Schizophrenia, “Just the Facts” What we know in 2008.
2. Epidemiology and etiology
Rajiv Tandona, Matcheri S. Keshavanb, Henry A. Nasrallahc
aUniversity of Florida, 3706 Glin Circle, Tallahassee, FL 32309, United States
bWayne State University, Detroit, Michigan, United States
cUniversity of Cinncinnatti, Cinncinnatti, Ohio, United States
Received 15 February 2008; received in revised form 31 March 2008; accepted 2 April 2008
Although wehave studied schizophreniaasa major disease entity overthe past century, its causesand pathogenesis remainobscure.
In this article, we critically review genetic and other epidemiological findings and discuss the insights they provide into the causes of
schizophrenia. The annual incidence of schizophrenia averages 15 per 100,000, the point prevalence averages approximately 4.5 per
significant variations in the incidence of schizophrenia, with urbanicity, male gender, and a history of migration being associated with a
developing schizophrenia and a number of chromosomal regions and genes have been “linked” to the risk for developing the disease.
Despite intensive research and spectacular advances in molecular biology, however, no single gene variation has been consistently
associated with a greater likelihood of developing the illness and the precise nature of the genetic contribution remains obscure at this
time. Environmental factors linked to a higher likelihood of developing schizophrenia include cannabis use, prenatal infection or
malnutrition, perinatal complications, and a history of winter birth; the exact relevance or nature of these contributions is, however,
unclear. How various genetic and environmental factors interact to cause schizophrenia and via which precise neurobiological
interaction, and inadequately elucidated schizophrenia pathophysiology are among the explanations invoked to explain our inadequate
understanding of the etio-pathogenesis of schizophrenia. The ability to question some of our basic assumptions about the etiology and
nature of schizophrenia and greater rigor in its study appear critical to improving our understanding about its causation.
© 2008 Elsevier B.V. All rights reserved.
Keywords: Schizophrenia; Facts; Epidemiology; Genetics; Environmental risk factors; Incidence; Chromosomes; Genes; Prevalence; Linkage;
Association; Pregnancy; Etiology; Causes
Epidemiology is the study of distribution and
determinants of disease (MacMahon and Pugh, 1970).
Distinguishing characteristics and experiences of persons
who develop a disease from those of individuals who do
not allows one to identify factors related to causation of
that disease. Determinants of disease constitute the
this includes both genetic and environmental risk factors
which need to be considered together since both are
important in the etiology of schizophrenia and neither
appears to operate in isolation (Tsuang et al., 2004).
In this paper, we summarize major epidemiological
findings in schizophrenia and discuss what they tell us
about genetic and environmental factors involved in its
Available online at www.sciencedirect.com
Schizophrenia Research 102 (2008) 1–18
0920-9964/$ - see front matter © 2008 Elsevier B.V. All rights reserved.
causation. We first summarize current knowledge about
variations in the occurrence of schizophrenia across
populations, socio-demographic characteristics and
time. We then briefly review key genetic findings and
environmental risk factors linked to the development of
schizophrenia and critically discuss our state of under-
standing about the etiology of schizophrenia. We
highlight key conceptual issues, outline approaches to
dissecting genetic and environmental contributions to its
causation, and consider major challenges towards
elucidating the etio-pathogenesis of this disease.
2. Incidence and prevalence
The distribution of a disease is generally expressed in
terms of incidence (new cases), and prevalence (total
number of cases: existing+new). Incidence rate refers to
the number of new cases of the disease that develop over a
specific period of time among people who are at risk for
developing the disease. Instead of a rate (new cases per
disease (e.g., lifetime risk). Differences between the
characteristics of people who develop versus do not
develop the disease help to define the risk and protective
factors for and against development of the disease,
respectively. Thus knowledge about the distribution of
newdisease development (incidence) over time,place,and
person points to etiological factors (determinants) for
developing the disease. Prevalence refers to the proportion
given time (point prevalence) or over a given time-span
disease and those who newly develop the disease over this
specified time period.
2.1. Incidence and lifetime risk
Since incidence is a measure of the number of new
cases of a disease occurring among people who are at risk
for developing the disease over a specified period of time
(generally one year), it requires knowing who is a case at
the beginning (and excluding them from both the
numerator and denominator), the number of people at
risk for newly developing the disease (denominator), and
the number of people who newly develop the disease
ofnew cases can be determined by communitysurveys or
by identifying them as they seek services (first contact
with health worker, hospitalization, etc.). Correctly
determining the distribution of a disease depends upon
ability to precisely demarcate those with disease from
those without it. In the absence of any pathognomonic
feature and several impediments to constructing a fully
reliable patient clinical profile, it becomes a greater art to
al., 2007). Additionally, consistent case definition (when
does a possible case become a case — e.g., persons with
prodromal symptoms) and identification (e.g., a person
may not seek treatment/s and is thereby missed as a case)
can be problematic. Furthermore, although we have made
substantial advances over the past two decades in being
unclear if we have made any progress with regard to
validity (McCormick and Flaum, 2005).
These challenges have contributed, in significant part,
to varying estimates of incidence obtained across the
multitude of studies. In the only global study that directly
et al., 1986; Jablensky et al., 1992), the annual incidence
14/100,000 using narrow criteria (CATEGO class S+
identifying nuclear schizophrenia; Wing et al., 1974) for
was detected in the U.S.A.-based five community site
National Institute of Mental Health Epidemiological
Catchment Area (ECA) program (Tien and Eaton,
1992), but these results were derived from community
surveys conducted by individuals with minimal or no
clinical experience rather than on the basis of service
provision and clinician diagnosis, which is how most
other studies derived their data; this likely resulted in
several false positives (Anthony et al.,1985; Regier et al.,
1998). Studies based on service provision, on the other
hand, might underestimate rates of schizophrenia because
some affected individuals may not seek treatment. A
recent meta-analysis of all published studies between
1965 through 2001 obtained a median incidence rate of
15.2/100,000/year with 80% confidence interval rates
(10th–90th decile) ranging from 8–43 per 100,000 per
year (McGrath et al., 2004). Data were derived from 55
studies conducted across 33 countries. Rates were not
found to vary by broad world regions or economic status
of the country (Saha et al., 2006). Contrary to prior
assumptions of uniform rates of schizophrenia across the
world, however, this meta-analysis revealed robust
variations in incidence of schizophrenia, with urbanicity,
migration, and male gender found to be associated with
a higher risk for developing schizophrenia.
Recent findings confirm and clarify longstanding
suggestions of a link between urbanicity and schizo-
phrenia (Faris and Dunham, 1939). For many decades,
2 R. Tandon et al. / Schizophrenia Research 102 (2008) 1–18
there was controversy about whether this association
hypothesis”) or whether persons with schizophrenia
migrated to urban settings (“selection hypothesis”). For
the past half-century, this argument was seemingly
resolvedinfavor ofthe later perspective andthe observed
association was ascribed to the “social drift” of persons
with schizophrenia to inner city areas with cheaper ac-
1992). Even as the social drift phenomenon has been
corroborated, well designed recent studies have also
confirmed an association between urban birth and
upbringing (upto the age of 15) and an increased risk of
developing schizophrenia (Lewis et al., 1992; Mortensen
response relationship between degree of urbanicity and
risk of schizophrenia strongly supports the proposition
related to schizophrenia (Pedersen and Mortensen, 2001).
What that specific risk-modifying factor linked to
urbanicity might be, however, is unclear. Several
candidates have been proposed — these include urban–
rural differences in rates of cannabis and other substance
use, prenatal and perinatal health, degree of social stress
and social connectedness, poverty, rates and nature of
migration, environmental toxins, various infectious dis-
eases, or vitamin D deficiency. Whereas some of these
factors have independently been linked to schizophrenia
(e.g., migration) and others to urbanicity (e.g., vitamin D
deficiency), none has been convincinglylinked toboth or
established as the schizophrenia risk-modifying factor
that satisfactorily explains the urbanicity–schizophrenia
Ever since Odegaard (1932) documented a higher
occurrence of “schizophrenic breakdown” among Nor-
wegians who had migrated to Minnesota than among
those who remained in Norway, several studies have
confirmed an association between migration and an
increased risk of developing schizophrenia (Malzberg,
1964; Bhugra, 2004). A meta-analysis of 18 studies
published between 1977 through 2003 identified a
personal or family history of migration as a significant
risk factor for schizophrenia (Cantor-Graae and Selten,
2005); the relative risk for developing schizophrenia was
second-generation immigrants. Both selective migration
(Odegaard, 1932) and diagnostic bias (Sashidharan,
1993) have been cited as explanations; neither of them
appears to adequately account for the association. The
migration–schizophrenia link has been found to be more
the population is predominantly black to a country where
the population is predominantly white; similarly, migrat-
ing to areas with a lower density of people with a similar
ethnic background has been found to be associated with a
higher liability for psychotic illness (Kirkbride et al.,
2007; Veling et al., 2008). What factor/s then might
mediate the link between migration and schizophrenia?
Social adversity associated with being a migrant (social
isolation, discrimination and “racism”, experience of
“social defeat”, etc.) has been cited as the major factor
(Boydell et al., 2001; Cooper et al., 2008), although
“biological” explanationssuchasvitaminD insufficiency
and epigenetic mechanisms have also been suggested
increased risk of developing schizophrenia provides
compelling evidence supporting a role for social factors
in its etiology (Cantor-Graae, 2007); the specific risk-
mediating factor (social or biological), however, remains
to be elucidated.
Estimates of the risk of developing schizophrenia over
one's lifetime range from 0.3–2.0% with an average of
approximately 0.7% (Saha et al., 2005). Although gender
differences in the clinical expression and outcome of
schizophrenia have long been recognized (Seeman,
1982), it has generally been believed that the risk of
developing schizophrenia over one's lifetime is similar
among males and females (e.g., Wyatt et al., 1988). More
recent studies have undermined this assumption and two
recent meta-analyses revealed that males have a higher
lifetime risk of developing schizophrenia with a male–
female relative risk of about 1.4 (Aleman et al., 2003;
McGrath et al., 2004). The male–female ratio in
morbid risk for schizophrenia is found to increase as
more stringent current diagnostic criteria are utilized
(Beauchamp and Gagnon, 2004). Studies from develop-
ing countries have not found such a difference and study
samples obtained prior to 1980 were much less likely
to reveal a gender difference in the risk of schizo-
phrenia (Aleman et al., 2003). This observed discrepancy
between findings of studies conducted in the past two
decades and those conducted earlier is of obvious
importance but poorly understood, although proposed
explanations include differences between the two time
periods with regard to diagnostic criteria, case-ascertain-
ment methods, or differential changes in a variety of
two genders (Hambrecht et al., 1992; Aleman et al.,
2.1.1. Incidence of schizophrenia over time: is schizo-
phrenia a new disease?
Schizophrenia has been more consistently and
frequently described over the past two centuries
3R. Tandon et al. / Schizophrenia Research 102 (2008) 1–18
(Bleuler, 1950; Kraepelin, 1971). Although loose
descriptions resembling schizophrenia are obtained in
texts dating back several thousand years (Jeste et al.,
1985; Ellard, 1987), easily recognizable descriptions of
schizophrenia are much less common than those of other
psychiatric or neurological disorders (Evans et al.,
2003). This has led some to suggest that schizophrenia is
a disease that has afflicted humans only over the past
two centuries and that some factor related to indus-
trialization, urbanization, or increasing population
density may have contributed to the emergence of this
disease (Torrey, 1980; Hare, 1988). The broadly even
distribution of schizophrenia across the world in the
context of its strong genetic underpinnings (Crow,
1995), however, argues against the proposition that it is
a recent disease and most experts believe that schizo-
phrenia, like many other diseases, had been present for a
long time before its first lucid description in the early
19th century. Resolution of this controversy is unlikely
until we have a better understanding of the etio-
pathophysiology of the illness.
What is less controversial is the fact that descriptions
of schizophrenia have been fairly consistent over the
past two centuries and that its occurrence has been
relatively stable over this period even though specific
diagnostic criteria have changed. Its presentation has,
however, evolved over the past century with a modest
improvement in the overall prognosis (Bleuler, 1972;
Hegarty et al., 1994) and reduced occurrence of more
severe forms of the disease such as hebephrenia and
catatonia (Morrison, 1974; Stompe et al., 2002). Some
studies suggest a decline in the incidence of schizo-
phrenia (Eagles et al., 1988; Woogh, 2001) whereas
others suggest an increase (Tsuchiya and Munk-
Jorgensen, 2002; Bray et al., 2006); changing diagnostic
criteria and case detection methods make such compar-
isons difficult (Stromgren, 1987; Kendell et al., 1993).
Prevalence is a measure of the proportion of
individuals in a defined population who either are
manifesting a given disease at a particular time (point or
period prevalence) or have manifested the disease at any
time during their life (lifetime prevalence). Point
prevalence thus refers to the proportion of the popula-
tion with the disease on a given day, period prevalence
to the proportion with the disease during a particular
time-frame (generally 6 months or one year), and
lifetime prevalence to the proportion that ever had the
disease at any time during their life regardless of
whether they currently do or do not have the disease.
Logically, estimates of period prevalence should equal
or exceed those of point prevalence and estimates of
lifetime prevalence should equal or exceed those of
period prevalence. The prevalence of any condition in a
community is influenced by several factors including
rates of new case development (incidence), duration of
the condition, and differential mortality or migration
patterns associated with the condition (Fig. 1). Although
variable degrees of “recovery” do occur (Harding et al.,
1987), complete cures are uncommon and the average
duration that an affected person lives with schizophrenia
is approximately 30 years. Based on a median incidence
rate of 15.2/100,000/year, one would roughly predict a
median point prevalence of about 456/100,000 or 4.56/
are found tovaryseveral-fold,the average isveryclose to
this predicted estimate. Saha et al. (2005) conducted a
systematic review of 188 studies from 46 countries and
derived a range of different prevalence estimates in
schizophrenia. Based on a meta-analysis of 21 studies,
they obtained a median point prevalence estimate of 4.6
per 1000 persons with 80% confidence interval estimates
meta-analysis of 34 studies, they obtained a median
period (upto 1 year) prevalence estimate of 3.3 per 1000
persons with 80% confidence interval estimates (10th–
analysis of 24 studies, they obtained a median lifetime
prevalence estimate of 4.0 per 1000 persons with 80%
confidence interval estimates (10th–90th decile) ranging
from 1.6–12.1/1000. Sixty-seven distinct studies pro-
vided data towards these three estimates: two studies for
all three meta-analyses,8for twoofthe estimates,andthe
remainder for just one of these analyses.
Although these estimates of prevalence were some-
what lower than previously believed (e.g., Kessler et al.,
1994) and more recently reported (e.g., Perala et al.,
2007), this systematic review confirmed our notions of
worldwide prevalence with pockets of low and high
prevalence. Similar to the observed higher incidence of
schizophrenia among migrants, this comprehensive
review also found the prevalence of schizophrenia to
be higher among this group. In contrast to observed
differences in incidence across gender and urban–rural
settings, however, no such differences in prevalence
were observed. Prevalence was found to be similar
among males and females as also among urban and rural
dwellers. In comparison to the similar incidence across
less developed and more developed countries, on the
other hand, a significantly higher prevalence of schizo-
phrenia was observed in more developed versus less
4 R. Tandon et al. / Schizophrenia Research 102 (2008) 1–18
developed countries. A higher prevalence of schizo-
phrenia among lower versus higher socio-economic
classes within communities has also been consistently
documented over the past century.
The combinations of incidence-prevalence findings
observed in schizophrenia are not easily explained.
Variables linked to both higher incidence and prevalence
are likely relevant to the etiology and possibly to
persistence of the disease. Factors associated with
higher incidence but equal prevalence of schizophrenia
may be related in complex ways to both etiology and
outcome differences (e.g., hypothetically, a greater risk
of developing the illness along with greater illness-
related mortality in males versus females might explain
the higher incidence but equal prevalence of schizo-
phrenia among males versus females; alternatively, this
set of gender findings could hypothetically also be
explained by a greater risk of development but higher
rate of “cure” among males versus females, Fig. 1).
Variables associated with equal incidence but higher
prevalence are probably unrelated to etiology but
relevant to outcome. Although the basis of these
incidence-lifetime risk-prevalence findings is not well
understood, they do provide a rich substrate for
developing and testing hypotheses about what causes
schizophrenia (McGrath, 2007): we need to better
understand what these patterns of distribution of
schizophrenia are telling us about the specific genetic
and environmental risk factors related to its causation
and the neurobiological mechanisms that might mediate
3. The genetic basis for schizophrenia
It is well known that schizophrenia aggregates in
families. Although over two-thirds of the cases occur
sporadically, having an affected family member sub-
stantially increases the risk of developing schizophrenia.
This risk increases as the degree of genetic affinity with
the affected family member increases (Kendler et al.,
1993). Although a genetic basis for schizophrenia has
long been suggested (Kallman, 1946), family dynamic
and interactional explanations were commonly invoked
to explain this familiality until the 1960s (Bateson et al.,
1956; Lidz et al., 1965). To differentiate between these
explanations, a series of seminal studies (Heston, 1966;
Kety et al., 1968) examined the risk of schizophrenia in
the adopted-away offspring of parents with schizophre-
nia raised by parents without the illness and adopted-
away offspring of parents without schizophrenia raised
by parents with the illness; they found that the risk of
schizophrenia was related to the presence of the illness
in biological parents but not in the adoptive parents.
In keeping with the genetic basis for schizophrenia
implied by this finding, twin studies have consistently
found more than a three-fold greater concordance for the
Fig. 1. Relation between incidence and prevalence in a given population.
5 R. Tandon et al. / Schizophrenia Research 102 (2008) 1–18
disease among monozygotic twins than among dizygo-
tic twins (Gottesman et al., 1987; Sullivan et al., 2003)
(Table 1). Dizygotic twins share 50% of their genetic
material and if one twin has schizophrenia the risk of the
other having the illness is 10–15% (similar to that in
siblings of a person with schizophrenia — who also
share 50% of their genes). In contrast, monozygotic
twins share 100% of their genetic material and if one
twin has schizophrenia, the risk of schizophrenia in the
other is about 40–50%.
Twin concordance rates are also utilized to estimate
the heritability of a disease. Heritability refers to the
proportion of variance in liability for an illness in the
general population that is accounted for by genetic
effects — by themselves and through interactions with
environmental factors, they contribute about 80% of the
liability for schizophrenia (Cannon et al., 1998; Cardno
et al., 1999; Sullivan et al., 2003).
In reviewing the role of genetic factors in schizo-
phrenia twenty years ago, Gottesman et al. (1987)
suggested that the above clinical genetic data merely
provided clues to the “real” genetics of schizophrenia
which would be elucidated by the thousands of
molecular genetic studies (linkage, association, gene
knock-out, etc.) that were to follow in the next two
decades. In assessing the genetic underpinnings of a
disease, clinical genetic studies provide information
about the presence and extent of genetic contributions to
where in the genome relevant risk genes for the disease
may exist, association studies about which particular
gene variation modifies the risk for the disease, and gene
knock-out and related studies about what specific brain
how this may result in schizophrenia. Gottesman et al.
(1987) had subtitled their review “A decade of modest
gains while playing for time”. Despite phenomenal
advances in the science and technology of molecular
biology over the past two decades highlighted by the
mapping of the human genome seven years ago, it could
be argued that we have not learned very much more and
that we are still playing for time (Sullivan, 2008);
although a genetic basis for schizophrenia is now clearly
established, the precise mechanism of inheritance still
3.1. Chromosomal abnormalities and linkage studies:
Where on the human genome are the risk genes for
Although a number of “structural” chromosomal
abnormalities have been described in schizophrenia
(MacIntyre et al., 2003), the three most often noted are
deletion of 22q11, a balanced reciprocal translocation of
1q42/11q14, and involving the X chromosome (DeLisi
et al., 1994; Blackwood et al., 2001; Williams et al.,
2006b) implicating them as chromosomal regions which
might harbor a risk gene or genes for schizophrenia. The
complete mapping of the human genome in the past
decade (Lander et al., 2001; Venter et al., 2001) has
allowed a more detailed assessment of the linkage of
specific chromosomal segments to differences in
liability for schizophrenia. Linkage analysis utilizes
genetic information from families with multiply affected
Estimates of relative risk for schizophrenia due to various genetic and environmental risk factors
Risk factorAverage relative risk of schizophrenia
if risk factor present (approximate)
Family history of schizophrenia
Both parents affected
Dizygotic twin or 1st degree relative
2nddegree relative (e.g., grandparent)
3rddegree relative (e.g., 1st. cousin)
Any specific single gene variant
1stor 2ndtrimester maternal infection or malnutrition
Obstetric and perinatal complications
Gottesman et al. (1987); Kendler et al.
(1993); Sullivan et al. (2003)
Allen et al. (2008)
Pedersen and Mortensen (2001)
Cantor-Graae and Selten (2005)
Penner and Brown (2007)
Davies et al. (2003)
Geddes and Lawrie (1995); Geddes et al.
(1999); Byrne et al. (2007)
Semple et al. (2005)
Wohl and Gorwood (2007)
Aleman et al. (2003)
Cannabis or stimulant use
Paternal age N35 years
6R. Tandon et al. / Schizophrenia Research 102 (2008) 1–18
individuals with schizophrenia and seeks to identify
regions of the genome linked to the illness; i.e., which
chromosomal segments are shared among affected re-
latives but not among unaffected relatives. More than
thirty genome-wide scans have been conducted in schi-
zophrenia and two meta-analyses (Badner and Gershon,
2002; Lewis et al., 2003) both pinpointed chromosomal
regions 8p21–22 and 22q11–12 as harboring schizo-
phrenia risk genes. Lewis and co-workers meta-an-
alyzed results from 20 genome scans and in descending
likelihood identified chromosomal regions 2p12–q22,
5q23–q34, 3p25–p22, 11q22–q24, 6pter–p22, 2q22–
q23, 1p13–q23, 22pter–q12, 8p22–p21, 6p22–p21,
20p20–p11, 14pter–q13, 16p13–q12, 18q22–qter,
10pter–p14, 1q23–q31, 15q21–q26, 6q15–q23, and
17q21–q24 as containing susceptibility genes for schi-
zophrenia. A genome-wide scan for linkage in sibling
pairs (DeLisi et al., 2002) also identified chromosomal
regions 10p15–p13, 2 centromere, and 22q12.
Linkage analysis does not, however, identify the
particular susceptibility genes themselves and the total
number of genes in chromosomal regions linked to
schizophrenia suggested by the above meta-analyses
approximates 4000 genes (about one-quarter of all
known genes), which indicates the extreme lack of
precision of this approach by itself. The power to detect
linkage depends on the available samples; unfortunately,
the samples currently available worldwide may be
insufficient to detect genes of relatively small effect
(odds ratio ~1.8, as is believed to be the case in
schizophrenia) (Risch and Merinkangas, 1996; Moldin,
1997). Genetic heterogeneity, or the presence of several
independent risk genes, further reduces the sensitivity of
linkage analysis (Sawa and Snyder, 2002; Fanous and
Kendler, 2005). Finally, the difficulties in finding large
multiplex families for such analyses and technological
advances that allow relatively inexpensive rapid
throughput genome-wide scanning have diminished
interest in this approach to locating likely schizophrenia
3.2. Association studies and susceptibility genes: Which
genes cause schizophrenia?
Linkage analysis (which requires family samples)
and association studies (which can be conducted on
samples of related or unrelated individuals) are two
complementary molecular approaches to connecting
genes to disease. Genetic association studies evaluate
the relationship between specific gene variants and the
risk of developing schizophrenia. Such studies are more
suitable than linkage analysis for detecting genes of
relatively small effect but require careful attention to the
possibility of false positive (type 1 error) and false
negative (type 2 error) results in view of the large
number of gene variants that can potentially be eva-
luated (Hunter and Kraft, 2007). Publication of an
extensive catalogue of common human DNA variants
(International HapMap Consortium, 2005), develop-
ment of sophisticated data-analytic tools, ready avail-
ability of high-throughput methods of genomic analysis,
increased sharing of genetic materials across research
groups, and broad international collaboration have
significantly facilitated the search for the association
between specific variations of defined genes and the risk
for developing schizophrenia. Variations in specific
gene sequences are compared between individuals with
and without schizophrenia and variants found with sig-
nificantly different frequency among those with schizo-
phrenia considered to confer susceptibility to the
disease. As such associations may also be detected
due to numerous artifacts, replication is a critical sine
qua non (Hunter and Kraft, 2007). After case–control
comparisons of the gene variant, the next steps are
assessment of whether the protein product of the gene is
expressed in the brain and its function, if the different
forms of the gene yield functionally different proteins,
whether there is differential expression of the gene pro-
duct in persons with schizophrenia, and if the gene
product may plausibly be relevant in terms of the
hypothesized pathophysiology of the illness.
Over the past decade, several genetic associations for
schizophrenia (Owen et al., 2005; Gogos and Gerber,
2006; Straub and Weinberger, 2006) have been reported
and these have been supported by varying amounts of
evidence. There are several ongoing efforts to collate
and update these data (e.g., Becker et al., 2004; Lin
et al., 2006; Allen et al., 2008); despite these resources,
staying on top of these association findings can be
challenging in view of the sheer volume and discre-
pancies. In addition to data suggesting an association
between gene variants and risk for schizophrenia,
messenger RNA of many of these genes is expressed in
the brain and varying amounts of data suggest that they
may be differentially expressed in individuals with the
illness. Furthermore, neurobiological data plausibly link
many of these genes to pathophysiological processes
considered relevant in schizophrenia (Harrison and
Weinberger, 2005; Law et al., 2006; Lang et al., 2007;
O'Tuathaigh et al., 2007; Tan et al., 2007a; Talkowski
et al., 2008). Some of the genes (with their protein
schizophrenia include NRG1 (neuroregulin 1), DTNBP1
(dysbindin), DRD1-4 (dopamine receptors D1–D4),
7R. Tandon et al. / Schizophrenia Research 102 (2008) 1–18
DISC1 (disrupted in schizophrenia 1), COMT (catechol-
O-methyl-transferase) and GRM3 (metabotropic gluta-
mate receptor), (Duan et al., 2007; Lewandowski, 2007;
Li and He, 2007; Nicodemus et al., 2007; Tan et al.,
et al., 2008; Schwab et al., 2008; Talkowski et al., 2008).
Even for these “most promising” genes, however, there is
a remarkable failure to replicate exactly the same markers
andhaplotypesacrossstudies anda lackofconsistency in
implicating particular alleles in liability for schizophrenia
are ways to explain discrepancies, the veracity of these
explanations has not been adequately tested.
Therefore, we cannot as yet assert with certainty that
any particular gene variant increases the risk for schizo-
phrenia and we have considerable work to do before we
will be able to precisely define the pathogenetic me-
chanisms mediating the effects of various risk genes to
“cause” schizophrenia. The several large case-controlled
whole genome association studies (e.g., GAIN, 2008;
Kingsmore et al., 2008) currently underway will hope-
fully provide useful insights.
3.3. The genetic basis of schizophrenia, Circa 2008.
The promise and the challenge
Isthe glass half-full or half-empty? Genetic factors are
critically important and our increasingly powerful
technological tools are enabling us to better study the
nature of these genetic contributions to the etiology of
schizophrenia. But failures of clear and consistent
replication need to be considered in the context of our
history of previous highly publicized “solid” genetic
findings in schizophrenia that could subsequently not be
confirmed (e.g., Sherrington et al., 1988; Brzustowicz
et al., 2000). Four broad issues that warrant specific
consideration include the desirability of adopting stan-
dards for interpretation of future genetic studies, explain-
ing the evolutionary-genetic paradox of the relatively
constant incidence of schizophrenia over the past century
despite its evolutionary disadvantages, suitability of our
current genetic framework of schizophrenia, and whether
schizophrenia is the appropriate phenotype for us to be
conducting these genetic studies on.
There is considerable disagreement in our field about
the degree of appropriate concern about our failure to
consistently and unambiguously replicate findings
implicating a particular gene variant as a risk factor
for schizophrenia (DeLisi, 2000). Some experts suggest
that this is only to be expected in view of the fact that
schizophrenia is a heterogeneous disease with multiple
genes of small effect (Owen et al., 2005) that might vary
across populations with different genetic ancestry, and
that the allelic diversity (leading to discrepant findings)
being observed in schizophrenia is no different from that
seen in other complex genetic disorders (Straub and
Weinberger, 2006); these experts caution against an
overly rigid “nihilistic” approach and argue for the need
to pursue each “promising lead” in order to avoid type 2
errors in our difficult search for the precise genetic basis
for schizophrenia. Other experts suggest, however, that
more consistent genetic findings have been noted in
other complex genetic diseases (Welcome Trust Case
Control Consortium, 2007) and there is no obvious
reason why schizophrenia should be considered more
complex (Sullivan, 2007); they provide a strong case for
“hard” replication in order to avoid type 1 errors
(Ioannidis, 2005; DeLisi and Faraone, 2006). Both
concerns merit attention and a balanced “middle-of-the-
road” approachwouldentail vigorous pursuit of all leads
in a rigorous manner in conjunction with explicit testing
of explanations offered for discrepant findings. In any
event, a key concern should be the power of a particular
study to replicate prior reports.
How has schizophrenia persisted across world
populations at a relatively stable rate despite its obvious
evolutionary disadvantages such as decreased repro-
ductivity and increased mortality (Svensson et al., 2007;
Tandon et al., 2008)? While some may question the
premise that incidence rates of schizophrenia have been
stable over time, this assertion appears to be well-
founded at least over the past two centuries (see section
on incidence above). Although we do not have
definitive explanations, it has been suggested that the
genes for schizophrenia may also be relevant to adaptive
human evolution and thereby confer evolutionary
advantages to unaffected family members (Crow,
1995; Williams et al., 2006a; Crespi et al., 2007).
There has also been much debate about other models to
explain the persistence of schizophrenia in the context of
the plausibility of mutation rates that such models
invoke (Doi and Hoshi, 2007).
Currently, the predominant genetic view of schizo-
phrenia is that it is a heterogeneous, polygenic/multi-
factorial disease (Risch, 1990; Lichtermann et al., 2000)
with multiple common genetic polymorphisms, each of
which contributes a small effect to disease susceptibility.
This “common disease-common alleles with multiple
genes of small effect” (Chakravarti, 1999) model of
schizophrenia is the basis for the large-scale genetic
association studies conducted around the world in the
past decade and the current emphasis on population
case–control genome-wide association studies. Some
8R. Tandon et al. / Schizophrenia Research 102 (2008) 1–18
experts suggest that our genetic conceptualization of
schizophrenia is wrong and this flawed model is the
reason for our difficulties in elucidating the precise
nature of the genetic basis for schizophrenia (McClellan
et al., 2007; Crow, 2007a). They instead provide two
alternate genetic models for schizophrenia that they
suggest are more appropriate. McClellan et al. (2007)
suggest that instead of viewing schizophrenia as
resulting from the combined effects of multiple common
and weakly penetrant genetic polymorphisms, it is better
conceptualized as a highly heterogeneous genetic entity
caused by multiple, highly penetrant and individually
very rare mutations that may be specific to single cases
or individual families. This model points to a very
different approach towards elucidating the genetic basis
for schizophrenia emphasizing intensive study of
individual cases or single families. While recent
findings of increased runs of homozygosity that reveal
highly penetrant recessive loci in schizophrenia (Lencz
et al., 2007) are suggestive, there are several limitations
to this idea (Craddock et al., 2007; Crow, 2007b).
Another genetic model proposed for schizophrenia is
that it is not DNA sequence variation but heritable
changes in gene expression that explain its genetic
origins (DeLisi et al., 2002; Costa et al., 2006; Crow,
2007a). Such epigenetic factors exert their effect on
genomic functions principally through DNA methyla-
tion and histone remodeling of chromatin structure.
Although epigenetic explanations for the genetic basis
for schizophrenia bear much promise, our understanding
of the role of epigenetic factors in the etio-pathogenesis
of complex diseases such as schizophrenia is still in its
infancy. While it is conceivable that epigenetic mechan-
isms are relevant in schizophrenia (Mill et al., 2008), the
extent and precise nature of their contributions remain
unclear. Copy number variations account for a sub-
stantial proportion of human genomic variation and
have been found to be relevant to the expression of
various neurodevelopmental disorders; their specific
role in risk for schizophrenia remains to be clarified
(Sutrala et al., 2007; Kirov et al., 2008; Mulle, 2008).
The phenotypic heterogeneity of schizophrenia has
been cited as another reason for the difficulties in precise
delineation of its genetic basis and it has been suggested
that the “schizophrenia genes” do not code for schi-
zophrenia per se, but for some broader clinical construct
such as psychosis (Kendler et al., 1998; Weiser et al.,
2005; Craddock and Owen, 2007) or neurocognitive
deficits that occur in schizophrenia and other conditions
(Whalley et al., 2005; Toulopoulou et al., 2007). In-
creasingly, the use of intermediate phenotypes (endo-
phenotypes) to improve etiological homogeneity and
thereby reduce the problem of nonreplication in genetic
association studies is being advocated (Gottesman and
Gold, 2003; Bearden et al., 2007; Braff et al., 2007;
Glahn et al., 2007; Gur et al., 2007; Owen et al., 2007;
Tan et al., 2008). Although this approach is being found
to be useful (Greenwood et al., 2007), the extent to
which it will facilitate the elucidation of the genetic
basis of schizophrenia is still an open question. Another
approach towards reducing etiological heterogeneity is
to utilize subtypes or dimensions of schizophrenia as the
phenotype for genetic association studies (Jablensky,
2006). Even if such approaches lead to more consistent
genetic findings, the question of how and why different
dimensions or endophenotypes co-occur in schizophre-
nia would still need to be answered.
What is the status of our understanding of the nature
of genetic contributions to the etio-pathogenesis of
schizophrenia in 2008? To the best of our knowledge,
this is what we do know:
(i) Heritability is high and genetic factors contribute
about 80% of the liability for the illness.
(ii) There is no ‘major’ gene locus that could explain
a substantial portion of the heritability and a large
number of candidate susceptibility genes may con-
tribute to the liability for the illness.
(iii) No gene appears to be either sufficient or ne-
cessary for the development of schizophrenia.
(iv) Although there are many “findings” of genetic
variations being linked to differential risk for devel-
oping the illness, inconsistent replication prevents the
consideration of any single allelic variant as a gene for
schizophrenia with absolute certainty at this time.
4. Environmental risk factors
A variety of specific environmental exposures have
been implicated in the etiology of schizophrenia
(Table 1). These include both biological and psychoso-
cial risk factors during the antenatal and perinatal
periods, early and late childhood, adolescence and early
adulthood (Maki et al., 2005).
In the antenatal period, maternal infections and
nutritional deficiency during the first and early second
trimesters of pregnancy have been linked to an increased
liability for developing schizophrenia (Penner and
Brown, 2007; Meyer et al., 2007); these associations
have not, however, been consistently detected (Crow and
most frequently linked to an increased risk of developing
schizophrenia (Mednick et al., 1988), other maternal in-
fections (e.g., rubella, toxoplasmosis, etc.) during this
9R. Tandon et al. / Schizophrenia Research 102 (2008) 1–18
developing schizophrenia as well (Brown et al., 2001,
2002). Although the precise neurobiological mechanism
whereby this increased risk might be mediated is not
clearly understood, a role for cytokines and an aberrant
immune response to these infections that interfere with
normal fetal brain development during this period is
commonly invoked (Ashdown et al., 2006). Severe
nutritional deficiency (Susser et al., 1996; St Clair et al.,
2005) and severe adverse life events (Khashan et al.,
of pregnancy have been linked to an increased risk for
developing schizophrenia; these effects are hypothesized
to be mediated by “stress sensitization” (Koenig et al.,
hyperdopaminergia (Lipska et al., 1993).
A range of obstetric and perinatal complications have
been linked to an approximate doubling of the risk of
developing schizophrenia in the offspring (Geddes and
Lawrie, 1995; Cannon et al., 2002b; Byrne et al., 2007);
there are, however, some discrepant findings (Done et
al., 1991). Although the precise mechanism whereby
exposure to obstetric/perinatal complications might
increase the risk for developing schizophrenia has not
been delineated, fetal hypoxia is most commonly cited
as the mediating factor (Geddes et al., 1999; Byrne et al.,
Although maternal risk factors for schizophrenia
during the prenatal–perinatal period receive the most
attention (Patterson, 2007), older paternal age at
conception has been linked to an approximate doubling
of the risk for developing schizophrenia (Malaspina
et al., 2001; Byrne et al., 2003; Wohl and Gorwood,
2007). While we do not understand the precise
mechanism whereby this increased risk is mediated,
impaired spermatogenesis leading to an increased
likelihood of de novo mutation and aberrant epigenetic
regulation have been advanced as explanations (Byrne
et al., 2003; Perrin et al., 2007; Cheng et al., 2008).
Birth during late winter or early spring has been
1999; Davies et al., 2003), although some statistical
artifacts are inadequately explained (Lewis, 1989). This
season of birth effect appears to become stronger with
increasing latitudeand increasingseverityofwinter. How
this season of birth effect might be mediated is not fully
understood, but it is suggested that it represents a proxy
for one of the above three factors (prenatal infection,
prenatal malnutrition, or risk of mutation).
Although a range of risk factors in childhood have
been suggested as increasing the risk for schizophrenia,
confidence in any of these associations is limited by
discrepancies in findings and several methodological
constraints. Such factors include childhood trauma (Read
and Nasrallah, 1987; David and Prince, 2005), parental
separation or death (Morgan et al., 2006), adverse child
rearing (Tienari et al., 2004), and infection (Dalman et al.,
2008). As earlier discussed in the section on incidence,
urbanicity during the childhood years and migration are
important risk factors for developing schizophrenia.
During adolescence, cannabis use has been linked to
an increased risk of developing schizophrenia (Semple
et al., 2005; Moore et al., 2007). Although an etiological
role is probable, some experts question this cause–effect
relationship and suggest instead that cannabis use might
precipitate schizophrenia in vulnerable individuals or
otherwise modify the expression of schizophrenia but
not the risk for developing it (Degenhardt and Hall,
2006; Barnes et al., 2006). Although social adversity
and stressful life events have long been linked to the
precipitation of schizophrenia (Norman and Malla,
1993); some suggest that these might actually increase
the liability for developing the illness (Harrison, 2004;
Allardayce and Boydell, 2006).
Delayed attainment of various developmental mile-
stones (e.g., language) and a range of “premorbid”
impairments during childhood and adolescence (cogni-
tive — e.g., specific impairments and poor academic
achievement, physical — “minor physical anomalies”
and “soft neurological signs”, and social — e.g.,
“schizotaxia” and poor social adjustment) have been
linked to an increased likelihood of developing schizo-
phrenia (Walker and Lewine, 1990; Fish et al., 1992;
Jones et al., 1994; Cornblatt et al., 1999; Cannon et al.,
2002a; Keshavan et al., 2005). It is unclear, however,
whether such impairments represent risk factors for
developing schizophrenia or are instead early manifesta-
tions of the disease itself.
A range of environmental risk exposures have thus
been linked to liability to develop schizophrenia, but
their exact relevance remains unclear. Many associa-
tions have been suggested by less reliable observational
studies and several putative environmental factors (e.g.,
urbanicity, migration, and ethnicity) are proxies for
some other specific risk exposure whose nature remains
obscure. None of the environmental risk factors appear
sufficient or necessary to cause schizophrenia and no
single factor fully satisfies the nine epidemiological
criteria for an exposure-disease cause–effect relation-
ship (Hill, 1965).
Although a role for both genetic and environmental
risk factors in the etiology of schizophrenia has long
10R. Tandon et al. / Schizophrenia Research 102 (2008) 1–18
been proposed, previously these were considered
dichotomously and questions such as “is it genetic or
environmental in origin” and “what is different about the
schizophrenia caused by genetic versus environmental
factors” focused upon. It is only in the past couple of
decades that investigators have instead seriously begun
to explore issues such as “exactly how do genetic and
environmental elements interact to cause schizophrenia”
(Tienari et al., 2004; Caspi et al., 2005; Krabbendam and
van Os, 2005; Benzel et al., 2007; Cougnard et al., 2007;
Mathew et al., 2007; Nicodemus et al., 2007; Sei et al.,
2007; Zammit et al., 2007; Cheng et al., 2008; Hanninen
et al., 2008). How these factors might interact to cause
schizophrenia and what neurobiological processes
Epidemiological “facts”Reproducibility Whether
Annual incidence=8–40 per 100,000 per year with
relatively similar incidence across broad regions
Higher incidence associated with urbanicity.
*** ***** What specific causal factors — social or
biological — explain differences in incidence?
**** **Does a dose–response relationship exist for
Higher incidence associated with migration.
Lifetime risk=approximately 0.7%
Greater lifetime risk in males
Point prevalence=2–10/1000 with pockets of
high and low prevalence.
What specific factors explain sex differences?
To what extent do variations in diagnostic
criteria/case-ascertainment methods explain
Higher prevalence among lower socio-economic classes.
Schizophrenia is highly heritable and genetic factors
contribute to approximately 80% of the liability for the
There is genetic heterogeneity, with multiple genes
(no single one of which is necessary or sufficient
by itself) related to risk of illness.
Multiple chromosomal regions across the genome are
linked to illness liability.
***What genetic model best explains these genetic
******Why is consistent identification of any single
susceptibility gene variant proving so difficult?
*****What do the risk genes code for —
schizophrenia, psychosis, cognitive deficit,
physiological abnormality, endophenotype?
Specific gene variants of small effect in several genes
have been linked to illness liability and/or illness
Several environmental factors of small effect have been
associated with an increased risk of developing
****** What neurobiological mechanisms mediate
– To *** SCALE to be used to score reproducibility, specificity, and durability of each “fact”
–: very few studies OR Few–Fair number of studies with contradictory findings
*: Few studies with consistent replication OR Fair–Many studies with inconsistent replication
**: Fair number of studies with consistent replication OR Many studies with fairly consistent replication
***:Many independent studies with consistent replication and no contradictory findings
2. Whether primary to schizophrenia
–: finding certainly because of some other confounding variable and definitely not related to schizophrenia.
*: finding possibly because of some other confounding variable but may be related to schizophrenia.
**: finding probably not because of some other confounding variable and likely related to schizophrenia.
***: finding certainly not because of some other confounding variable and definitely related to schizophrenia.
3. Long-term durability
–: very new finding (b5 years) not in previous 2 versions of “FACTS” in 1998 and 1999.
*: relatively new finding (5–15 years). Not in 1988 version, but may have been noted in 1999 version
**: fairly established finding (15–30 years). Listed in 1999 and may have been noted in 1988 versions
***: long established finding, well known for over 30 years. Listed in both 1988 and 1999 versions
From Table 1, Tandon et al., 2008. “Schizophrenia, Just the Facts, Circa 2008”.
11R. Tandon et al. / Schizophrenia Research 102 (2008) 1–18
might mediate such gene–gene, gene–environment, and
environment–environment interactive effects is not
understood at this time.
5. Etiology: what do genetic and environmental
“facts” tell us about the causes of schizophrenia
Although it appears that our understanding of the
causation of schizophrenia has substantially increased
over the past two decades, what we can confidently
assert is essentially the same — both genetic and
environmental factors are important, but exactly which
specific exposures and exactly how they cause schizo-
phrenia is still unknown (Table 2). For the past twenty
years, we have been biding time and asserting that
certain etiological information is just around the corner
(Gottesman et al., 1987); we still wait (Sullivan, 2008).
A reconsideration of our basic strategies and funda-
mental assumptions may be in order.
To make progress, we may need to exert substantially
greater rigor in evaluating findings, better identifying
and explaining discrepancies, developing clear and
testable hypotheses (and then actually testing them!),
and explicitly discarding explanations or assumptions
that are disproved by these efforts. We need to be more
precise in defining the contribution of each putative risk
factor. Assuming that a particular risk factor is convin-
cingly linked to liability for developing schizophrenia,
precisely what is the role of that risk factor and exactly
how are its effects mediated? Does this factor itself
modify the risk for developing schizophrenia or does it
moderate the effect of some other factor (Bauman et al.,
2002; Fanous and Kendler, 2005). Alternatively, is this
factor found to be linked to schizophrenia not because it
is a risk modifier, but a risk mediator (Edwards and
Lambert, 2007); if so whose effects does it mediate?
Finally, does this putative factor modify the risk for
developing schizophrenia or does it instead influence its
expression (e.g., Cougnard et al., 2007; Shaner et al.,
2007)? Table 3 summarizes a set of critical questions
that must be answered with regard to each risk factor
(genetic or environmental) in order for us to acquire a
better understanding of its role in the etio-pathogenesis
There is also a clear need to effectively integrate the
vast amounts of epidemiological data generated across
different fields of inquiry by research groups around the
world utilizing an assortment of paradigms and
approaches. Otherwise, our field at large runs the risk
of being buried under a plethora of unrelated and
undigested findings (Tandon, 1999). As individual
research groups, we are confronted with the challenge
of keeping up with new findings whose veracity we
cannot ascertain and whose significance we cannot
comprehend. This leads to different research groups
working in relative silos and ignoring large swaths of
established findings or worse misinterpreting and
misrepresenting them. In addition to appreciating the
need for and importance of meaningful integration, we
need to invest substantial effort and discipline in order to
make this happen. In our individual research endeavors,
greater rigor and healthy skepticism, a more inductive
(“hypothesis-testing”) approach, in conjunction with
clear and precise explication of our findings would be
useful. In our areas of expertise, it would be helpful to
Critical issues that need to be addressed for all putative etiological
factors linked to schizophrenia
Substantial specific questions
1. Is this the “real” risk-modifying factor or merely a surrogate marker
for some other etiological factor?
2. Does a dose–response relationship exist between intensity of
exposure to this risk factor (genetic or environmental) AND risk of
developing the illness?
3. Does this factor modify the risk of developing schizophrenia,
moderate the risk of some other etiological factor, or mediate the
effect of some other risk factor?
4. Is the risk factor necessary or sufficient to cause schizophrenia? [No
factor can be both necessary and sufficient to cause schizophrenia as
that would mean that it is the sole cause for the disease and we know
multiple etiological factors are relevant].
5. What specific neurobiological mechanisms mediate the effects of
this risk factor to “cause” schizophrenia?
6.Exactly whatdisease orgroup of diseases does the risk factorincrease
the risk for(e.g.,schizophrenia OR some psychoticdisorderORsome
disorder with specific cognitive impairment, etc.)?
7. Exactly how do different genetic risk factors interact with each other
and with environmental risk factors to modify risk of developing the
a) is there a summing of risk factors that determines individual
b) are there interactions between specificsets of risk factors that lead
to development of schizophrenia?
c) are there windows of time (e.g., based on age or developmental
a set of factors) leads to increased risk of developing schizophrenia?
8. Are these effects similar across different populations and if not, why
not? Exactly how do these environmental and genetic risk factors
interact in different populations?
General or methodological
1. Might variations in diagnostic criteria or case-ascertainment
methods explain observed differences in incidence across different
2. Can findings be replicated, exactly replicated? If not, are
explanations of failure to replicate explicitly tested?
3. What specific causal factors (genetic and/or environmental and/or
interactional) explain differences in incidence across different
populations (e.g., differences based on gender, migration/ethnicity
status, urbanicity, etc.)?
12 R. Tandon et al. / Schizophrenia Research 102 (2008) 1–18
update what we know and don't know and how well we
know what we know. Furthermore, it would be crucial
for us to regularly take stock of findings that survive
over time and those that don't (see Table 2); we often
hold on to untrue findings in our field and expend
enormous and obviously unproductive effort in trying to
“explain them” (e.g., McGrath, 2007). To paraphrase
Mark Twain in this regard (Anonymous, 2003), “it ain't
what people don't know that hurts them it's what they
know that ain't so”.
Finally, we need to consider the possibility that there
is no “one” schizophrenia, whose etiological basis we
are trying to define. Perhaps, schizophrenia includes
several (possibly hundreds) of different diseases whose
clinical manifestations are similar. Alternatively, schizo-
phrenia may represent a confluence of many distinct
dimensions (with different etiologies); but we then need
to explain why they co-occur. Fig. 2 illustrates these
models along with the traditional “single common
pathway” construct (Williamson, 2006) and depicts how
multiple etiological factors might interact to produce
neurobiological aberrations that, in turn, lead to the
expression of schizophrenia.
We have accumulated a significant amount of in-
formation pertaining to the causes of schizophrenia, but
our comprehension of its etiology remains limited. It is
vital that we examine the reasons for this continuing gap
between “findings” and “understanding”.
Role of funding source
Independently prepared by authors. No external funding.
Contributors to research and writing of manuscript. Rajiv Tandon,
Matcheri Keshavan, and Henry Nasrallah.
Conflict of interest
This statement was independently developed by Rajiv Tandon,
Matcheri Keshavan, and Henry Nasrallah. The content of the article is
not part of the purview of Dr. Tandon's current employment by the
State of Florida which bears no responsibility its contents.
Fig. 2. Etiology to pathophysiology to illness: models of schizophrenia.
13R. Tandon et al. / Schizophrenia Research 102 (2008) 1–18
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