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Association study of dysbindin gene with clinical and outcome measures in a representative cohort of Italian schizophrenic patients.

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American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 144B:647 –659 (2007)
Association Study of Dysbindin Gene With
Clinical and Outcome Measures in a Representative
Cohort of Italian Schizophrenic Patients
Sarah Tosato,1* Mirella Ruggeri,1 Chiara Bonetto,1 Mariaelena Bertani,1 Giovanna Marrella,1
Antonio Lasalvia,1 Doriana Cristofalo,1 Giuseppe Aprili,2 Michele Tansella,1 Paola Dazzan,3
Marta DiForti,3 Robin M. Murray,3 and David A. Collier4
1
Section of Psychiatry and Clinical Psychology, University of Verona, Verona, Italy
Blood Transfusion Service, Azienda Ospedaliero-Universitaria di Verona, Verona, Italy
3
Institute of Psychiatry, Division of Psychological Medicine, King’s College London, London, United Kingdom
4
SGDP Centre, Institute of Psychiatry, King’s College London, London, United Kingdom
2
There is evidence suggesting that Dysbindin
(DTNBP1) is a susceptibility gene for schizophrenia in Caucasian, Chinese, and Japanese populations. We sought to determine if dysbindin was
associated with schizophrenia and its symptoms
in a representative group of schizophrenic
patients from a Community-Based Mental Health
Service (CMHS) in Verona, Italy. A prevalence
cohort of schizophrenic patients (n ¼ 141) was
assessed at baseline and then 3 and 6 years later.
Eighty patients and 106 healthy controls were
genotyped for polymorphisms in dysbindin. We
tested if diagnosis, clinical symptoms as measured
by the Brief Psychiatric Rating Scale (BPRS), and
functioning as measured by the Global Assessment of Functioning Scale (GAF), were associated
with the presence of certain dysbindin polymorphisms. Finally, using the longitudinal clinical data, we tested if patients carrying dysbindin
high-risk haplotypes had a more unfavorable
longitudinal clinical outcome. A trend towards
statistical association (P ¼ 0.058) between schizophrenia and rs2619538 was found. Using GENECOUNTING software, we found that rs2619538P1583 (P ¼ 0.048), P1320-P1757 (P ¼ 0.034), and
rs2619538-P1583-P1578 (P ¼ 0.040) haplotypes
occurred more often in cases compared to controls
before correction for multiple testing. The
rs2619538-P1583 haplotype was more likely to be
transmitted to subjects with more severe and
persistent psychopathology. These preliminary
results are compatible with the view that DTNBP1
is a susceptibility factor for schizophrenia, and is
associated with worse psychopathology.
ß 2007 Wiley-Liss, Inc.
This article contains supplementary material, which may be
viewed at the American Journal of Medical Genetics website
at http://www.interscience.wiley.com/jpages/1552-4841/suppmat/
index.html.
*Correspondence to: Sarah Tosato, M.D., Department of
Medicine and Public Health, Section of Psychiatry and Clinical
Psychology, Policlinico G.B. Rossi, P.le L.A. Scuro 10, 37134
Verona, Italy. E-mail: sarah.tosato@univr.it
Received 28 July 2006; Accepted 14 November 2006
DOI 10.1002/ajmg.b.30484
ß 2007 Wiley-Liss, Inc.
KEY WORDS: dysbindin; candidate gene; schizophrenia; outcome; longitudinal
data
Please cite this article as follows: Tosato S, Ruggeri M,
Bonetto C, Bertani M, Marrella G, Lasalvia A, Cristofalo
D, Aprili G, Tansella M, Dazzan P, DiForti M, Murray
RM, Collier DA. 2007. Association Study of Dysbindin
Gene With Clinical and Outcome Measures in a Representative Cohort of Italian Schizophrenic Patients. Am
J Med Genet Part B 144B:647–659.
INTRODUCTION
Family [Kendler, 1983], twin [Cardno et al., 1999] and
adoption [Kety, 1987] studies suggest a substantial genetic
component for schizophrenia, with twin studies placing the
heritability of the disease at more than 80% [Cardno and
Gottesman, 2000]. Linkage analysis has identified several loci
which appear to harbor susceptibility genes for schizophrenia,
including chromosome 6p [Lewis et al., 2003]. In particular, the
gene dysbindin (dystrobrevin-binding protein 1, DTNBP1),
which maps to chromosome 6p, is now considered a susceptibility gene [Williams et al., 2005]. There is quite impressive
evidence supporting the association between genetic variants
in dysbindin and schizophrenia in Caucasian, Chinese, and
Japanese populations [Straub et al., 2002; Schwab et al., 2003;
Tang et al., 2003; van den Oord et al., 2003; Funke et al., 2004;
Numakawa et al., 2004; Williams et al., 2004; Li et al., 2005
(Chinese population)] with only three studies failing to
replicate positive association [Morris et al., 2003; van den
Bogaert et al., 2003; Li et al., 2005 (Scottish population)].
Furthermore, it has been pointed out [Kirov et al., 2005] that
the negative study of van den Bogaert et al. [2003] did show a
positive association of the dysbindin gene in the subgroup of
schizophrenic patients with a familial loading for the disease.
In addition, a significant association was found in the initially
negative sample of Morris and colleagues, when one additional
marker that defined the risk haplotype was genotyped
[Williams et al., 2004].
One approach to clarifying these findings is the use of clinical
characteristics as phenotypes for genetic analysis, as these
may show a more direct relationship with the underlying
genetic variants [Gottesman and Gould, 2003; Jablensky,
2005; Tansella, 2005]. Recently Gornick et al. [2005] found an
association between SNPs in the dysbindin and premorbid
function in subjects with childhood-onset schizophrenia,
suggesting that, more than the condition of being schizophrenic per se, are some course of the illness characteristics (in this
648
Tosato et al.
case, early onset) which might be caused by certain genetic
variations. On the other hand, several epidemiological studies
have so far pointed at a marked heterogeneity in the outcome of
schizophrenia. A previous study from our group has found that
a marked heterogeneity of outcome is present also when an
optimal community treatment (constituted by an integrated
therapeutic strategy, including psychotropic drugs, rehabilitation, psychotherapy, adapted to the individual patient’s needs)
is provided [Ruggeri et al., 2004]. This heterogeneity seems to
be part of the natural course of illness and depends on the
intrinsic characteristics of the disorder. Further refinements of
the phenotypes studied in genetic studies should thus take into
account the information that is obtained in longitudinal
studies.
This study examines the genetic, clinical, and functioning
characteristics of a representative 1 year treated prevalence
cohort of patients with schizophrenia assessed at a Community-Based Mental Health Service (CMHS) at baseline and
then at 3 and 6 years. The study tests three hypotheses. The
first hypothesis is that polymorphisms of DTNBP1 reported in
association with schizophrenia in previous case-control studies
will be significantly associated with schizophrenia also in our
sample. The second hypothesis is that worse clinical and
functioning condition observed in patients will be crosssectionally associated with the presence of dysbindin. The
third hypothesis is that patients carrying these polymorphisms
and the high-risk haplotypes will have a more unfavorable
longitudinal clinical outcome.
MATERIALS AND METHODS
Study Design
First, we performed a case-control study to investigate the
association between DTNBP1 and schizophrenia, with cases
belonging to the EPSILON (European Psychiatric Services:
Inputs Linked to Outcome Domains and Needs) study, a
comparative cross-national and cross-sectional study of the
characteristics, needs, quality of life, pattern of care, associated costs, and satisfaction levels of people with schizophrenia in five European countries [Becker et al., 1999]. The sample
investigated consists of the 1 year treated prevalence cohort of
subjects with a diagnosis of schizophrenia who where in
contact with the South Verona CMHS in 1997. Second, we
examined whether there was an association between polymorphisms and haplotypes of DTNBP1 and the clinical and
functioning characteristics in this cohort of patients, by both
considering each cross-sectional assessment individually and
all three assessments in longitudinal sequence to prospectively
characterize the illness course.
Subjects
An administrative prevalence sample of people with a
diagnosis of psychotic disorders attending the South Verona
CMHS (ICD-10, F20-F25) was initially identified from the
South Verona Psychiatric Case Register. Cases identified were
then diagnosed using the Item Group Checklist (IGC) of the
Schedule for Clinical Assessment in Neuropsychiatry (SCAN)
[World Health Organization, 1994]. Only patients with an
ICD-10 research diagnosis of schizophrenia were finally
included as cases. These cases were assessed at the study
baseline and then traced after 3 and 6 years. All patients
assessed in the 6 year follow-up were asked to give a blood
sample for DNA extraction.
Controls, selected from a population similar to the patients
in ethnicity, were recruited from repeat blood donors via the
Blood Transfusion Service from the same area of Verona. The
policy of the Blood Transfusion Centre is not to collect blood
from individuals who are on medication. The absence of
personal and family history of psychotic disorders has been
ascertained, respectively, by using the SCID-NP and the
Family Interview for Genetics Study [FIGS; Maxwell, 1992].
Place of birth of both parents and grandparents was assessed
with the aim to match controls by ethnicity.
Clinical Assessments
Patients were assessed at baseline and then at follow-ups
with the official, standardized Italian versions of the Brief
Psychiatric Rating Scale, expanded version [BPRS; Ventura
et al., 1993] and the Global Assessment of Functioning Scale
[GAF; American Psychiatric Association, 1994]. The BPRS
expanded version consists of 24 items rated on a seven-point
Likert scale (1 ¼ no symptom; 7 ¼ extremely severe symptom).
As shown in a previous factor analysis [Ruggeri et al., 2005],
the items cover four dimensions: anxiety/depression, positive
psychotic symptoms, negative symptoms, and mania. GAF is a
measure of individual functioning that includes the impact of
symptoms and disability on a continuous scale from 0, which
denotes extremely severe dysfunction, to 100, which denotes
extremely good function.
To establish any family history of psychiatric problems, the
Italian version of the FIGS was completed. The FIGS is a
structured clinical interview designed to draw the family’s
pedigree and to collect information about the presence of a
mental disorder in relatives of probands. Controls who had a
positive family history of psychotic disorders or psychotic
depression were excluded.
The study was approved by the Ethical Committee of the
Azienda Ospedaliera di Verona (Italy). All participants
provided written informed consent after receiving a description of the study.
Genotyping
Venous blood samples (15 ml) were collected in EDTAcontaining tubes. DNA was extracted from blood leukocytes.
Subsequently, a total of 10 DTNBP1 SNPs were analyzed
(P1583, P1578, P1763, P1320, P1757, P1765, P1325, P1635,
P1655, and P1287) as described in the study of Straub et al.
[2002]. An 11th SNP, rs2619538, described by Williams et al.
[2004], was also genotyped. All genotyping was performed
blind to status by K-Biosciences (Cambridge, UK; http://
www.kbioscience.co.uk/) using a competitive allele-specific
PCR system (CASP). Quality control criteria were that
genotypes form three distinct clusters: water controls were
negative, number of genotypes callable was >90%, minor allele
frequency was greater than 2%. In addition, interplate and
intraplate duplicate testing of known DNAs was performed.
There were no discrepancies in allele calling for duplicate
samples, nor was amplification of negative controls found. All
genotyping was performed sequentially by the same method.
Statistical Analyses
Genetic data. Tests of allelic association were performed
using Chi-square (P < 0.05). Haplotype analyses were performed using the support program RUNGC implemented
in GENECOUNTING software (http://www.smd.qmul.ac.uk/
statgen/dcurtis/software.html). The program allows the following analyses: comparisons of haplotype frequencies in cases
and controls, tests for significant differences using likelihood
ratio tests and permutation tests with 1,000 simulations, tests
of the frequencies of individual haplotypes from each group
side by side so that they could be easily compared and
identification of the haplotype pertaining to each subject
[Curtis et al., 2006].
Association Study of Dysbindin With Clinical Outcome in Schizophrenia
Genetic and cross-sectional clinical data. To examine if there was an association between the mean scores of
psychopathology and functioning and markers significant
in the case-control study (categorized using the number of
alleles), a series of linear regression models were constructed
by considering, in turn, as dependent variables: the mean
scores of the positive and negative symptoms BPRS sub-scales,
the two sub-scales’ individual items, and GAF, at baseline,
3 and 6 year follow-up, respectively. For each multi-marker
haplotype, statistically significant in the case-control study,
comparisons between mean BPRS negative and positive
dimension sub-scales, individual items, and functioning scores
in the groups with and without the high-risk haplotype, were
performed for baseline, first, and second follow-up assessments
(t-test, P < 0.05).
Genetic and longitudinal clinical data. To obtain
groups of patients with homogeneous longitudinal patterns of
psychopathology, subjects’ scores in each BPRS item of the
positive and negative symptoms’ sub-scale were dichotomized
into ‘‘low severity in all three assessments’’ (baseline, 3 and
6 year follow-up with individual item score <3 in all three
occasions) versus ‘‘higher illness severity in at least one of the
three assessment occasions.’’ Subjects’ scores in GAF were also
dichotomized into ‘‘high functioning in all three assessment
occasions (score 70)’’ versus ‘‘lower functioning in at least one
of the three assessment occasions.’’ The possible association of
longitudinal psychopathology and functioning with genetic
markers and haplotypes significant in the case-control study
was examined. A series of logistic models were estimated with,
in turn, each dichotomized score of the BPRS items and GAF as
dependent variable and, as the independent variables, genetic
markers, categorized using the number of alleles. The same
strategy was repeated for each multi-marker haplotype by
means of a test on the equality of proportions in two
independent samples (Stata 8.0 ‘prtest’ command). Statistical
analyses were performed by Stata 8.0 for Windows [StataCorp., 2003].
RESULTS
Sample
At baseline, 141 subjects with an ICD-10 SCAN-confirmed
F20 diagnosis were identified. Of these, 8 had such a severe
illness that they were not able to participate in the assessment,
so the eligible patients were 133. Twenty-five refused to be
interviewed, and one was not traceable. One hundred seven-
649
teen subjects completed all baseline assessment scales and
constitute the baseline cohort. At 3 year follow-up, 5 persons
out of 141 had died, 3 were not traceable, 1 had moved from
Verona, and 12 refused to be interviewed; 120 subjects
completed all 3 year follow-up assessment scales. At the 6 year
follow-up, 6 persons out of 141 had died, 1 could not be
interviewed due to severe psychopathology, 3 had moved from
Verona, 5 were not traceable, and 11 refused to be interviewed;
115 subjects completed all 6 year follow-up assessment scales.
All these subjects were asked to give a blood sample for genetic
analyses; 80 subjects gave their consent. Of these, 66 had been
evaluated in all three assessment occasions. For the remaining
14, one assessment had not been completed; this missing value
was imputed by calculating the mean of the two valid
assessments. On average, the 3 year follow-up assessment
was performed at 36.1 months (SD 5.1, median 36.9, range
31.9–43.9) after the baseline assessment; the 6 year follow-up
was performed at 75.1 months (SD 3.4, median 75.1, range
67.8–81.5) after the baseline assessment.
The subjects who gave their consent to genetic analysis
(n ¼ 80) differed from those interviewed at the 6-year follow-up
who refused to gave their DNAs (n ¼ 35) in that they had a
lower BPRS total score (1.75 vs. 2.19, P < 0.05, t-test), in
particular on the negative (1.59 vs. 2.14, P < 0.05, t-test) and
mania dimensions (1.39 vs. 1.86, P < 0.05, t-test), and a higher
number of day-care contacts (20.51 vs. 3.57, P < 0.05, t-test).
The 80 subjects were 51% male, with a mean age of 42 years;
43.7% had a diagnosis of paranoid, 10.0% of hebephrenic, and
46.3% of undifferentiated schizophrenia. The mean number of
years of illness was 10.35 (SD 6.93). One hundred six blood
donors satisfying the inclusion criteria were randomly selected
among those attending the Blood Transfusion Service. Fiftythree percent of the controls were male, with a mean age of 38
years. All subjects were Italian and had Italian parents and
grandparents.
Genetic Data
Case-control study
Hardy–Weinberg equilibrium. The presence of Hardy–
Weinberg equilibrium for the genotype distributions was
examined (Chi-square test, P < 0.05). There was no evidence
of deviance from Hardy–Weinberger equilibrium for any SNPs
(Appendix I).
Individual SNPs. Table I compares allele frequencies in
the cases and controls. No significant differences were found
between cases and controls for any of the 10 DTNBP1 markers
TABLE I. Case-Control Study (Allele Frequencies for all the SNPs)
Frequencyb
DTNBP1
markers
Marker 1
Marker 2
Marker 3
Marker 4
Marker 5
Marker 6
Marker 7
Marker 8
Marker 9
Marker 10
Marker 11
a
SNP
NCBI numbera
Polymorphism
Common allele
Cases
(n ¼ 80)
Controls
(n ¼ 106)
P-value*
SNP ‘‘A’’
P1583
P1578
P1763
P1320
P1757
P1765
P1325
P1635
P1655
P1287
rs2619538
rs909706
rs1018381
rs2619522
rs760761
rs2005979
rs2619528
rs10111313
rs3213207
rs2619539
rs760666
A/T
G/A
C/T
T/G
C/T
G/A
G/A
G/A
A/G
G/C
C/T
A
G
C
T
T
G
G
G
A
G
C
0.62
0.67
0.89
0.79
0.52
0.79
0.79
0.91
0.89
0.58
0.78
0.52
0.72
0.92
0.83
0.53
0.84
0.90
0.93
0.90
0.63
0.82
0.058
0.238
0.342
0.317
0.781
0.250
0.403
0.460
0.750
0.340
0.386
Reference identification number for each SNP, from the dbSNP database.
Frequency of the common allele.
*Chi-square test, P < 0.05.
b
650
Tosato et al.
(Chi-square test, P < 0.05). A trend towards statistical
significance (P ¼ 0.058) for rs2619538 was found, with the
more frequent allele ‘A’ overrepresented in the cases, in the
same direction as the original study by Williams et al. [2004].
Haplotype analysis. The two-marker haplotype analysis
(Table II) with GENECOUNTING software and 1,000 permutations showed that rs2619538-P1583 (P ¼ 0.048) and P1320P1757 (P ¼ 0.034) occurred more often in cases compared to
controls than expected by chance. The three-marker analysis
(Table II) showed that rs2619538-P1583-P1578 (P ¼ 0.040)
also occurred more frequently in the cases (Appendices II
and III).
Genetic and cross-sectional clinical data. To examine if there was a cross-sectional association between psychopathology and functioning and genetic markers, a series of
linear regression models were constructed with genetic
variables as independent variable. As dependent variables,
the positive and negative symptom BPRS sub-scale scores, the
sub-scales’ individual items, and GAF score were used, taking
into account in turn their baseline and the 3 and 6 year followup values, respectively.
SNPs and clinical/social characteristics. The marker
rs2619538, the only polymorphism that showed any indication
towards statistical significance, was categorized using the
number of alleles (number of T ¼ 2, 1, 0) and put as an
independent variable in the linear regression model. Patients
carrying the allele A had been found to have higher level of
psychopathology in some BPRS items. Specifically, in the
3 year follow-up data, the item ‘disorientation,’ pertaining to
the negative dimension, was weakly associated to rs2619538
(P ¼ 0.05). When considering the 6 year follow-up scores,
among the items pertaining to the negative dimension, there
was a weak association between ‘‘motor retardation’’ and
rs2619538 (P ¼ 0.05); regarding the positive dimension, only
the item ‘‘hallucinations’’ was found to be associated with
rs2619538 (P < 0.01). No significant association was found
with baseline scores (Appendix IV).
Haplotypes and clinical/social characteristics. For each
multi-marker haplotype which was significant in genetic
TABLE II. Case-Control Study (Analysis of Two- and
Three-Marker Haplotypes Which Resulted Significant at P < 0.05
(GENECOUNTING Software)*,**)
Individual haplotype test
SNPA-P1583
P1320-P1757
SNPA-P1583-P1578
Alleles
(case/control
frequency)
LRT
mean
Global
P-value
A-G 0.48/0.46
A-A 0.14/0.06
T-G 0.19/0.26
T-A 0.19/0.22
C-G 0.35/0.44
C-A 0.13/0.03
T-G 0.44/0.40
T-A 0.08/0.13
A-G-C 0.39/0.41
A-G-T 0.09/0.05
A-A-C 0.13/0.06
A-A-T 0.01/0.00
T-G-C 0.18/0.24
T-G-T 0.00/0.03
T-A-C 0.19/0.22
T-A-T 0.00/0.00
0.06
4.69
1.73
0.21
1.26
9.76
0.21
1.78
0.04
1.55
3.38
3.20
0.88
4.73
0.23
0.03
0.048
0.034
0.040
*P-values are corrected by permutation tests (1,000 simulations).
**The results of the complete analyses are reported in Appendices 2 and 3 of
the online supplement.
analyses, the clinical characteristics of the groups with and
without the high-risk haplotype were compared. No significant
difference in mean scores at the 6 year follow-up was found
between the two groups (t-test, P < 0.05; Appendices V–VII).
However, a trend in the high-risk haplotype group was found
for higher 6 year follow-up scores in negative and positive
BPRS sub-scales and a lower GAF, thus suggesting a more
marked deterioration in psychopathology and functioning.
Genetic and longitudinal clinical data. A series of
logistic models were estimated with, in turn, positive and
negative BPRS sub-scale scores, individual items and GAF,
dichotomized into ‘low severity in all three assessments
(baseline, 3 and 6 year follow-up)’ versus ‘higher illness
severity in at least one of the three assessments’ as a dependent
variable and rs2619538, categorized using the number of
alleles, as the independent variable. No significant association
was found (data available from the authors). The same
regression strategy was repeated using the multi-marker
haplotypes as dependent variables. As shown in Table III
concerning rs2619538-P1583, subjects with lower levels of
‘‘conceptual disorganization’’ (44.7% vs. 71.4%, test for equality
of proportions, P < 0.01) and ‘‘emotional withdrawal’’ (50.0%
vs. 71.4%, test for equality of proportions, P < 0.05) over time
were significantly underrepresented in the group with the
high-risk haplotype.
DISCUSSION
To our knowledge, this is the first longitudinal study testing
the relationship between clinical features and functioning in
schizophrenia and the DTNBP1 gene, both at the crosssectional and longitudinal level. Moreover, this is the first
study investigating the relationship between genetic patterns
and clinical and social characteristics of schizophrenia in a
prevalence cohort of patients in charge to a CMHS and
including a prospective multi-wave assessment of the course
of illness. The principal limitations of the study are the sample
size and the number of variables analyzed tested. Although
inclusive of all prevalence cases that agreed to give their blood,
sample size is relatively small and therefore this reduces the
power of genetic analyses. Furthermore, we performed a
substantial number of tests, which means that any Bonferroni
correction for multiple testing would be large, and any
significant P values should be regarded as nominal. Consequently, our analyses should be considered as exploratory and
the results need to be replicated in larger samples.
Regarding the first hypothesis, we attempted to replicate the
previous findings showing an association between DTNBP1
and schizophrenia. We found some evidence for an association
between schizophrenia and the marker rs2619538, in the
putative promoter region of the gene, in agreement with
findings from a previous study of this SNP [Williams et al.,
2004]. Furthermore, the analysis of the multi-marker haplotypes showed that some haplotypes in DTNBP1 were nominally associated with schizophrenia. In particular, the results
indicate that the regions around rs2619538 and SNP P1320
may be responsible for the DTNBP1 conferring risk of
schizophrenia in the Italian population. For the two-marker
haplotype P1320-P1757, the association is similar to that found
in a Scottish sample [Li et al., 2005]. Moreover, in the present
study, two novel at-risk haplotypes have been identified:
rs2619538-P1583 and rs2619538-P1583-P1578 haplotypes,
both located in the promoter region of the gene. These latter
findings, although not previously detected, could suggest a
population-specific susceptibility allele in Italian population.
Overall the present study suggests a possible role for dysbindin
as a susceptibility gene for schizophrenia.
The second hypothesis explored if worse clinical and
functioning condition is associated with the presence of
Association Study of Dysbindin With Clinical Outcome in Schizophrenia
TABLE III. Percentage of Patients With Low Levels of BPRS and High Levels of GAF Scores
Overtime in the Groups With and Without High-Risk Haplotypes
% Patients with ‘low’ psychopathology at BL,
3 and 6 year FU
SNPA-P1583 haplotype
Schedule
BPRS
Positive symptoms
Grandiosity
Suspiciousness
Hallucinations
Unusual thought content
Conceptual disorganization
Negative symptoms
Blunted affect
Emotional withdrawal
Motor retardation
Uncooperativeness
Disorientation
Self-neglect
Mannerisms and posturing
GAF
n
With the high-risk
haplotype (n ¼ 38)
Without the high-risk
haplotype (n ¼ 42)
53
32
39
29
47
60.5
36.8
47.4
34.2
44.7**
71.4
42.9
50.0
38.1
71.4**
39
49
50
63
60
51
56
64
39.5
50.0*
57.9
71.1
65.8
57.9
63.2
73.7
57.1
71.4*
66.7
85.7
83.3
69.0
76.2
85.7
P1320-P1757 haplotype
BPRS
Positive symptoms
Grandiosity
Suspiciousness
Hallucinations
Unusual thought content
Conceptual disorganization
Negative symptoms
Blunted affect
Emotional withdrawal
Motor retardation
Uncooperativeness
Disorientation
Self-neglect
Mannerisms and posturing
GAF
With the high-risk
haplotype (n ¼ 24)
Without the high-risk
haplotype (n ¼ 56)
53
32
39
29
47
75.0
45.8
54.2
29.2
70.8
62.5
37.5
46.4
39.3
53.6
39
49
50
63
60
51
56
64
54.2
70.8
58.3
87.5
83.3
62.5
83.3
75.0
46.4
57.1
64.3
75.0
71.4
64.3
64.3
82.1
SNPA-P1583-P1578 haplotype
BPRS
Positive symptoms
Grandiosity
Suspiciousness
Hallucinations
Unusual thought content
Conceptual disorganization
Negative symptoms
Blunted affect
Emotional withdrawal
Motor retardation
Uncooperativeness
Disorientation
Self-neglect
Mannerisms and posturing
GAF
With the high-risk
haplotype (n ¼ 29)
Without the high-risk
haplotype (n ¼ 48)
53
32
39
29
47
58.1
38.7
48.4
38.7
48.4
71.4
40.8
49.0
34.7
65.3
39
49
50
63
60
51
56
64
45.2
58.1
64.5
71.0
67.7
64.5
64.5
80.6
51.0
63.3
61.2
83.7
79.6
63.3
73.5
79.6
*P < 0.05 test for equality of proportions in two independent samples.
**P < 0.01 test for equality of proportions in two independent samples.
651
652
Tosato et al.
dysbindin variants. In this study an association between
rs2619538 and the items ‘‘motor retardation’’ and ‘‘hallucinations,’’ relevant to the negative and positive dimensions of
BPRS, is found. Data from the Irish Study of High-Density
Schizophrenia Families have shown that schizophrenic
patients with prevailing negative symptoms are more likely
to inherit the dysbindin risk haplotype [Fanous et al., 2005].
This association was confirmed subsequently [DeRosse et al.,
2006]. As our sample shows an association between the
dysbindin gene haplotypes and one of the symptoms of the
negative domain—motor retardation—whose presence more
than the others greatly contributes in increasing the degree of
severity of the patient’s clinical condition, the data may
suggest that the patients with the high-risk haplotypes may
have a greater likelihood of a severe course of the disease.
The third hypothesis explored the relationship between
genetic variants and the clinical course of schizophrenia
overtime. This showed that the rs2619538-P1583 haplotype
was more likely to be transmitted to subjects with high scores
persistent overtime in the items ‘‘conceptual disorganization’’
and ‘‘emotional withdrawal.’’ This result suggests that dysbindin could also be responsible for specific clinical features of the
disease in the negative symptom domain. It should be noted
that, in this prevalence cohort of patients, in treatment for
more than 10 years, we expected the majority of subjects to
have low levels of psychopathology over time, and this
expectation proved correct. In a setting where integrated
community treatment is provided according to high-quality
standards and the individual patient’s needs [Bonizzato et al.,
2000], those who were not in such a condition can be considered
‘‘treatment-resistant’’ subjects, and interestingly, we found
that a larger proportion of them had the high-risk haplotype.
The results of the present study are compatible with the view
that DTNBP1 is a susceptibility gene for schizophrenia in the
Italian population, and that it may be associated with a worse
course of illness. However, these results need further replication due to the small sample size of the present study.
ACKNOWLEDGMENTS
We are grateful to the patients who participated in the study.
We are indebted to the colleagues who contributed to the
assessments and specifically thank Lorenza Lazzarotto,
Simona Bonfanti, Chiara Benedetti, Gianandrea Perego,
Giovanni Salvi, Francesca Malchiodi, Alberto Parabiaghi,
and Benedetta Stefani. We thank the blood donors of the
Azienda Ospedaliero-Universitaria of Verona for giving their
blood samples for research purposes and Dr. Marzia De
Gironcoli and the staff of the Blood Service Transfusion,
Ospedale Maggiore and Ospedale Policlinico of the Azienda
Ospedaliero-universitaria di Verona for their kind collaboration. The project has been supported by the grant of Fondazione
Lugli to Prof. Michele Tansella. This study was funded by the
Ministry of Health, Ricerca Sanitaria Finalizzata 2004 and
2005, with Grants to Prof. M. Ruggeri.
APPENDIX
APPENDIX I. Case-Control Study (Genotype Frequencies for all the SNPs Tested)
DTNBP1
markers
SNP
NCBI numbera
Genotype
Cases: genotype number
and frequency
Controls: genotype
number and frequency
Marker 1
SNP ‘‘A’’
rs2619538
Marker 2
P1583
rs909706
Marker 3
P1578
rs1018381
Marker 4
P1763
rs2619522
Marker 5
P1320
rs760761
Marker 6
P1757
rs2005979
Marker 7
P1765
rs2619528
Marker 8
P1325
rs10111313
Marker 9
P1635
rs3213207
Marker 10
P1655
rs2619539
Marker 11
P1287
rs760666
A:A
A:T
T:T
G:G
G:A
A:A
C:C
C:T
T:T
G:G
G:T
T:T
C:C
C:T
T:T
G:G
G:A
A:A
G:G
G:A
A:A
G:C
G:A
A:A
G:G
G:A
A:A
G:G
G:C
C:C
C:C
C:T
T:T
27 (36.5)
38 (51.3)
9 (12.2)
32 (41.0)
40 (51.3)
6 (7.7)
63 (81.8)
12 (15.6)
2 (2.6)
3 (4.0)
26 (34.7)
46 (61.3)
17 (21.5)
42 (53.2)
20 (25.3)
49 (62.0)
27 (34.2)
3 (3.8)
48 (62.3)
26 (33.8)
3 (3.9)
65 (83.3)
13 (16.7)
0 (0.0)
1 (1.2)
15 (18.8)
64 (80.0)
24 (34.8)
32 (46.4)
13 (18.8)
51 (66.2)
19 (24.7)
7 (9.1)
26 (25.7)
53 (52.5)
22 (21.8)
55 (52.8)
42 (40.0)
8 (7.2)
91 (85.9)
14 (13.2)
1 (0.9)
3 (2.8)
30 (28.6)
72 (68.6)
23 (22.1)
51 (49.0)
30 (28.9)
71 (69.6)
29 (28.4)
2 (2.0)
71 (68.3)
30 (28.8)
3 (2.9)
91 (88.3)
11 (10.7)
1 (1.0)
1 (1.0)
18 (17.5)
85 (81.5)
40 (40.4)
45 (45.4)
14 (14.2)
72 (69.2)
27 (26.1)
5 (4.8)
a
Reference identification number for each SNP, from the dbSNP database.
*Fisher’s exact test, P < 0.05.
P-value*
0.149
0.297
0.592
0.622
0.835
0.459
0.680
0.320
0.925
0.631
0.570
Association Study of Dysbindin With Clinical Outcome in Schizophrenia
APPENDIX II. Case-Control Study (Two-Marker-Haplotype Analysis (GENECOUNTING
Software))
Individual haplotype test
SNPA-P1583
P1583-P1578
P1578-P1763
P1763-P1320
P1320-P1757
P1757-P1765
P1765-P1325
P1325-P1635
P1635-P1655
P1655-P1287
Alleles (case/control frequency)
LRT mean
Global P-value*
A-G 0.48/0.46
A-A 0.14/0.06
T-G 0.19/0.26
T-A 0.19/0.22
G-C 0.58/0.65
G-T 0.09/0.07
A-C 0.32/0.28
A-T 0.02/0.00
C-T 0.79/0.83
C-G 0.10/0.09
T-T 0.00/0.00
T-G 0.10/0.07
T-C 0.35/0.42
T-T 0.44/0.40
G-C 0.13/0.04
G-T 0.08/0.13
C-G 0.35/0.44
C-A 0.13/0.03
T-G 0.44/0.40
T-A 0.08/0.13
G-G 0.79/0.83
G-A 0.00/0.00
A-A 0.20/0.17
G-G 0.74/0.76
G-A 0.05/0.06
A-G 0.17/0.17
A-A 0.03/0.00
G-A 0.82/0.84
G-G 0.10/0.10
A-A 0.07/0.06
A-G 0.00/0.00
A-C 0.32/0.27
A-G 0.57/0.63
G-C 0.10/0.09
G-G 0.00/0.00
C-C 0.42/0.37
C-T 0.00/0.00
G-C 0.36/0.45
G-T 0.21/0.18
0.06
4.69
1.73
0.21
0.53
0.14
0.37
3.31
0.12
0.11
0.00
0.51
0.90
0.14
6.32
1.31
1.26
9.76
0.21
1.78
0.12
0.00
0.50
0.04
0.27
0.00
5.38
0.04
0.00
0.13
1.79
0.54
0.40
0.08
0.01
0.46
0.00
1.28
0.44
0.048
0.247
0.632
0.112
0.034
0.401
0.335
0.671
0.563
0.349
P-values are corrected by permutation tests (1,000 simulations).
*Significance at P < 0.05.
APPENDIX III. Case-Control Study (Three-Marker-Haplotype Analysis
(GENECOUNTING Software))
Individual haplotype test
SNPA-P1583-P1578
Alleles (case/control frequency)
LRT mean
Global P-value*
A-G-C 0.39/0.41
A-G-T 0.09/0.05
A-A-C 0.13/0.06
A-A-T 0.01/0.00
T-G-C 0.18/0.24
T-G-T 0.00/0.03
T-A-C 0.19/0.22
T-A-T 0.00/0.00
0.04
1.55
3.38
3.20
0.88
4.73
0.23
0.03
0.040
(Continued )
653
654
Tosato et al.
APPENDIX III. (Continued )
Individual haplotype test
P1583-P1578-P1763
P1578-P1763-P1320
P1763-P1320-P1757
P1320-P1757-P1765
P1757-P1765-P1325
P1765-P1325-P1635
P1325-P1635-P1655
P1635-P1655-P1287
Alleles (case/control frequency)
LRT mean
Global P-value*
G-C-T 0.46/0.55
G-C-G 0.10/0.09
G-T-G 0.10/0.07
A-C-T 0.33/0.28
A-C-G 0.00/0.00
A-T-G 0.00/0.00
C-T-C 0.35/0.42
C-T-T 0.44/0.40
C-G-C 0.04/0.07
C-G-T 0.06/0.07
T-T-C 0.00/0.00
T-G-C 0.08/0.02
T-G-T 0.02/0.06
T-C-G 0.35/0.42
T-T-G 0.44/0.40
G-C-G 0.00/0.00
G-C-A 0.13/0.04
G-T-A 0.08/0.13
C-G-G 0.35/0.42
C-G-A 0.00/0.00
C-A-A 0.13/0.04
T-G-G 0.44/0.40
T-A-A 0.08/0.13
G-G-G 0.74/0.77
G-G-A 0.05/0.06
A-A-G 0.17/0.17
A-A-A 0.03/0.00
G-G-A 0.74/0.77
G-G-G 0.00/0.00
G-A-A 0.05/0.06
A-G-A 0.08/0.07
A-G-G 0.09/0.09
A-A-A 0.02/0.00
A-A-G 0.01/0.00
G-A-C 0.23/0.21
G-A-G 0.58/0.63
G-G-C 0.10/0.09
G-G-G 0.00/0.00
A-A-C 0.08/0.06
A-A-G 0.00/0.00
A-G-C 0.00/0.00
A-G-G 0.00/0.00
A-C-C 0.32/0.27
A-C-T 0.00/0.00
A-G-C 0.36/0.45
A-G-T 0.21/0.18
G-C-C 0.10/0.09
G-C-T 0.00/0.00
G-G-C 0.00/0.00
G-G-T 0.00/0.00
1.16
0.10
0.44
0.71
0.01
0.34
0.83
0.16
0.73
0.04
0.00
6.58
2.73
0.94
0.22
0.00
6.82
1.83
0.94
0.00
6.82
0.22
1.83
0.07
0.11
0.02
4.43
0.08
0.00
0.17
0.08
0.00
2.18
2.50
0.13
0.34
0.18
0.00
0.53
0.00
0.80
0.00
0.55
0.01
1.53
0.44
0.08
0.00
0.00
0.00
0.425
P-values are corrected by permutation tests (1,000 simulations).
*Significance at P < 0.05.
0.185
0.105
0.097
0.420
0.653
0.876
0.438
56.03 (18.02)
1.56 (1.08)
1.38 (0.75)
1.59 (1.08)
1.13 (0.55)
1.19 (0.60)
1.22 (0.55)
1.16 (0.63)
1.31 (0.49)
2.17 (1.94)
1.83 (1.60)
1.83 (1.33)
1.17 (0.41)
1.00 (0.00)
1.50 (0.84)
1.50 (0.84)
1.57 (0.77)
54.14 (10.65)
1.06 (0.36)
1.72 (1.30)
1.80 (1.45)
1.91 (1.60)
1.53 (1.32)
1.68 (1.11)
2.57 (2.15)
1.43 (0.79)
1.71 (1.11)
3.83 (1.72)
2.00 (1.26)
2.25 (0.90)
Total
1.44 (0.50)
1.66 (0.43)
Total
Positive symptoms
Grandiosity
Suspiciousness
Hallucinations
Unusual thought content
Conceptual disorganization
Total
Negative symptoms
Blunted affect
Emotional withdrawal
Motor retardation
Uncooperativeness
Disorientation
Self-neglect
Mannerisms and posturing
Total
Mean (SD)
Mean (SD)
Patients
with A:T
(n ¼ 32)
Schedule
Patients
with T:T
(n ¼ 7)
Baseline
55.09 (15.50)
1.52 (1.04)
1.35 (0.93)
1.48 (1.12)
1.00 (0.00)
1.00 (0.00)
1.23 (0.75)
1.09 (0.48)
1.24 (0.50)
1.35 (1.11)
1.87 (1.42)
2.36 (1.89)
2.09 (1.70)
1.26 (0.91)
1.78 (1.06)
1.51 (0.57)
Mean (SD)
Patients
with A:A
(n ¼ 23)
2.22 (1.72)
1.89 (1.54)
1.78 (1.40)
1.78 (1.72)
1.78 (1.10)
1.56 (1.13)
1.00 (0.00)
1.71 (0.89)
GAF
53.89 (25.98)
53.39 (18.18)
2.72 (1.70)
2.08 (1.50)
1.69 (1.28)
1.19 (0.52)
1.14 (0.59)
1.75 (1.16)
1.14 (0.83)
1.67 (0.75)
1.06 (0.33)
1.71 (1.15)
1.39 (0.96)
2.26 (1.81)
1.83 (1.40)
1.66 (0.71)
1.60 (0.45)
BPRS
1.87 (0.84)
1.67 (2.00)
2.00 (1.41)
2.00 (1.77)
3.33 (2.60)
2.67 (2.06)
2.37 (1.51)
Mean (SD)
Patients
with A:T
(n ¼ 36)
Mean (SD)
Patients
with T:T
(n ¼ 9)
3 year follow-up
50.92 (16.30)
2.08 (1.52)
1.88 (1.37)
1.62 (0.98)
1.27 (1.04)
1.12 (0.59)
1.62 (0.98)
1.00 (0.00)
1.51 (0.63)
1.92 (1.98)
2.08 (1.65)
2.36 (2.20)
2.88 (2.32)
1.65 (1.16)
2.19 (1.41)
1.72 (0.62)
Mean (SD)
Patients
with A:A
(n ¼ 23)
48.33 (19.04)
2.00 (1.12)
1.56 (0.73)
1.22 (0.67)
1.00 (0.00)
1.44 (1.01)
1.44 (0.73)
1.33 (1.00)
1.51 (0.47)
1.78 (1.53)
2.78 (2.11)
1.22 (0.44)
3.56 (2.13)
2.11 (1.96)
2.29 (1.07)
1.74 (0.62)
Mean (SD)
Patients
with T:T
(n ¼ 9)
49.74 (15.66)
2.29 (1.37)
1.89 (1.33)
1.39 (0.95)
1.21 (0.62)
1.68 (1.36)
1.45 (0.92)
1.47 (1.11)
1.70 (0.84)
1.26 (0.98)
2.18 (1.45)
1.74 (1.35)
2.57 (1.64)
1.86 (1.38)
1.91 (0.98)
1.69 (0.61)
Mean (SD)
Patients
with A:T
(n ¼ 38)
6 year follow-up
APPENDIX IV. Comparisons of BPRS/GAF Mean Scores at Baseline and Follow-Ups Regarding the Genotype of SNPA
47.33 (14.96)
2.15 (1.38)
1.67 (1.30)
1.74 (0.81)
1.48 (1.48)
1.22 (0.98)
1.74 (1.06)
1.15 (0.60)
1.69 (0.64)
1.56 (1.34)
2.19 (1.71)
2.81 (2.25)
3.07 (2.35)
1.85 (1.49)
2.30 (1.37)
1.79 (0.66)
Mean (SD)
Patients
with A:A
(n ¼ 27)
*t-test for independent samples, P < 0.05.
56.51 (14.87)
1.83 (1.36)
1.44 (1.03)
1.58 (1.16)
1.08 (0.28)
1.03 (0.17)
1.23 (0.69)
1.08 (0.37)
1.33 (0.55)
1.53 (0.94)
1.40 (0.77)
1.57 (1.01)
1.13 (0.57)
1.70 (1.49)
1.23 (0.59)
1.23 (0.73)
1.33 (0.49)
53.10 (18.51)
1.30 (1.08)
1.86 (1.34)
2.14 (1.55)
2.39 (1.68)
1.31 (0.83)
1.80 (0.86)
1.34 (1.05)
1.80 (1.38)
2.04 (1.80)
2.10 (1.88)
1.70 (1.50)
1.89 (1.31)
Total
1.51 (0.51)
1.50 (0.54)
Total
Positive symptoms
Grandiosity
Suspiciousness
Hallucinations
Unusual thought content
Conceptual disorganization
Total
Negative symptoms
Blunted affect
Emotional withdrawal
Motor retardation
Uncooperativeness
Disorientation
Self-neglect
Mannerisms and posturing
Total
Mean (SD)
Mean (SD)
Patients without
the high-risk
haplotype
(n ¼ 42)
Schedule
Patients with
the high-risk
haplotype
(n ¼ 38)
Baseline
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
P-value*
2.69 (1.84)
2.22 (1.62)
1.81 (1.35)
1.19 (0.52)
1.14 (0.59)
1.92 (1.23)
1.14 (0.84)
1.73 (0.78)
GAF
49.44 (19.24)
54.73 (18.05)
2.22 (1.54)
1.88 (1.43)
1.49 (0.92)
1.49 (1.45)
1.39 (1.16)
1.54 (1.18)
1.15 (0.94)
1.59 (0.95)
1.37 (1.28)
2.07 (1.51)
1.80 (1.67)
2.63 (2.25)
1.83 (1.58)
1.95 (1.14)
1.70 (0.78)
BPRS
1.73 (0.54)
1.50 (1.52)
1.86 (1.42)
1.86 (1.77)
2.86 (2.25)
1.97 (1.45)
2.02 (1.25)
Mean (SD)
Patients without
the high-risk
haplotype
(n ¼ 42)
Mean (SD)
Patients with
the high-risk
haplotype
(n ¼ 38)
3 year follow-up
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
P-value*
46.50 (15.58)
2.42 (1.39)
1.95 (1.45)
1.55 (1.03)
1.37 (1.12)
1.71 (1.35)
1.68 (1.10)
1.45 (1.08)
2.26 (1.24)
1.37 (1.17)
2.53 (1.72)
2.16 (1.65)
3.22 (2.251.99)
2.11 (1.45)
2.26 (1.24)
1.86 (0.70)
Mean (SD)
Patients with the
high-risk haplotype (n ¼ 38)
50.45 (16.48)
1.90 (1.204)
1.67 (1.16)
1.40 (0.66)
1.19 (0.80)
1.36 (1.26)
1.48 (0.92)
1.26 (0.83)
1.99 (1.13)
1.43 (1.17)
2.07 (1.57)
1.95 (1.86)
2.67 (2.06)
1.86 (1.82)
1.99 (1.13)
1.65 (0.57)
Mean (SD)
Patients without
the high-risk
haplotype
(n ¼ 42)
6 year follow-up
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
P-value*
APPENDIX V. Comparisons of BPRS/GAF Mean Scores at Baseline and Follow-Ups in the Groups With and Without the Two-Marker Haplotype SNPA-P1583
*t-test for independent samples, P < 0.05.
55.50 (16.71)
1.78 (1.30)
1.47 (1.01)
1.60 (1.21)
1.13 (0.50)
1.16 (0.52)
1.25 (0.65)
1.18 (0.61)
1.36 (0.58)
1.52 (0.93)
1.33 (0.66)
1.52 (0.75)
1.05 (0.22)
1.00 (0.00)
1.19 (0.60)
1.10 (0.44)
1.24 (0.35)
53.86 (16.56)
1.33 (1.04)
1.89 (1.29)
1.95 (1.29)
2.36 (1.78)
1.56 (1.27)
1.86 (1.07)
1.29 (1.10)
1.71 (1.49)
1.71 (1.49)
2.05 (1.77)
1.33 (0.97)
1.75 (1.11)
Total
1.55 (0.57)
1.43 (0.39)
Total
Positive symptoms
Grandiosity
Suspiciousness
Hallucinations
Unusual thought content
Conceptual disorganization
Total
Negative symptoms
Blunted affect
Emotional withdrawal
Motor retardation
Uncooperativeness
Disorientation
Self-neglect
Mannerisms and posturing
Total
Mean (SD)
Mean (SD)
Patients without
the high-risk
haplotype
(n ¼ 56)
Schedule
Patients with
the high-risk
haplotype
(n ¼ 24)
Baseline
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
P-value*
2.70 (2.18)
2.00 (1.81)
1.74 (1.42)
1.35 (1.30)
1.26 (1.25)
1.96 (1.58)
1.26 (1.25)
1.75 (1.22)
GAF
50.22 (18.35)
1.70 (1.84)
1.87 (1.46)
2.09 (2.00)
3.48 (2.54)
1.78 (1.51)
2.18 (1.34)
BPRS
1.76 (0.88)
Mean (SD)
Patients with
the high-risk
haplotype
(n ¼ 24)
53.13 (18.92)
2.33 (1.44)
2.06 (1.41)
1.59 (1.02)
1.35 (1.05)
1.28 (0.79)
1.61 (1.02)
1.09 (0.68)
1.62 (0.69)
1.31 (1.15)
2.02 (1.47)
1.71 (1.56)
2.40 (1.92)
1.94 (1.52)
1.90 (1.11)
1.69 (0.57)
Mean (SD)
Patients without
the high-risk
haplotype
(n ¼ 56)
3 year follow-up
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
P-value*
48.08 (15.47)
2.08 (1.35)
1.50 (1.14)
1.58 (0.83)
1.00 (0.00)
1.42 (1.23)
1.88 (1.20)
1.17 (0.64)
1.64 (0.71)
1.46 (1.32)
2.54 (1.81)
2.08 (1.86)
3.33 (2.16)
1.75 (1.51)
2.23 (1.21)
1.72 (0.70)
Mean (SD)
Patients with
the high-risk
haplotype
(n ¼ 24)
48.79 (16.46)
2.18 (1.31)
1.93 (1.36)
1.43 (0.88)
1.45 (0.90)
1.57 (1.33)
1.45 (0.90)
1.43 (1.06)
1.68 (0.76)
1.38 (1.09)
2.18 (1.57)
2.04 (1.77)
2.75 (1.96)
2.07 (1.71)
2.07 (1.18)
1.76 (0.61)
Mean (SD)
Patients without
the high-risk
haplotype
(n ¼ 56)
6 year follow-up
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
P-value*
APPENDIX VI. Comparisons of BPRS/GAF Mean Scores at Baseline and Follow-Ups in the Groups With and Without the Two-Marker Haplotype P1320-P1757
*t-test for independent samples, P < 0.05.
1.79 (1.32)
1.50 (1.04)
1.62 (1.12)
1.14 (0.52)
1.10 (0.48)
1.32 (0.76)
1.19 (0.63)
1.38 (0.58)
54.72 (15.34)
1.54 (0.93)
1.29 (0.62)
1.50 (1.02)
1.04 (0.20)
1.13 (0.34)
1.08 (0.28)
1.08 (0.41)
1.24 (0.37)
55.46 (18.88)
1.56 (0.57)
1.40 (1.24)
1.79 (1.30)
2.24 (1.71)
2.36 (1.75)
1.48 (1.11)
1.85 (0.99)
1.41 (0.41)
Total
Positive symptoms
Grandiosity
Suspiciousness
Hallucinations
Unusual thought content
Conceptual disorganization
Total
Negative symptoms
Blunted affect
Emotional withdrawal
Motor retardation
Uncooperativeness
Disorientation
Self-neglect
Mannerisms and posturing
Total
Total
Mean (SD)
Patients without
the high-risk
haplotype
(n ¼ 48)
1.17 (0.58)
1.92 (1.44)
1.83 (1.53)
2.08 (1.82)
1.50 (1.32)
1.79 (1.23)
Mean (SD)
Schedule
Patients with
the high-risk
haplotype
(n ¼ 29)
Baseline
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
P-value*
2.55 (1.62)
2.07 (1.41)
1.62 (1.08)
1.21 (0.56)
1.17 (0.66)
1.69 (0.93)
1.00 (0.00)
1.62 (0.60)
53.17 (18.88)
1.24 (0.99)
1.86 (1.46)
1.75 (1.67)
2.45 (1.94)
1.86 (1.38)
1.84 (1.15)
1.65 (0.47)
Mean (SD)
Patients with
the high-risk
haplotype
(n ¼ 29)
2.38 (1.75)
2.02 (1.60)
1.65 (1.19)
1.44 (1.35)
1.33 (1.08)
1.73 (1.36)
1.23 (1.11)
1.68 (1.01)
51.71 (18.74)
1.54 (1.58)
2.04 (1.47)
1.87 (1.74)
2.91 (2.31)
1.92 (1.60)
2.06 (1.21)
1.75 (0.78)
Mean (SD)
Patients without
the high-risk
haplotype
(n ¼ 48)
3 year follow-up
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
P-value*
2.69 (1.83)
2.22 (1.62)
1.81 (1.35)
1.19 (0.53)
1.14 (0.60)
1.92 (1.22)
1.14 (0.83)
1.73 (0.78)
49.44 (19.23)
1.50 (1.52)
1.86 (1.42)
1.86 (1.77)
2.86 (2.25)
1.97 (1.44)
2.02 (1.25)
1.73 (0.54)
Mean (SD)
Patients with
the high-risk
haplotype
(n ¼ 29)
2.55 (1.62)
2.07 (1.41)
1.62 (1.08)
1.21 (0.56)
1.17 (0.66)
1.69 (0.93)
1.00 (0.00)
1.61 (0.60)
53.17 (18.88)
1.24 (0.99)
1.86 (1.46)
1.75 (1.67)
2.45 (1.94)
1.86 (1.38)
1.84 (0.71)
1.65 (0.47)
Mean (SD)
Patients without
the high-risk
haplotype
(n ¼ 48)
6 year follow-up
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
P-value*
APPENDIX VII. Comparisons of BPRS/GAF Mean Scores at Baseline and Follow-Ups in the Groups With and Without the Three-Marker Haplotype SNPA-P1583-P1578
Association Study of Dysbindin With Clinical Outcome in Schizophrenia
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