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©2002 CRC Press LLC
Figure 2.5
Lifetime risk of developing schizophrenia in relatives of schizophrenic individuals. Data from reference 3
General population
Spouses of patient
First cousins (third degree)
Uncles, aunts
Nephews, nieces
Grandchildren
Half siblings
Children
Siblings
Siblings with one schizophrenic parent
Dizygotic twins
Parents
Monozygotic twins
Offspring of dual matings
0
10 20
Lifetime risk of developing schizophrenia (%)
Second-degree relatives
First-degree relatives
50
40
30
LIFETIME RISK OF DEVELOPING SCHIZOPHRENIA
Figure 2.6
Concordance
rates for schizophrenia
in studies of
monozygotic and
dizygotic twins. The
implication of the lack
of 100% concordance in
monozygotic twins is
that there must be
e n v i r o n m e n t a l
etiological factors
involved in the genesis
of schizophrenia. Data
from references 4–10
Study
Kringlen6
Fischer7
Shields &
Gottesman4
Tienari8
Pollin et al.9
Cardno et al.10
Monozygotic Dizygotic
Number
of pairs
Number
of pairs
Concordance
rate (%)
Concordance
rate (%)
55
21
22
17
95
49
90
41
33
20
125
57
45
56
58
35
41
43
5
26
12
13
9
15
CONCORDANCE RATES FOR SCHIZOPHRENIA FROM TWIN STUDIES
©2002 CRC Press LLC
GENETICS
The most important risk factor for schizophrenia
is having an affected relative (
Figure 2.5
and
Table
2.1
)
3–5
. Twin and adoption studies have been used
to show that this is consequent upon genetic
transmission.
The consistently greater concordance in
monozygotic (MZ) than dizygotic (DZ) twins
4–10
(
Figure 2.6
) has been taken to indicate a genetic
effect but does not prove this beyond doubt, since
MZ twins may be treated more similarly by their
parents (
Figure 2.7
). However, adoption studies
have demonstrated conclusively that liability to
schizophrenia is transmitted through genes and
not through some intrafamilial environmental
effect (
Figure 2.8
)
11,12
.
Various models of genetic transmission of
schizophrenia have been considered but found not
to fit the data. There is no evidence to support the
single major locus model, which implies that a
gene of major effect causes schizophrenia but has
incomplete penetrance or variable expression. The
polygenic model implies that there are many
contributing genes, while the multifactorial model
postulates that there are both genetic and
environmental factors. The so-called multifactorial
polygenic model involves an interaction between
multiple loci and environmental factors, with
schizophrenia being expressed only in individuals
who exceed a certain threshold of liability.
Although the mode of transmission has not
been absolutely clarified, molecular and genetic
epidemiological studies concur that it is most
likely to involve a number of genes of small effect
interacting with environmental factors, i.e. the
multifactorial polygenic model. An alternative not
yet excluded is the heterogeneity model, which
proposes that schizophrenia consists of several
distinct conditions, each with a distinct etiology.
Molecular genetic studies have attempted to
identify the particular genes that may be involved
in the predisposition to schizophrenia. To date, no
loci have been consistently replicated. This
indicates that the susceptibility genes must each
Figure 2.7
A pair of monozygotic twins discordant for
schizophrenia. The twin on the right has schizophrenia
Percentage
Relationship
schizophrenic
Parent
5.6
Sibling
10.1
Sibling and one parent affected
16.7
Children of one affected parent
12.8
Children of two affected parents
46.3
Uncles/aunts/nephews/nieces
2.8
Grandchildren
3.7
Unrelated
0.86
Table 2.1
Lifetime expectancy of broadly defined schizo-
phrenia in the relatives of schizophrenics. Table
reproduced with permission from Kendell RE, Zealley AK.
Companion to Psychiatric Studies
. Edinburgh: Churchill
©2002 CRC Press LLC
Figure 2.8
Studies of people
with schizophrenia adopted
away from home show con-
clusively that there is genetic
liability to schizophrenia:
there is an increase in the risk
of schizophrenia associated
with being a biological, but
not an adoptive parent of an
individual with
schizophrenia. Data from
references 11 and 12
Study
Kety et al.11:
Biological parents of schizophrenic
adoptees
Biological parents of control
(normal) adoptees
Adoptive parents of schizophrenic
adoptees
Adoptive parents of control adoptees
Rosenthal et al.12:
Children of schizophrenics adopted
away
Children of normals adopted away
No.
Schizophrenia
spectrum
disorders (%)
66
65
63
68
69
79
12.1
6.2
1.6
4.4
10.1
18.8
ADOPTION STUDIES
Figure 2.9
Obstetric compli-
cations are more common in
people with schizophrenia
compared with controls.
Patients with schizophrenia
are especially likely to have
suffered multiple compli-
cations
30
25
20
15
10
7
5
0
F
requency (%)
Cases
Controls
8
9
10
11
Number of obstetric complications
6
5
4
3
2
1
0
EXPOSURE TO OBSTETRIC COMPLICATIONS
©2002 CRC Press LLC
2.9
). Meta-analyses show that exposure to
obstetric complications roughly doubles the risk of
later schizophrenia; however, this effect only
operates for schizophrenic patients who present
before the age of 25 years; obstetric complications
are not involved in the etiology of late-onset
schizophrenia (
Figure 2.10
)
13–17
. There has been a
search to identify which particular obstetric
complications are responsible. However, the
evidence is that a range of prenatal and perinatal
factors may be involved. Hypoxic ischemia has
been particularly implicated; in the pre- or peri-
natal period this can lead to intraventricular or
periventricular bleeds, resulting in ventricular
enlargement; this might be one mechanism for
ventriculomegaly in schizophrenia. Exocitotoxic
damage associated with perinatal hypoxia may
also account for some of the neurochemical
abnormalities (e.g. of glutamatergic function) that
are found. However, complications arising around
the time of birth may reflect much earlier abnor-
mal fetal development associated with defective
genetic control of neurodevelopment and adverse
environmental exposure (
Figure 2.11
)
18
.
be of relatively small effect so as to have escaped
detection. Much interest centers on so-called
hotspots that may contain susceptibility genes on
chromosomes 6, 8, 10, 13 and 22. There has also
been interest in genes involved in the metabolism
of dopamine and other catecholamines, and also in
genes involved in the control of neurodevelop-
ment.
ENVIRONMENTAL INFLUENCES
There is no doubt that there is a heritable compo-
nent to the etiology of schizophrenia. It is equally
clear that genetic predisposition is not the whole
story. Concordance in MZ twins is only about
50%; the rest of the variance must depend on the
person’s environment. These are often split into
early and late environmental factors (
Figure 2.4
).
Early environmental factors
Obstetric complications
Large population-based studies have demonst-
rated that obstetric complications are more
common in schizophrenic populations (
Figure
Figure 2.10
Obstetric comp-
lications are a risk factor for
schizophrenia in patients
with a younger age of onset;
they do not seem to be
involved in the etiology of
late-onset schizophrenia.
Those patients who suffered
obstetric complications
showed an earlier onset than
patients who did not
Pollack and Greenberg,
199613
Pearlson et al.,
198514
Owen et al.,
198815
O'Callaghan et al.,
199216
O'Callaghan et al.,
199017
15
20 25
Mean age at onset of schizophrenia (years)
30
No obstetric
complications
Obstetric
complications
OBSTETRIC COMPLICATIONS AND AGE OF ONSET
©2002 CRC Press LLC
maternal infection in the cold winter months.
There is some evidence to suggest that an increase
in the number of births of individuals subseq-
uently diagnosed as schizophrenic follows
influenza epidemics, although both the existence
and the importance of this effect remain contro-
versial. Exposure in later pregnancy to several
other viral infections, including rubella, has also
been implicated in some studies. An increase in
the rate of schizophrenia has also been described
among those subjected to severe malnutrition
during the third trimester in utero
18
. Further evid-
ence for the importance of the uterine environ-
ment in the pathogenesis of schizophrenia comes
from data suggesting that preschizophrenic babies
have a smaller head circumference than controls,
and from studies suggesting that schizophrenic
Several studies have found men with
schizophrenia to be at greater risk of obstetric
complications and of preschizophrenic behavioral
abnormalities, and male schizophrenics also have
more marked structural brain changes. This may
contribute to the fact that schizophrenia, tightly
defined, is more common in men. It is also of
earlier onset and greater severity, a pattern that is
also seen in other neurodevelopmental disorders.
Prenatal infection
Schizophrenia is more common among those born
in the late winter and early spring (
Figure 2.3
), so
one environmental stressor potentially affecting
fetal brain development that has received
considerable attention is in utero exposure to
Figure 2.11
Exposure to nutritional deficiency during fetal development may be a risk factor for
schizophrenia, as demonstrated by this study where the incidence of schizophrenia rose twofold in the
group whose early fetal development occured between February and April 1945 – a period of severe
famine in wartime Holland. Figure reproduced with permission from Susser E, Neugebauer R, Hoek HW,
et al.
Schizophrenia after prenatal famine: further evidence.
Arch Gen Psychiatry
1996;53:25–31
5
1
Jan–Feb 1944
Mar–Apr 1944
May–Jun 1944
Jul–Au
g 1
944
Sep–Oct 1944
Nov–Dec 1944
Jan–Feb 1
945
Mar–Apr 1
945
May–Jun 1945
Jul–Aug 1945
Sep–Oct 1
945
Nov–Dec 1
945
Mar–Apr 1946
Jan–Feb 1
946
May–Jun 1946
Jul–Aug 1946
Sep–Oct 1
946
Nov–Dec 1946
2
3
4
0
ADVERSE PRENATAL ENVIRONMENTAL EXPOSURE
AND INCIDENCE OF SCHIZOPHRENIA
Incidence (per 1000)
Month of birth