including the primary PGC GWAS dataset
and the MGS samples, were included in the analysis
(PGC2) (Schizophrenia Working Group of the Psychiatric
Genomics Consortium, 2014). 128 SNPs covering 108
defined loci including 83 novel loci were discovered
at a genome-wide level of significance (Schizophrenia
Working Group of the Psychiatric Genomics Consortium,
2014). Recently, Li et al. (2017) performed a GWAS
including 7699 cases and 18 327 controls of Chinese
ancestry that identified four novel schizophrenia risk loci
(Li et al., 2017). A transancestral GWAS meta-analysis of

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 4 Psychiatric Genetics 2020, Vol 30 No 1
Chinese individuals from the Li et al. (2017) study with
PGC2 samples identified 30 new risk loci for schizophre-
nia (Supplementary Table, Supplemental digital content
1, http://links.lww.com/PG/A231). This large molecular
genetic study of schizophrenia highlighted the power
of GWAS with large sample sizes to find additional risk
loci and indicated the existence of shared genetic risk
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across populations (Schizophrenia Working Group of the
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Psychiatric Genomics Consortium, 2014). Ikeda et al.
(2019) reported the shared genetic risk of schizophrenia
across East Asian and European populations and found 15
novel association loci with schizophrenia across Japanese,
East Asian and European populations.
Associated loci were enriched with genes expressed in
tissues with central immune functions in addition to the
brain such as dopamine receptor D2 (DRD2) and several
genes involved in glutamatergic neurotransmission and
synaptic plasticity (Schizophrenia Working Group of the
Psychiatric Genomics Consortium, 2014). Furthermore,
association between variants within the MHC locus
and schizophrenia has been replicated in several studies
implicating the MHC locus as the strongest schizophre-
nia locus (Ripke et al., 2013; Shi et al., 2009; Stefansson
et al., 2009; Schizophrenia Psychiatric Genome-Wide
Association Study, 2011; Schizophrenia Working Group
of the Psychiatric Genomics Consortium, 2014; Sekar
et al., 2016). The fact that schizophrenia associations
were also strongly enriched among immune system-re-
lated genes such as CD19 and CD20 provide genetic
support for the hypothetical role of immune dysregula-
tion in schizophrenia (Schizophrenia Working Group of
the Psychiatric Genomics Consortium, 2014). Recently,
Inoubli et al. (2018) replicated an association of variants
within TNFA and LTA genes with paranoid schizophrenia
in the Tunisian population.
Higher polygenic risk score (PRS) for schizophrenia has
been significantly associated with lower cognitive func-
tion with a potential to act as a predictor of decline in
brain structure in apparently healthy populations (Alloza
et al., 2018). The recent longitudinal study conducted by
Alloza et al. (2018) has confirmed the link between the
higher genetic liability for schizophrenia and the accel-
erated brain aging among healthy older adults. The
cross-sectional data have showed the age-related declines
in structural brain connectivity (Alloza et al., 2018).
Santoro et al. (2018) reported that schizophrenia PRS is
also associated with different clinical symptoms in differ-
ent stages of first-episode psychosis treatment (Santoro
et al., 2018). Zhang et al. (2019) reported the less favora-
ble improvement with antipsychotic drug treatment in
patients with higher PRS for schizophrenia and therefore
suggested using the PRS as a predictor of antipsychotic
efficacy in first-episode psychosis.
Cai et al. (2018) integrated the expression quantitative
trait locus (eQTL) mapping analysis and GWAS data from
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ten brain tissues of patients with schizophrenia to inves-
tigate the genes related to schizophrenia. Cerebellum
tissue has been reported to be the most closely linked tis-
sue in brain and sought to play a role in the pathogenesis
of schizophrenia. Bettella et al. (2018) reported significant
enrichment of schizophrenia associations among eQTLs
in four non-CNS tissues including adipose tissue, epider-
mal tissue, lymphoblastoid cells, and blood.
Pathway enrichment analysis using the hypergeomet-
ric test identified three major pathways to confer risk of
schizophrenia including EIF2, IGF-1, and 14-3-3-medi-
ated signaling pathway (Cai et al., 2018). Wang et al.
(2018) conducted the KEGG pathway enrichment anal-
ysis on schizophrenia GWAS data and found axon guid-
ance pathway-related genes are significantly associated
with schizophrenia risk. Chang et al. (2018) reported
ERBB, MAPK, synaptic plasticity, T cell receptor, and
N-methyl-D-aspartate receptor (NMDAR) signaling
pathways among the most enrichment pathways relevant
to schizophrenia (Chang et al., 2018). Genes interacting
with the NMDAR pathway such as ERBB4, GABRB2,
and GRIN2B are highly targeted by common SNPs and
harboring the de-novo mutations and NMDAR pathway
has been suggested to plays a leading role in the pathol-
ogy of schizophrenia (Chang et al., 2018).
Transcriptome analysis of ~2000 postmortem brains
revealed some new insights into biological networks
involved in schizophrenia and related neuropsychi-
atric disorders (Gandal et al., 2018). Integrating of
RNA-sequencing data and genomic data revealed the
differential splicing or expression in over 25% of tran-
scriptome in neuropsychiatric disorders including schizo-
phrenia (Gandal et al., 2018). Next-generation sequencing
and in particular whole-exome sequencing revealed the
implications of de-novo mutations in the disease etiology.
Functional analyses of the disrupted downstream biolog-
ical process by these de-novo events warrant a further
investigation for potential therapeutics adventure (Wang
et al., 2019).
Role of immune system in schizophrenia
The etiologies of schizophrenia are best explained by a
multi-factorial polygenic threshold model that invokes
multiple genetic risk factors modified by the environ-
ment (Malavia et al., 2017). Immunological alterations
observed in schizophrenia indicate the involvement of a
immune-related pathway in schizophrenia (de la Fontaine
et al., 2006). Several studies have reported the contribu-
tion of an active immunological system in the etiology
of schizophrenia (de la Fontaine et al., 2006). The role of
inflammatory mechanisms in schizophrenia is supported
by the role of immune dysregulation and alterations in
neuroinflammatory pathways in schizophrenia (Altamura
et al., 2014; Malavia et al., 2017). This might be explained
by the genetically modulated inflammatory reactions

such as dopamine-induced activation of autoimmune
T cells in the brain tissue and/or immune system (de la
Fontaine et al., 2006). Several studies suggest the role of
cytokines as a mediator of metabolic/brain changes asso-
ciated with clinical symptoms of schizophrenia (Kronfol
and Remick, 2000; Monji et al., 2009; Altamura et al., 2014;
Gallego et al., 2018; Misiak et al., 2018). Elevated levels of
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proinflammatory markers and cytokines have been found
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in the peripheral blood, cerebrospinal fluid and prefron-
tal cortex neurons of schizophrenic patients (Altamura et
al., 2014; Malavia et al., 2017). Cytokines play a critical
role in infectious and inflammatory processes by medi-
ating between immune abnormalities and neurodevel-
opment (Altamura et al., 2014). Cytokines interact with
monoaminergic system such as dopamine, serotonin, and
glutamate, and the autonomic nervous system (Kim et al.,
2007; Altamura et al., 2014). Schizophrenia is associated
with an imbalance in inflammatory cytokines suggesting a
possible target for pharmacological treatments (Altamura
et al., 2014). The positive effect of non-steroidal anti-in-
flammatory drugs to reduce psychotic symptom severity
supports the possibility of inflammatory mechanisms
underlying schizophrenia pathogenesis (Malavia et al.,
2017). This immune-based anti-inflammatory therapeu-
tic approach opens interesting perspectives for immune
therapy in schizophrenia (Müller et al., 2016).
Increased serum level of cytokines such as IL-6 in schizo-
phrenia suggests the implication of the adaptive immune
response and supports brain immune activation in schiz-
ophrenic patients (Altamura et al., 2014; Schwieler et al.,
2015). IL-6 plays a critical role by stimulation of B lym-
phocyte proliferation through hyperactivation of humoral
immunity that stimulates the conversion of the amino
acid tryptophan into kynurenic acid that acts as an antago-
nist of glutamatergic NMDARs (Altamura et al., 2014; Hu
et al., 2015). Abnormal kynurenic acid levels are involved
in the pathophysiology of schizophrenia (Schwieler et al.,
2015; Plitman et al., 2017). Neurotransmitter dysfunc-
tions as a result of cytokine-induced neuroinflammation
through microglial activation, leads to the inflamma-
tory process and neurodegeneration in schizophrenia
(Aricioglu et al., 2016).
Analysis of the network of protein-protein interactions or
interactome analyses demonstrated several immune-re-
lated pathways schizophrenia interactome such as inter-
leukins and natural killer cell signaling, NF-kB signaling,
and B cell receptor signaling, that are associated with
immune function and inflammation (Malavia et al., 2017).
The NF-kB signaling pathway has been implicated in
schizophrenia as NF-kB pathway plays a role in immune
response regulation and also in synaptic plasticity and
memory (Roman-Blas and Jimenez, 2006; Snow et al.,
2014; Malavia et al., 2017).
The HLA system is the most studied locus candidate
genes for association with schizophrenia (Gorwood et al.,
Copyright © 2020 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Schizophrenia in a genomic era by Zamanpoor 5
2004). The MHC region is the most associated region
in GWAS of schizophrenia. This considerably strong
genetic evidence supports the immune hypothesis that
variation within immune genes contributes to schizo-
phrenia (Pouget et al., 2016). HLA class II, containing the
HLA-DR4 (DRB1*04) allele of the HLA-DRB1 gene, is
the most frequently reported genetic allele in association
with schizophrenia (Wright et al., 2001). Associated HLA
class II antigens or alleles include HLA-DRB1*0101 and
HLA-DRB1*04 (*0401, *0403, *0405, and *0406) that
control antibody-mediated immune responses (Wright et
al., 2001). HLA-DRB1, including the HLA-DR4 serotype,
is associated inversely with schizophrenia (Watanabe et
al., 2009).
Environmental factors that contribute to
schizophrenia
Environmental risk factors play an important role in
the development of schizophrenia (Caspi and Moffitt,
2006). Schizophrenia has been associated with several
infectious agents and this has been supported by dif-
ferent immunologic, epidemiologic, microbiologic, and
neuropsychiatric studies (Yolken et al., 2000; Fatemi,
2005). Many infections have been associated with
schizophrenia, including influenza, rubella, herpes
simplex virus (HSV), cytomegalovirus, poliovirus, and
toxoplasma gondii (Brown and Susser, 2002; Ross et al.,
2006; Brown and Derkits, 2010). Infections have been
implicated as disrupters of fetal neurodevelopment
leading to brain and behavioral abnormalities (Brown
and Derkits, 2010). Maternal HSV-2 IgG antibody lev-
els are associated with a significantly increased risk of
schizophrenia in offspring (Buka et al., 2001; Brown
and Derkits, 2010). Another study showed significant
elevation in risk of schizophrenic among offspring of
mothers who were seropositive for HSV-2 antibody
(Buka et al., 2001; Brown and Derkits, 2010).
Schizophrenia development has been associated with
the birth season, and schizophrenia patients are more
likely to be born during the winter months (Torrey et al.,
1997; Davies et al., 2003; Messias et al., 2007). It has been
hypothesized that this winter birth effect might be due
to the increased chance of the prenatal viral infections
during winter months (Fatemi et al., 2012). Childhood
viral infections have also been suggested to be associated
with schizophrenia by some population-based studies
(Khandaker et al., 2012; Nielsen et al., 2014; Birnbaum
and Weinberger, 2017). There is evidence for the possi-
ble effect of prenatal exposure to infections on fetal brain
development (Ross et al., 2006; Clarke et al., 2009). This
can influence brain development through several physi-
ological and immunological processes including trigger-
ing proinflammatory cytokine responses or by releasing
stress hormones, producing hypoxia, hyperthermia, or
malnutrition (Gilmore and Jarskog, 1997; Verdoux, 2004;
Ross et al., 2006).
 6 Psychiatric Genetics 2020, Vol 30 No 1
Many obstetric complications such as premature birth,
low birth weight, preeclampsia, rhesus incompatibility,
and prenatal nutritional deficiency have been implicated
as early environmental risk factors for neurodevelop-
mental conditions such as schizophrenia (Cannon et al.,
2002; St Clair et al., 2005; Kyle and Pichard, 2006; Ross
et al., 2006). There are inconsistent findings from several
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studies exploring the relationship between schizophre-
hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 09/13/2023
nia and obstetric complications including hypertensive
disorders of pregnancy and low birth-weight (Clarke and
Kelleher, 2017; Dachew et al., 2018). Meta-analysis of
population-based association studies between low birth-
weight (<2500 g) and schizophrenia showed no significant
increase in the risk of developing schizophrenia among
those with a low birth-weight compared to those within
the healthy birth-weight range (Clarke and Kelleher,
2017). However, a recent meta-analysis showed that
there was 37% higher risk of developing schizophrenia
in offspring exposed to maternal preeclampsia (relative
risk = 1.37; 95% confidence interval: 1.08–1.72) (Dachew
et al., 2018).
Advancing paternal age has been found as a risk fac-
tor for schizophrenia (Messias et al., 2007). It has been
suggested that epigenetic processes such as age-re-
lated imprinting errors and DNA methylation changes
in several brain-expressed imprinted genes contribute
to the effect of advanced paternal age on schizophre-
nia (Perrin et al., 2007; Petersen et al., 2011; Smith et al.,
2013). Accumulated de-novo mutations in paternal sperm
have been also suggested to contribute to neurodevelop-
mental disorders in offspring (Janecka et al., 2017). The
link between advanced paternal age and schizophrenia
remains significant after controlling for possible con-
founders, including socioeconomic status, paternal psy-
chiatric morbidity, and maternal age (Janecka et al., 2017).
Diagnosis of schizophrenia
Schizophrenia is defined as a heterogeneous clinical syn-
drome and shares a common presentation with several
other psychosocial disorders making diagnosis of schizo-
phrenia difficult (Wong and Van Tol, 2003). To address its
heterogeneity, schizophrenia is currently diagnosed as a
disorder with subtypes. However, subtypes are based on
several common clinical features that make the diagnosis
imprecise (Keller et al., 2011).
Diagnosis of schizophrenia is based on the Diagnostic
and Statistical Manual of Mental Disorders. The patients
must have two or more of the defined symptoms for 1
month (American-Psychiatric-Association, 2013). These
symptoms include delusions, hallucinations, disorgan-
ized speech, grossly disorganized behavior or catatonic
behavior, or negative symptoms (such as affective flat-
tening, alogia, avolition) (Keller et al., 2011; American-
Psychiatric-Association, 2013). Onsets of schizophrenia
have been reported to be different between individuals
Copyright © 2020 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
from acute onset to an extended prodrome (Messias et
al., 2007). The negative symptoms might be observed
about 5 years before the manifestation of the initial psy-
chotic episode (Häfner et al., 1999). Recent advances in
discovery of schizophrenia-associated loci together with
the definition of distinct sets of schizophrenic pheno-
types are promising that the associated SNPs can be used
as potential biomarkers to assist the diagnosis of schizo-
phrenia in the genomic era.
Treatment of schizophrenia
There is not much known about the pathophysiology of
schizophrenia and therefore successful treatments are
limited (Lewis and Levitt, 2002). There is no cure for
schizophrenia and the available symptomatic treatment
is only partially successful (Ross et al., 2006). Dopamine
dysfunction is the core psychopathology of schizophrenia
and the development of novel treatment targets requires
consideration of the complex interactions between dopa-
mine and other neurotransmitter systems (Yang and Tsai,
2017). The majority of schizophrenia treatment strategies
are aimed at blockade of the dopamine receptors in the
dopamine reward pathway in the central nervous system
(Yang and Tsai, 2017).
The positive symptoms can be managed by using the
typical antipsychotic drugs (first generation) such as
chlorpromazine, haloperidol, and perphenazine (Jarskog
et al., 2007). The typical antipsychotic drugs have shown
little impact on negative symptoms or cognitive impair-
ment in schizophrenia patients (Jarskog et al., 2007).
Atypical antipsychotic drugs (second-generation drugs)
such as clozapine or olanzapine have serotonin-dopa-
mine antagonism that improve the psychotic symptoms
of schizophrenia by partially blocking dopamine recep-
tors (particularly D2 receptor) to prevent over-activity of
dopamine in the striatum (Blasi et al., 2011). Clozapine is
primarily used in schizophrenia that is unresponsive to
at least two different antipsychotic drugs (Jarskog et al.,
2007). Cognitive behavioral treatment is a recommended
therapy to help schizophrenia patients to lower the stress
of psychotic symptoms by linking their distressed feelings
and patterns of thinking (Jones et al., 2004). Advances in
pharmacogenomics and genetic findings in schizophrenia
have generated optimism about developing more effec-
tive and specific treatments for schizophrenia (Yang and
Tsai, 2017).
Conclusion and perspectives
Schizophrenia is a heterogeneous clinical syndrome with
a high heritability. Genetic studies including gene map-
ping, linkage analysis, and GWAS have confirmed many
chromosomal regions may contain schizophrenia suscep-
tibility loci. Many genes play a role each with small to
moderate effect sizes in schizophrenia. Findings of the
recent GWAS studies confirmed the association of vari-
ants within the MHC region with schizophrenia as the

most significantly associated locus with schizophrenia.
This considerably strong genetic evidence for the impli-
cating the MHC locus in schizophrenia pathophysiology
and supports the hypothesis that variation within immune
genes contributes to schizophrenia. Despite the increase
in discovering more risk loci in recent years, the molecu-
lar and pathogenic mechanisms are still need to be fully
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understood. GWAS confirmed known genetic risk loci
hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 09/13/2023
and provided further biological insights into the etiology
and pathogenesis of this complex disorder. Although the
role of genetic-environment interaction in schizophrenia
pathogenesis and development are remained as chal-
lenge that requires further investigation.
Acknowledgements
I would like to thank Professor Tony Merriman and
Professor Ian Morison for their helpful discussion and
advice.
Conflicts of interest
There are no conflicts of interest.
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