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Volumes of Brain Structures in Twins Discordant for Schizophrenia
William F. C. Baaré, MS;
Clarine J. van Oel, MS;
Hilleke E. Hulshoff Pol, PhD;
Hugo G. Schnack, PhD;
Sarah Durston, MS;
Margriet M. Sitskoorn, PhD;
René S. Kahn, MD, PhD
Arch Gen Psychiatry. 2001;58:33-40.
ABSTRACT
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Background The study was designed to examine the relative contributions of genetic
and nongenetic factors to structural brain abnormalities in schizophrenia
and subjects at risk to develop the disorder.
Methods The brains of 15 monozygotic and 14 same-sex dizygotic twins discordant
for schizophrenia (patients) and 29 healthy twins pair-wise matched for zygosity,
sex, age, and birth order were studied using high-resolution magnetic resonance
imaging scans.
Results Intracranial and whole-brain corrected frontal lobe volumes were smaller
(4.6% and 2.7%, respectively) in discordant monozygotic twins as compared
with healthy monozygotic twins. Irrespective of zygosity, discordant twins
had smaller whole-brain (2%), parahippocampal (9%), and hippocampal (8%) volumes
than healthy twins. Moreover, patients had smaller whole-brain volumes (2.2%)
than their nonschizophrenic cotwins, who in turn had smaller brains (1%) than
healthy twins. Lateral and third-ventricle volumes were increased in discordant
dizygotic twins as compared with healthy dizygotic twins (60.6% and 56.6%,
respectively). Finally, within discordant twins, lateral ventricles were larger
(14.4%) in patients than in their nonschizophrenic cotwins.
Conclusions Smaller intracranial volumes in the monozygotic patients and their cotwins
suggest that increased genetic risk to develop schizophrenia is related to
reduced brain growth early in life. The additional reduction in whole-brain
volume found in the patients suggests that the manifestation of the disorder
is related to (neurodegenerative) processes that are most likely nongenetic
in origin.
INTRODUCTION
SCHIZOPHRENIA is a severe chronic psychiatric disorder that affects
around 1% of the general population.1 Although
its cause is unknown, family, twin, and adoption studies have established
the importance of genetic factors. Indeed, the risk to develop schizophrenia
increases with the degree of kinship and is highest (48%) in monozygotic (MZ)
twins, who share the same genome.2 Environmental
factors, such as intrauterine and perinatal factors, are involved as well.3, 4, 5 However, the relative contributions
of genetic and environmental factors to the cause of schizophrenia remain
equivocal.6
Pathophysiologically, schizophrenia is understood as a brain disease.
Postmortem studies7 and studies using in vivo
imaging techniques such as computed tomography and magnetic resonance imaging
(MRI) scanning have convincingly demonstrated morphological abnormalities
in the brains of patients with schizophrenia.8, 9
However, it is unclear whether the brain abnormalities associated with schizophrenia
are genetic or environmental in origin. A genetic component is suggested by
increased sulcal cerebrospinal fluid and reduced gray matter volumes,10 smaller thalamic volumes,11
and enlarged ventricles12, 13 in
patients with schizophrenia as well as in their nonschizophrenic siblings
(who share, on average, 50% of the genes) as compared with healthy controls.
Furthermore, enlarged ventricles and increased sulcal cerebrospinal fluid
have been found in subjects with an increased genetic risk to develop schizophrenia,
such as obligate carriers, subjects with a schizotypal personality disorder,
and offspring of mothers with schizophrenia.14, 15, 16
However, not all studies found a familial component or increased genetic risk
related to increased ventricle size.2, 15, 16
The involvement of nongenetic factors is emphasized by studies researching
monozygotic twins discordant for schizophrenia, in which the ill twins were
found to have smaller brain and hippocampal volumes and larger ventricles
than their nonschizophrenic cotwins.17, 18, 19
The present study was designed to examine the neuroanatomical correlates of
a (possible) genetic predisposition to develop schizophrenia and the relative
contributions of genetic and nongenetic factors to these structural brain
abnormalities. High-resolution MRI scans of the brain were obtained from MZ
and dizygotic (DZ) twins discordant for schizophrenia and healthy twin pairs
who were pair-wise matched on zygosity, sex, age, and birth order. The study
of twins discordant for schizophrenia significantly enhances the sensitivity
to detect brain abnormalities because shared genetic and prenatal and postnatal
environmental factors that contribute to the variation in brain morphology
are controlled for. Importantly, discordant MZ twin pairs, unlike discordant
DZ twin pairs, have the same genetic predisposition to develop schizophrenia.
A genetic role is suggested when MZ patients and their cotwins differ from
healthy MZ twins but do not differ from each other, and the finding is more
pronounced in discordant MZ than in discordant DZ twin pairs. The degree to
which brain structure is genetically controlled can be estimated by comparing
the within-pair similarity of the MZ twins with that of the DZ twins.
SUBJECTS AND METHODS
SUBJECTS
Twenty-nine pairs of twins, 15 MZ and 14 same-sex DZ discordant for
schizophrenia, and 15 MZ and 14 DZ healthy control twins pair-wise matched
on zygosity, sex, age, and birth order took part in the study (Table 1). Subjects were recruited in collaboration with psychiatric
services and by advertisements in national newspapers. All subjects gave written
informed consent to participate in the study after full explanation of the
study aims and procedures. Zygosity was determined by DNA fingerprinting using
either the polymorphic markers D06S474, D07S1804, D07S1870, D12S811, D13S119,
D13S126, D13S788, D20S119, D22S683, DXS1001, and ELN, or D13S317, VWA, D74520,
D35158, TH01, TP0X, CSF1P0, and D55818. Except for 1 control twin pair, all
twins were reared together. The 1 control twin pair was separated at age 12
years when both their parents died.
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Table 1. Demographic Data*
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All subjects underwent extensive psychiatric assessment procedures using
the Comprehensive Assessment of Symptoms and History interview,20
the Schedule for Affective Disorders and Schizophrenia: Lifetime Version,21 the Structured Interviews for DSM-III-R (Diagnostic and Statistical Manual of Mental Disorders,
Revised Third Edition) and DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition),22, 23 the Family Interview for Genetic Studies,24 and a medical history inventory. Psychiatric diagnosis
was established according to criteria of DSM-IV.
Diagnostic assessments were conducted by trained and experienced psychologists
and psychiatrists at the Department of Psychiatry of the University Medical
Center, Utrecht, the Netherlands. Consensus was reached in presence of a senior
psychiatrist. The following subtypes were diagnosed in the twins with schizophrenia:
paranoid (7 MZ; 4 DZ), disorganized (3 MZ; 3 DZ), undifferentiated (2 MZ;
5 DZ), residual (2 MZ; 2 DZ), and catatonic (1 MZ). Furthermore, 3 MZ patients
and 1 DZ patient had an additional diagnosis of depressive disorder not otherwise
specified. Diagnoses in nonschizophrenic cotwins included paranoid personality
disorder (2 MZ: 1 of which also had a schizoid personality disorder and a
recurrent major depressive disorder; 1 DZ), schizotypical personality disorder
(2 MZ), schizoid personality disorder (1 DZ), major depressive disorder (4
MZ: 1 recurrent and 3 single episodes [1 with psychotic symptoms and 1 with
agoraphobia]; 2 DZ: single episode), avoidant personality disorder (2 DZ:
1 with social phobia and 1 with partial epilepsy), generalized anxiety disorder
with a dependent personality disorder (1 MZ), and no psychiatric diagnoses
(5 MZ; 8 DZ). Moreover, 5 MZ and 4 DZ patients and 1 MZ and 1 DZ cotwin had
histories of substance or alcohol abuse. Healthy control twins had no psychiatric
illness, no schizophrenic spectrum disorders, no first-degree relatives with
a history of psychiatric illness, and no second-degree relatives with a psychotic
disorder. Two patients had never been on antipsychotic medication. Six patients
used atypical antipsychotic medications (mean daily dose, 458.33 chlorpromazine
equivalents; SD, 206.56) and 21 patients received typical antipsychotic medications
(mean daily dose, 641.67 chlorpromazine equivalents; SD, 821.71).
ACQUISITION OF MAGNETIC RESONANCE IMAGES
Magnetic resonance imaging scans were obtained using a 1.5-T and a 0.5-T
(13 discordant twin pairs, 7 MZ and 6 DZ) Philips Gyroscan scanner (Philips
Medical Systems, Best, the Netherlands). Eight controls were scanned on both
scanners to evaluate the effect of scanner type. For volumetric analysis on
the 1.5-T scanner a 3-dimensional (3-D) T1-weighted, coronal, spoiled gradient
echo scan (FFE) of the whole head (echo time [TE], 4.6 ms; time to repeat
[TR], 30 ms; flip angle, 30°; 170-180 contiguous slices; 1 x 1 x
1.2-mm3 voxels), and a coronal dual-contrast turbo spin echo of
the whole brain (TE1, 14 milliseconds; TE2, 80 milliseconds;
TR, 6350 milliseconds; 120 contiguous slices; 1 x 1 x 1.6-mm3 voxels) were acquired. Scans on the 0.5-T scanner included a 3D T1-weighted,
coronal FFE scan of the whole head (TE, 13 milliseconds; TR, 30 milliseconds;
flip angle, 30°; 170-180 contiguous slices; 1 x 1 x 1.2-mm3 voxels) and an inversion recovery (IR) scan (TE, 30 milliseconds;
TI, 300 ms; TR, 2720 milliseconds; 36 contiguous slices; 1 x 1 x
3.6-mm3 voxels, frontal and occipital poles not included).
IMAGE ANALYSIS
Raters were blind to subject identification and status and cerebral
hemisphere. Image volumes were Talairach corrected (no scaling25)
and corrected for magnetic field inhomogeneities.26, 27
Total intracranial, whole-brain lateral ventricle and third ventricle volumes
were measured automatically. The medial temporal structures (amygdala, hippocampus,
and parahippocampal gyrus) and frontal lobes, were delineated manually by
1 and 2 raters, respectively (Figure 1). Automatically segmented volumes of interest (VOI) were visually checked by
1 rater and edited if necessary.
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Figure 1. Volumes of interest. A, Intracranial.
B, Whole brain. C, Lateral ventricles (yellow) and third ventricle (green).
D, Frontal lobes. E, Hippocampi (purple and green) and parahippocampal gyri
(turquoise and yellow).
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Automatic segmentation software included histogram analysis algorithms
and series of mathematical morphological operators to connect all voxels of
interest. Intracranial volume was segmented on dual contrast turbo spin echo
and IR scans. Voxels inferior to the cerebellum midway of the foramen magnum
were excluded. Frontal and occipital poles were added manually to the IR intracranial
volumes by overlaying the IR intracranial volume over the corresponding 0.5-T
3-D data volume, which was resampled to fit IR scan dimensions.26
Whole-brain volume was segmented on the 3-D FFE scans. Whole-brain volumes
contained gray and white matter tissue only. In lateral ventricle segmentation,
automatic decision rules bridged connections not detectable and prevented
‘leaking' into cisterns. The third ventricle was limited by coronal
slices, clearly showing the anterior and posterior commissures. The upper
boundary was a plane through the plexus choroideus ventriculi tertii in the
midsagittal slice perpendicular to this slice.
Manual segmentation was performed in an anterior-posterior direction
on whole-brain volumes using ANALYZE (Biomedical Imaging Resource, Mayo Foundation
Clinic, Rochester, Minn).28 A volume-rendered
3D representation of the brain and simultaneous visualization and manipulation
of coronal, transverse, and sagittal slices enabled accurate localization
of landmarks. The frontal pole, the lateral fissure, and the interhemispheric,
circular insular, precentral, and cingulate sulci limited the frontal lobes.29 Amygdala segmentation started in the coronal slice,
above which the optic tract lies. The lateral border was defined by the gray
matter of this nucleus until the gray matter of the parahippocampal gyrus
was reached. From then on, the border was continued as a straight line in
direct continuation with the inferior and medial border of the amygdala. Segmentation
of the hippocampus started in the coronal slice in which the characteristic
oval shape of mammillary bodies was visible for the first time, and stopped
when the fornix was visible as a continuous tract.30
The border of the hippocampus was defined by its gray matter. Parahippocampal
gyrus segmentation began simultaneously with the amygdala. The posterior commissure
was its posterior border. The lateral border was defined by the collateral
sulcus, and the superior border was defined by a straight line from the most
superolateral point of the collateral sulcus to the most superior point of
the mediotemporal cortex in the crural cistern. The amygdala and hippocampus
were then excluded from the parahippocampal gyrus segmentation. Although the
collateral sulcus has considerable interindividual variability making it prone
to bias, we considered it adequate, as there was no reason to assume differences
in variability between groups.
Intrarater reliabilities, expressed as intraclass correlation coefficients
(ICC), for intracranial, whole-brain, and lateral and third ventricle volumes
calculated on 22, 14, and 18 scans, respectively, were all 0.99. For the amygdala,
hippocampus, parahippocampus, and frontal lobes, intrarater reliabilities
calculated on 14 scans were 0.49, 0.82, 0.84, and 0.99, respectively. Interrater
reliability for the frontal lobes was 0.98. Because of low reliabilities,
the amygdala volumes were excluded from further analysis.
Intraclass and Pearson correlations for the VOIs measured on the 1.5-T
and 0.5-T scans to evaluate scanner type effects were 0.99 and 0.99 for intracranial,
0.89 and 0.98 for whole brain, 0.97 and 0.99 for lateral ventricles, 0.75
and 0.87 for third ventricle, 0.94 and 0.97 for frontal lobe, 0.89 and 0.89
for hippocampal, and 0.83 and 0.84 for parahippocampal volumes. Most volumes
were highly comparable between scanners. Higher Pearson than intraclass correlations,
however, indicated a linear shift in some of the VOIs. To correct for this
shift, scaling factors were calculated (mean volume1.5T/ mean volume0.5T) and applied to the 0.5T VOIs measured in the study sample.
DATA ANALYSIS
Statistical analyses were performed with the SPSS package for Windows
version 6.1 (Statistical Product and Service Solutions 6.1; SPSS Inc, Chicago,
Ill). The data were normally distributed, except for the lateral ventricles,
the third ventricle, and the hippocampus. These variables were successfully
normalized using a logarithmic tranformation. Within–twin-pair similarity
for VOIs was estimated by calculating ICCs on standardized residuals corrected
for age and sex for discordant and healthy MZ and DZ twin pairs. Fisher r to z transformations were used
for statistical testing and to calculate 95% confidence intervals. Volume
measurements and variables such as age, height, parent education, and subject
education were pair-wise analyzed using repeated measures multivariate analysis
of covariance (rm-MANCOVA). Zygosity (monozygotic, dizygotic) was entered
as a between-subjects factor. Group (Discordant twin pairs, healthy twin pairs),
twin (1 = patient with schizophrenia or matched healthy control twin, 2 =
nonschizophrenic cotwin or matched healthy control twin), and side (left,
right) were analyzed as matched samples. The following main and interaction
effects were tested: zygosity, group, twin, zygosity x group; zygosity
x twin; group x twin; and zygosity x group x twin.
Second, any interaction with the side factor was evaluated. To evaluate the
effect of substance abuse and organic brain syndromes within discordant families
twin pairs in which 1 or both twins had a history of substance abuse (9 twin
pairs: 8 patients and 3 cotwins) and organic brain syndrome (1 twin pair:
1 cotwin) at some point during their lives were compared with twin pairs without
such histories using a rm-MANCOVA, with history (positive, negative) as a
between-subject factor and twin (patient, nonschizophrenic cotwin) as a within-subject
factor. Intracranial volume was used as a covariant for whole-brain, extracerebral
CSF (intracranial volume - whole-brain and ventricle volumes) and ventricle
volumes whereas whole-brain volume was a covariant for the frontal lobes and
the medial temporal structures. Significant interactions were followed up
with a priori special contrasts.31 All tests
were 2-tailed. The  level of significance was .05.
RESULTS
Table 2 presents absolute
volumetric data. Estimates of within–twin-pair similarity are presented
in Table 3.
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Table 2. Absolute Volumes*
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Table 3. Brain Structure Similarity Measures in Twins*
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The intraclass correlations for volumes of interest, except for parahippocampal
volume in discordant twin pairs, were higher for MZ twin pairs than for DZ
twin pairs. In particular, intracranial, whole-brain, frontal lobe, and hippocampal
volumes in both discordant and healthy twin pairs, and lateral ventricle volume
in healthy twin pairs only seemed to be under a high degree of genetic control.
Intraclass correlation coefficients for the parahippocampal gyrus and third
ventricle were substantially lower in discordant MZ twin pairs as compared
with healthy MZ twin pairs.
INTRACRANIAL VOLUME
A significant zygosity x group interaction (F1,27 =
4.43; P<.05) was found. This was attributable
to discordant MZ twin pairs having smaller intracranial volumes than healthy
MZ twin pairs and the discordant DZ twin pairs not differing from their controls.
Monozygotic patients and their cotwins did not differ from each other. Intracranial
volumes were not significantly different between MZ and DZ patients.
WHOLE-BRAIN VOLUME
A significant main effect for group (F1,26 = 15.71; P<.001), with both the patients and their cotwins having
significantly smaller brains than the healthy twin pairs (F1,27
= 15.72; P <.001 and F1,27 = 4.35; P < .05, respectively), and a group x twin interaction
(F1,26 = 12.82; P<.001) were found
(Figure 2). The group x twin
interaction was attributable to patients having significantly smaller brains
than their cotwins (F1,27 = 7.06; P<.05)
and the healthy twins not differing significantly from each other.
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Figure 2. Whole-brain volume. All values
are means ± SEMs. A significant group effect (A: F1,26 =
15.71; P<.001) indicated that twins discordant for schizophrenia
had significantly smaller whole-brain volumes than healthy twins. Patients
(B: F1,27 = 15.72; P<.001) as well as their cotwins
(C: F1,27 = 4.35; P<.05) had reduced whole-brain
volumes. Moreover, patients had significantly smaller brains than their cotwins
(D: F1,27 = 7.06; P<.05).
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FRONTAL LOBES
A significant zygosity x group interaction was found (F1,26 = 6.01; P<.05). This was attributable to
discordant MZ twin pairs having smaller frontal lobes than healthy MZ twin
pairs and discordant DZ twin pairs not differing from their controls.
HIPPOCAMPUS
A significant main effect for group (F1,26 = 4.92, P<.05) was found, with discordant twin pairs having
smaller hippocampal volumes than healthy twin pairs. For parahippocampal gyrus,
a significant main effect for group (F1,26 = 4.77; P<.05) was found, with discordant twin pairs having smaller parahippocampal
volumes as compared with healthy twin pairs.
EXTRACEREBRAL VOLUME
A significant group effect (F1,26 = 13,98; P<.001), with discordant twins having larger extracerebral volume
than control twins, and a group x twin interaction (F1,26
= 12.97; P<.001) were found. The group x
twin interaction was attributable to patients having significantly larger
extracerebral volumes than their cotwins and healthy twins not differing from
each other.
LATERAL VENTRICLES
Significant interactions were seen for zygosity x group (F1,26 = 6.24; P<.05), with discordant DZ
twins having larger lateral ventricles than control DZ twins and MZ twins
not differing from control MZ twins; for group x twin (F1,26
= 6.48, P<.05), with patients having larger lateral
ventricles than their cotwins; and for zygosity x side (F1,27
= 18.42; P<.01), with MZ but not DZ twins having
larger left than right lateral ventricles.
THIRD VENTRICLE
A significant main effect was found for group (F1,26 = 4.66; P<.05), with discordant twins having larger third ventricles
than control twins, and for a zygosity x group interaction (F1,26 = 6.44; P<.05), with discordant DZ twins
having larger third ventricles than control DZ twins and discordant MZ twins
not differing from control MZ twins.
SUBSTANCE ABUSE
There was no main effect for history of substance or alcohol abuse for
any of the total VOIs (F value range, 0.04-0.92; P
value range, .35-.84). When data were analyzed excluding subjects with a history
of substance abuse or alcohol abuse, results did not change.
COMMENT
This study compared brain structure in MZ and same-sex DZ twins discordant
for schizophrenia with those of healthy twins pair-wise matched on zygosity,
age, sex, and birth order. Most VOIs, particularly intracranial, whole-brain,
and frontal lobe volumes, seemed highly genetically controlled. Intracranial
and frontal lobe volumes were decreased in discordant MZ twin pairs, whereas
whole-brain, and parahippocampal volumes were reduced in discordant pairs
irrespective of zygosity. In addition to the decrements found in their cotwins,
patients showed additional reductions in whole-brain volume. Lateral and third
ventricle volumes were increased in discordant DZ twin pairs. Compared with
their cotwins, patients showed increased lateral ventricle volume.
The first major finding is that of reduced intracranial volumes in discordant
MZ twin pairs as compared with healthy MZ twin pairs, with intracranial volume
being highly genetically controlled. Notably, MZ patients and their cotwins
were affected to a similar degree. Since they share the same genetic vulnerability
to develop schizophrenia, and since this finding was more pronounced in the
discordant MZ twin pairs than in the discordant DZ twin pairs, smaller intracranial
volumes may reflect a neuroanatomical correlate of a genetically based vulnerability
to develop schizophrenia. Brain growth is the main factor determining cranial
growth in early development32; consequently,
these findings suggest that brain growth in schizophrenia is stunted early
in life. Although the finding of smaller intracranial volumes is consistent
with the result of a recent meta-analytic study of cranial size in schizophrenia,33 our results suggest that this volume reduction may
reflect a genetic vulnerability to developing schizophrenia, rather than being
related to the illness itself. However, an alternative explanation is that
an interaction between genetic vulnerability and environmental events occurring
predominantly in MZ (and not DZ) twin pairs leads to abnormal brain growth,
resulting in smaller intracranial volumes.
The second major finding is that whole-brain volume was reduced in discordant
twin pairs irrespective of zygosity. Since both patients and their cotwins
displayed decrements in total brain volumes, this probably reflects shared
factors that may be either genetic and/or environmental in origin. The finding
is consistent with those of a recent family study reporting decreased gray
matter volumes in patients with schizophrenia and their nonschizophrenic siblings.10 The additional decrease in whole-brain volume in the
patients as compared with their cotwins suggests that schizophrenia itself
is expressed by further reductions in brain tissue, which are most likely
attributable to nongenetic factors. Similarly, a study in discordant MZ twins
showed significant brain volume reductions in patients as compared with their
healthy cotwins.17 Our finding of reduced brain
volume in schizophrenia is consistent with the results of several other studies.8, 17, 33
Frontal lobe volumes were decreased in discordant MZ twin pairs as compared
with healthy MZ twin pairs in excess of the overall decrement in brain volume.
This finding is suggestive of a relationship between reductions in frontal
lobe volume and a genetically mediated vulnerability to develop schizophrenia.
Alternatively, genetic vulnerability and environmental factors might interact
predominantly in MZ twins. A genetic interpretation is supported by studies
showing that patients with disorders genetically related to schizophrenia,
such as schizotypal and schizoid personality disorder, display functional
abnormalities of the frontal lobe.34 It must
be noted, however, that our findings included the premotor, dorsolateral prefrontal,
and orbitofrontal areas, and did not distinguish between these functionally
separate frontal brain regions.
Hippocampal and parahippocampal volumes were reduced in discordant twin
pairs irrespective of zygosity, which may thus be secondary to genetic or
shared environmental effects. Parahippocampal reductions are most likely of
environmental origin because ICCs for this structure were substantially lower
in discordant MZ twin pairs than in healthy MZ twin pairs. Hippocampal volume
reductions in schizophrenia have been found in siblings of patients,35 while in MZ twins, hippocampal reductions were reported
in the MZ twins with schizophrenia as compared with the cotwins,19
suggesting additional environmental influences. Importantly, our finding that
both genetic as well as common environmental factors may be involved in the
medial temporal lobe decrease in schizophrenia seems to be supported by these
findings.
Lateral and third ventricular volumes were increased in discordant DZ
twin pairs as compared with control DZ twin pairs, and comparable in discordant
MZ twin pairs as compared with control MZ twin pairs. Our finding that discordant
MZ twins did not differ from healthy controls is in agreement with reported
findings.19, 36 Lateral ventricles
were enlarged in patients as compared with their cotwins, suggesting that
the enlargement is mainly due to environmental events. The finding is in agreement
with those for discordant MZ twin and sibling pairs.10, 19
Third ventricle enlargement also seems to be environmental in origin because
ICCs were substantially lower in discordant MZ twin pairs as compared with
healthy MZ twin pairs.
A limitation of this study was that by not including MZ twins concordant
for schizophrenia, a group was selected where environmental factors are important
in the development of the disorder,37 hereby
preventing estimation of the true genotypic population variance. Furthermore,
although attempts were made to ensure comparability of volumetric measures
across scanning platforms, we can not rule out the possibility that the use
of 2 different scanners influenced our results. Finally, it is not known to
which extent physiological factors such as medication intake may have contributed
to volume differences between twins with schizophrenia and nonschizophrenic
twins.
In conclusion, findings from this study suggest that increased genetic
risk to develop schizophrenia may lead to impaired brain development, possibly
early in life. The manifestation of the disorder itself appears related to
additional (perhaps degenerative) processes that are, at least partly, nongenetic
in origin.
AUTHOR INFORMATION
Accepted for publication July 20, 2000.
This paper was presented at the International Congress on Schizophrenia
Research, Santa Fe, NM, April 21, 1999.
We thank Alfons Bardoel and Eric Strengman at the Department of Medical
Genetics of the University Medical Center Utrecht, the Netherlands, Jeremy
Silverman, PhD, at the Department of Psychiatry of the Mt Sinai School of
Medicine, New York, NY, for their assistance in the zygosity determinations,
and Willie van de Weele, MS, for segmentation of the frontal lobe.
From the Department of Psychiatry, University Medical Center, Utrecht,
the Netherlands.
Corresponding author and reprints: René S. Kahn, MD, PhD,
Department of Psychiatry, University Medical Center Utrecht, Heidelberglaan
100, 3584 CX Utrecht, the Netherlands (e-mail: r.kahn{at}psych.azu.nl).
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